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The development of immunological relationship between mother and fetus under physiological and pathological conditions.
On the basis of results of our research and review of literature, the complex of immuno logical influences, operating during the development of the human fetus, were evaluated. It is obvious that during the early stages of pregnancy the conceptus is protected by non-specific mechanisms, i.e. hormonally (HCG, progesterone) and by certain properties of the trophoblast (barrier function, immunologically inert surface). Specific immunological tolerance is formed by gradual penetration of trophoblast particles and later by penetration of fetal blood cells into maternal circulation. Thus a specific suppression of maternal T lymphocytes against fetal antigens develops, other immunological functions being intact. - Following a strong antigenic stimulus (e.g. Rh-D), isoimmunization of the mother and serious risk for the fetus occur. Immunological causes of abortion could not be unequivocally proved in recurrent abortions. The explanation of the origin of EPH-gestosis on the basis of toxic action of immunocomplexes is highly probable, however the laboratory and experimental proof is still lacking. | {
"pile_set_name": "PubMed Abstracts"
} |
89 N.J. 595 (1982)
446 A.2d 871
E.E.B. AND J.E.B., HIS WIFE, PLAINTIFFS-RESPONDENTS,
v.
D.A. A/K/A D.M. AND J.M. AND CHILDREN'S SERVICES DIVISION, HOLMES COUNTY, DEPARTMENT OF PUBLIC WELFARE, DEFENDANTS-APPELLANTS.
The Supreme Court of New Jersey.
Argued January 26, 1982.
Decided June 21, 1982.
*598 Edward Emmett O'Farrell, a member of the Ohio Bar, argued the cause for appellants D.A. a/k/a D.M. and J.M. (John D. Atlas, Director, Passaic County Legal Aid Society; Madeline L. Houston, on the brief).
Donald M. Ferraiolo argued the cause for appellant Children's Services Division, Holmes County, Department of Public Welfare (Faro & Ferraiolo, attorneys).
Joseph T. Afflitto argued the cause for respondents (Diamond, Diamond & Afflitto, attorneys).
The opinion of the Court was delivered by POLLOCK, J.
The issue on this appeal is whether the courts of New Jersey have jurisdiction to determine the best interest of a child in an interstate custody dispute. In this case, prospective adoptive parents seek to retain custody of a three and one-half year old girl who has lived with them since six days after her birth. The Chancery Division determined that the best interest of the child was to remain with the adoptive parents. Previously, the natural mother had obtained a writ of habeas corpus from the Holmes County Juvenile Court in Ohio, the state of residence of the mother and adoptive parents at the time of the child's birth. In that proceeding, the Ohio courts determined the natural mother's right to custody and, without conducting a best interest hearing, ordered the return of the child to her.
We must determine whether the decision of the Chancery Division gave proper effect to the Ohio determination in light of the full faith and credit clause, U.S.Const., Art. IV, § 1, the Parental Kidnapping Prevention Act of 1980, § 8, 28 U.S.C.A., § 1738A (PKPA), and the Uniform Child Custody Jurisdiction Act, N.J.S.A. 2A:34-28 to -52 (UCCJA). We conclude that, by *599 declining to determine the best interest of the child, Ohio enabled the New Jersey courts to modify the determination without violating the full faith and credit clause or the federal and state statutes.
I
In the vortex of this interstate child custody dispute is a little girl. She was born in Ohio on October 13, 1978 and has lived in New Jersey since October, 1979. A month before the child's birth, her natural mother consulted with the Ohio Welfare Department concerning relinquishment of the child at birth. On October 16, 1978, three days after the child's birth, the natural mother and father, who were unmarried, signed a sworn "Permanent Surrender of Child" form that surrendered custody of the child to the Holmes County Welfare Department. Three days later the Department delivered the child to the prospective adoptive parents. On October 23, 1978, one week after signing the surrender form, the natural mother appeared at the Department and orally revoked the surrender. Nonetheless, the Department did not inform the Ohio Juvenile Court of the revocation, and that court approved the surrender on the following day.
Two months later, on December 29, 1978, the mother instituted a habeas corpus proceeding to obtain custody of the child. The natural father did not join in the Ohio proceeding, but is joined as a defendant in the present proceeding. In February, 1979, the Ohio Juvenile Court rendered a written opinion finding that the mother had validly consented to the surrender and denying the writ. The Ohio Court of Appeals affirmed that decision in June of 1979. In both courts, the adoptive parents not only opposed the issuance of the writ, but sought a best interest hearing for the child.
On July 23, 1979, the mother filed an appeal to the Supreme Court of Ohio. In October, 1979, while the case was pending before that Court, the adoptive parents and the child moved *600 from Ohio to New Jersey because the father, a clergyman, had been appointed pastor of a church in Wayne, New Jersey. Before leaving Ohio, the adoptive parents notified the Department of their plans and continued to communicate with the Department throughout the proceedings.
On July 23, 1980, the Ohio Supreme Court reversed and remanded the matter to the Juvenile Court. 63 Ohio St.2d 227, 407 N.E.2d 524 (1980). The Supreme Court concluded that the natural mother had revoked her consent before the Juvenile Court approved the surrender of the child to the Department. Id. at 229-31, 407 N.E.2d at 526-27. The adoptive parents filed a motion with the Ohio Supreme Court for a rehearing, asserting that the Court should have remanded the case to the Juvenile Court "to conduct a best interest hearing prior to any decision as to whether the writ of habeas corpus should issue."
While the motion for rehearing was pending, the Juvenile Court held an informal meeting attended by counsel for the natural mother, counsel for the Department and counsel for the adoptive parents. At the meeting, counsel for the adoptive parents stated that if the Ohio Supreme Court denied the motion, he would nonetheless press for a best interest hearing before the Juvenile Court. On September 12, 1980, the Ohio Supreme Court denied the motion for rehearing, and on September 23, 1980 the Juvenile Court issued the writ of habeas corpus.
The adoptive parents instituted this action for custody on September 29, 1980 in the Superior Court of New Jersey, Chancery Division. On December 1, 1980, the Chancery Division found that it had jurisdiction and ordered a best interest hearing. Although the Appellate Division denied the natural mother's motion for leave to appeal, we directed the Appellate Division to review the Chancery Division's finding of jurisdiction. In an unpublished opinion, the Appellate Division sustained the finding of jurisdiction of the New Jersey courts. We denied a motion for leave to appeal.
*601 Simultaneously with the remand to the Appellate Division, we remanded the matter to the Chancery Division for an expedited best interest hearing. 85 N.J. 503 (1981). Underlying our remand to the Chancery Division was the need for a hearing to resolve the competing claims of the natural mother and adoptive parents in the best interest of the child. We remanded out of a profound respect for the ties that normally bind natural parents and child. See Santosky v. Kramer, ___ U.S. ___, 102 S.Ct. 1388, 71 L.Ed.2d 599 (1982) (in an action determining rights of parents in natural child, due process requires proof of "permanent neglect" by clear and convincing evidence). Nonetheless, we also recognized that the psychological bonding between adoptive parents and child may become stronger than natural ties. Sorentino v. Family & Childrens Soc. of Elizabeth, 74 N.J. 313, 322-25 (1977); Sees v. Baber, 74 N.J. 201, 222-23 (1977).
Although duly notified, neither the mother nor her attorney appeared or participated in the best interest hearing in the Chancery Division. After appointing a guardian ad litem for the child, the Chancery Division concluded that her best interest was to remain with the adoptive parents. The guardian ad litem for the child supports that conclusion. On this appeal, the natural mother, who has never seen the child, does not challenge the finding that the best interest of the child is to remain with the adoptive parents, and we accept that finding.
Before us, the natural mother contends that under the full faith and credit clause, PKPA, and UCCJA, the Ohio decree precluded the New Jersey courts from considering the best interest of the child. The adoptive parents do not seek to relitigate the invalidity of the natural mother's surrender of the child. They accept that determination, but contend that because Ohio declined to conduct a best interest hearing, the New Jersey courts may determine the best interest of the child.
To summarize, although all parties resided in Ohio at the time of the commencement of the habeas corpus proceeding, by the time of the final decision of the Ohio courts, only the natural *602 mother remained in Ohio. Long before the commencement of the New Jersey proceedings, the adoptive parents and the child resided in New Jersey. The adoptive parents left Ohio for New Jersey not to evade an Ohio court order, but because of a change in the father's employment. They commenced the New Jersey proceeding only after the Ohio courts declined to order a best interest hearing.
We granted certification to re-examine the jurisdiction of New Jersey courts in interstate custody disputes in light of the significant changes in both federal and state legislation since our decision in Borys v. Borys, 76 N.J. 103 (1978). We now affirm the judgment of the Appellate Division that the New Jersey courts may conduct a best interest hearing.
II
At the outset, our attention centers on the confluence of the full faith and credit clause, PKPA, and UCCJA. We proceed in waters uncharted by the United States Supreme Court, which has declined to determine whether custody decrees are entitled to full faith and credit and has not yet construed PKPA. In analyzing PKPA and UCCJA, we must determine the extent to which they affect our decision in Borys that custody decrees are not entitled to full faith and credit.
In determining whether the New Jersey courts may conduct a best interest hearing, the first question is whether the full faith and credit clause requires our courts to follow the Ohio decision. That clause provides:
Full Faith and Credit shall be given in each State to the public Acts, Records, and Judicial Proceedings of every other State. And the Congress may by general Laws prescribe the Manner in which such Acts, Records and Proceedings shall be proved, and the Effect thereof. [U.S.Const., Art. IV, § 1.] See 28 U.S.C.A. § 1738.
Although interstate custody decrees arise with increasing frequency, the United States Supreme Court has refrained from determining whether custody decrees are entitled to full faith and credit in all circumstances. See Webb v. Webb, 451 U.S. *603 493, 101 S.Ct. 1889, 68 L.Ed.2d 392 (1981) (applicability of full faith and credit to foreign custody decree dismissed on jurisdictional grounds because of failure to preserve federal question in state court); Ford v. Ford, 371 U.S. 187, 83 S.Ct. 273, 9 L.Ed.2d 240 (1962) (custody settlement not res judicata as a matter of state law); Kovacs v. Brewer, 356 U.S. 604, 78 S.Ct. 963, 2 L.Ed.2d 1008 (1958) (forum state should give custody decree same effect as rendering state; because of changed circumstances, forum state need not give full faith and credit to custody decree from rendering state); May v. Anderson, 345 U.S. 528, 73 S.Ct. 840, 97 L.Ed. 1221 (1953) (rendering state did not obtain personal jurisdiction of mother and forum state not obliged to give full faith and credit to ex parte award of custody to father because child custody subject to strong local policies that outweigh demands of full faith and credit).
Confronted with the silence of the United States Supreme Court, litigants in custody disputes were tossed on a sea of uncertainty. In that setting, we concluded that the welfare of children in New Jersey could be protected better by treating foreign custody decrees as an exception to the full faith and credit clause. Borys v. Borys, supra, 76 N.J. at 120. Legislative efforts have taken a different tack. UCCJA sought to protect the welfare of children in interstate custody disputes by introducing certainty and stability in the choice of forum and by encouraging interstate cooperation in the interest of the child. UCCJA § 2; N.J.S.A. 2A:34-29. PKPA addresses the same concerns as UCCJA and determines as a matter of federal law the extraterritorial effect of foreign custody decrees.
To the extent that they limit the discretion of forum states to ignore foreign custody decrees, PKPA and UCCJA modify Borys, supra. As its title suggests, one of the purposes of PKPA was to deter interstate abduction of children by contesting parents in custody disputes. PKPA, however, has a broader reach and applies not only to abductions by parents, but to disputes between all persons who seek custody of a child. See Pub.L.No. 96-611, § 7, 94 Stat. 3568.
*604 For our purposes, the key provision of PKPA is section 8, 28 U.S.C.A. § 1738A.[1] It requires the courts of every state to enforce a child custody determination of a sister-state[2] made consistently with the provisions of the Act.[3] 28 U.S.C.A. § 1738A(a). Thus, the Act seeks to eliminate the incentive for a parent to remove a minor child to another jurisdiction while *605 shopping for a sympathetic forum. See Parental Kidnapping Act: Hearings on H.R. 1290 Before the Subcommittee on Crime of the House Committee on the Judiciary, 96th Cong., 2d Sess. 81 (1980) (Statement of Mark M. Richard, Deputy Assistant Attorney General).
To ascertain whether PKPA applies to this controversy, we turn first to the definition of a "custody determination", which includes "an order of a court providing for the custody" of a child. 28 U.S.C.A. § 1738A(b)(3). The Ohio writ of habeas corpus, which directed the adoptive parents "to present" the child to the mother at the Department, satisfies that definition. Furthermore, that determination was consistent with the PKPA. The child was living in Ohio during the commencement of the Ohio proceedings and the courts had jurisdiction under Ohio law. Therefore, the critical question is whether New Jersey courts have violated the Act by not enforcing the Ohio writ.[4]
In child custody determinations Ohio, like New Jersey, emphasizes the best interest of the child. See In re Cunningham, 59 Ohio St.2d 100, 105, 391 N.E.2d 1034, 1038 (1979). To protect this important interest, Ohio permits a hearing before executing a writ of habeas corpus concerning custody of a child. In re Hua, 62 Ohio St.2d 227, 233, 405 N.E.2d 255, 260-61 (1980); In re Haws, 64 Ohio App.2d 168, 168, 411 N.E.2d 802 (1977); In re Young, 58 Ohio St.2d 90, 90, 388 N.E.2d 1235, 1236 (1979); *606 Hughes v. Scaffide, 58 Ohio St.2d 88, 89, 388 N.E.2d 1233, 1234 (1979); In re Messner, 19 Ohio App.2d 33, 37, 249 N.E.2d 532, 535 (1969); In re Howland, 115 Ohio App. 186, 184 N.E.2d 228, 230 (1961). But see In re McTaggart, 2 Ohio App.2d 214, 222, 207 N.E.2d 562, 567 (1965). Thus, Ohio would permit modification of a writ of habeas corpus based on the best interest of the child. Because Ohio did not modify its decree, we must determine whether New Jersey may modify the decree in the best interest of the child.
Before PKPA, the New Jersey courts could have modified the Ohio decision because that decision was subject to modification in Ohio. New York ex rel. Halvey v. Halvey, 330 U.S. 610, 614, 67 S.Ct. 903, 906, 91 L.Ed. 1133 (1947). PKPA permits the courts of the forum state to modify the custody determination of another state on two conditions: the forum has jurisdiction over the matter and the other state has either lost jurisdiction or has declined to exercise it. 28 U.S.C.A. § 1738A(f). New Jersey, which has been the home of the child and parents for nearly three years, clearly has jurisdiction of the subject matter. Thus, the question is whether, by failing to grant a best interest hearing, the Ohio courts declined to exercise jurisdiction to modify the decree awarding custody to the natural mother.
Notwithstanding repeated requested by counsel for the adoptive parents, expressed most vividly in the motion for rehearing before the Ohio Supreme Court, no court in Ohio has determined the best interest of the child. Without making an express determination, the Ohio Supreme Court declined to order a best interest hearing both in its original decision and in its denial of the motion for rehearing. Possibly that Court contemplated, in light of its decision in In re Hua, supra, that the Juvenile Court would conduct a best interest hearing before issuing the writ. The Juvenile Court, however, proceeded to issue the writ without considering the best interest of the child. Perhaps, that court failed to conduct a best interest hearing because it recognized that neither the adoptive parents nor the child resided any longer in Ohio. We need not dwell on these speculations because *607 the clear implication is that the Ohio courts declined to exercise jurisdiction to conduct a best interest hearing.
We hold that Ohio's failure to conduct a best interest hearing constitutes a refusal to exercise jurisdiction under 28 U.S.C.A. § 1738A(f)(2). Under PKPA, therefore, New Jersey is free to modify the Ohio decree. This result comports with the congressional intent that child custody decisions be made in the state best able to determine the best interest of the child. See Pub.L.No. 96-611, § 7, 94 Stat. 3568.
III
The authority of the New Jersey courts to conduct a best interest hearing is controlled not only by PKPA, but also by UCCJA. Like PKPA, UCCJA attempts to bring order to the preexisting chaos in interstate child custody disputes. Commissioners' Prefatory Note to UCCJA, 9 U.L.A. at 114 (1979). Indeed, the National Conference of Commissioners on Uniform State Laws proposed UCCJA in response to the "public concern over the fact that thousands of children are shifted from state to state and from one family to another every year while their parents or other persons battle over their custody in the courts of several states." Commissioners' Prefatory Note to UCCJA, 9 U.L.A. at 111. To avoid jurisdictional conflicts and the accompanying trauma they inflict on the parties, especially the children, UCCJA urges that one state, albeit with help from others, should determine the issue of custody. UCCJA § 1, N.J.S.A. 2A:34-29.
While UCCJA focuses on custody disputes between family members, its operative provisions are broad enough to include a dispute between a natural parent and adoptive parents. A "custody proceeding" is defined to include a proceeding "in which a custody determination is one of several issues, such as an action for divorce or separation, and includes child neglect and dependency proceedings." UCCJA § 2(3), N.J.S.A. 2A:34-30(c). Furthermore, custody proceedings include habeas corpus *608 actions and other proceedings under state law to determine custody. See Slidell v. Valentine, Iowa, 298 N.W.2d 599, 601 (1980); UCCJA § 2, Commissioners' Note, 9 U.L.A. 120 (1979). Cf. Oregon ex rel. Butler v. Morgan, 34 Or. App. 393, 395, 578 P.2d 814, 815 (1978) (habeas corpus appropriate to enforce child custody determination). We conclude that the Ohio habeas corpus decree is included within the operative provisions of UCCJA.
At the time of our decision in Borys, the Legislature was considering, but had not enacted, UCCJA. That decision, like UCCJA and PKPA, sought to strike a balance between certainty in the enforcement of custody decrees and the desire to act in the best interest of the child. In the interim, the Legislature has enacted UCCJA, which takes a different approach to interstate custody disputes from that contained in Borys.
Section 3 of UCCJA strikes its balance by setting definite standards and establishing alternative bases for jurisdiction. UCCJA § 3, N.J.S.A. 2A:34-31. Succinctly stated, the four bases of jurisdiction are: (1) the forum is or has been within six months of the proceeding "the home state" of the child[5]; (2) it is in the best interest of the child to proceed in the forum state because the child and family have a "significant connection" to the forum[6]; (3) the child is present in the jurisdiction and is *609 abandoned or threatened with harm ("parens patriae jurisdiction")[7]; or (4) no other state has jurisdiction and it is in the best interest of the child that the forum entertain the dispute.[8]
The first two bases, "home state" and "significant connection" jurisdiction, are the major sources of a court's power to act in an interstate custody dispute. UCCJA § 3, Commissioners' Note, 9 U.L.A. at 123. The courts of the child's home state have jurisdiction, but if there is no home state or if the child and his family have equal or stronger ties with another state, the courts in the latter state have jurisdiction under UCCJA. Id. Some courts and commentators have interpreted section 3 as establishing a priority for home state jurisdiction. See Warman v. Warman, ___ Pa.Super. ___, ___, 439 A.2d 1203, 1209-11 (Super.Ct. 1982); Katz, Child Snatching: The Legal Response to the Abduction of Children, 36-37 (1981). Significant contact jurisdiction, however, "comes into play either when the home state test cannot be met or as an alternative to that test." UCCJA § 3, Commissioners' Note, 9 U.L.A. at 123. Thus, the home state and significant contact tests may produce concurrent jurisdiction in two or more states. In those circumstances, sections 6 and 7 of UCCJA determine the appropriate state to decide custody. See UCCJA § 3, Commissioners' Note, 9 U.L.A. at 123. Although section 6 of UCCJA gives precedence to the action *610 filed first in time, N.J.S.A. 2A:34-34,[9] section 7 permits a court to decline jurisdiction if it determines it is an "inconvenient forum" because there is a closer connection with or substantial evidence in another state." N.J.S.A. 2A:34-35.
Accordingly, we conclude that UCCJA does not contemplate blind obedience to home state jurisdiction. The state to decide a child custody dispute is not necessarily the home state, but the one best positioned to make the decision based on the best interest of the child. See UCCJA § 1(3), N.J.S.A. 2A:34-29(c); Commissioners' Prefatory Note to UCCJA, 9 U.L.A. at 114. Often the home state will also be the state with the most significant contacts with the child. UCCJA, however, rejects a rigid rule vesting jurisdiction automatically in the home state and favors, instead, a more flexible approach. See Foster & Freed, "Child Snatching and Custodial Fights: The Case for the Uniform Child Custody Jurisdiction Act," 28 Hast.L.J. 1011, 1020 (1977).
Thus construed, UCCJA differs from PKPA, which creates a clear priority for the home state. 28 U.S.C.A. § 1738A(c)(2)(A). Under PKPA, jurisdiction may be based on significant contacts only if no state qualifies as the home state. Id. at (2)(B).[10] While PKPA creates a preference for the home state under federal law, it does not significantly disrupt the jurisdictional provisions of UCCJA. PKPA permits a home state to defer jurisdiction to another state on the ground that the other is a *611 more appropriate forum. 28 U.S.C.A. § 1738A(c)(2)(D). In making that determination, the relevant factors are those that UCCJA enumerates as relevant in making a determination of inconvenient forum. UCCJA § 7, N.J.S.A. 2A:34-35. Those factors are, among others:
(1) if another state is or recently was the child's home state; (2) if another state has a closer connection with the child and his family or with the child and one or more of the contestants; (3) if substantial evidence concerning the child's present or future care, protection, training, and personal relationships is more readily available in another state; (4) if the parties have agreed on another forum which is no less appropriate; and (5) if the exercise of jurisdiction by a court of this state would contravene any of the purposes stated in section 1 of this act.
A custody dispute is more than a jurisdictional chess game in which winning depends on compliance with predetermined rules of play. A child is not a pawn. In exercising its discretion within the confines of UCCJA and PKPA, a court should consider not only the literal wording of the statutes but their purpose: to define and stabilize the right to custody in the best interest of the child.
PKPA and UCCJA also share a common goal of limiting the ability of sister-states to modify custody decrees. Both statutes permit modification only if the forum has jurisdiction and the rendering state has lost jurisdiction or has declined to exercise it. Compare 28 U.S.C.A. § 1738A(f) with UCCJA § 14(a), N.J.S.A. 2A:34-42(a). To the extent jurisdiction continued in Ohio, if at all, the Ohio courts declined to exercise it by refusing to hold a best interest hearing. Because the child and adoptive parents resided in New Jersey for almost a year before commencing the New Jersey action, New Jersey was both the home state and the state with the most significant contacts to the controversy. Thus, under both PKPA and UCCJA, New Jersey could modify the Ohio writ.
Both statutes define and limit the discretion of courts in recognizing sister-state decrees. Both restrict the jurisdiction to modify decrees of other states and remove, in many instances, the presence of the child as the sole basis for jurisdiction. *612 Nevertheless, like Borys, the statutes continue to recognize the crucial importance of considering the best interest of a child in an interstate custody dispute.
In retrospect, the Chancery Division would have been well advised to communicate with the courts in Ohio to determine whether Ohio courts expressly declined jurisdiction. In this case, however, the failure to communicate is understandable and excusable. PKPA was not in effect on December 1, 1980, when the Chancery Division decided that it had jurisdiction to conduct a best interest hearing, and UCCJA does not require communication with a sister-state that has declined to assume jurisdiction. See UCCJA § 6, N.J.S.A. 2A:34-34. Thus, the Chancery Division should not be criticized for the failure to communicate with the Ohio courts. In future cases, when there is doubt whether a sister-state has continuing jurisdiction or has declined to exercise it, the better practice would be to communicate with the courts of the sister-state. This interstate cooperation comports with the purposes of both statutes and assures a cooperative effort to achieve the best result for the child. See Bowden v. Bowden, 182 N.J. Super. 307, 314-15 (App.Div. 1982).
The judgment of the Appellate Division is affirmed.
For affirmance Chief Justice WILENTZ, and Justices PASHMAN, CLIFFORD, SCHREIBER, HANDLER, POLLOCK and O'HERN 7.
For reversal None.
NOTES
[1] Other sections of PKPA amend the Social Security Act to provide for a parent locator service, Pub.L.No. 96-611, § 9, 94 Stat. 3571 (amending various sections of 42 U.S.C.A.), and explicitly apply the Fugitive Felon Act to parental kidnapping. Pub.L.No. 96-611, § 10, 94 Stat. 3573.
[2] A child custody determination is a "judgment, decree, or other order of a court providing for the custody or visitation of a child, and includes permanent and temporary orders, and initial orders and modifications." 28 U.S.C.A. § 1738A(b)(3).
[3] A child custody determination is made consistently with the Act if:
(1) such court has jurisdiction under the law of such State; and
(2) one of the following conditions is met:
(A) such State (i) is the home State of the child on the date of the commencement of the proceeding, or (ii) had been the child's home State within six months before the date of the commencement of the proceeding and the child is absent from such State because of his removal or retention by a contestant or for other reasons, and a contestant continues to live in such State;
(B)(i) it appears that no other State would have jurisdiction under subparagraph (A), and (ii) it is in the best interest of the child that a court of such State assume jurisdiction because (I) the child and his parents, or the child and at least one contestant, have a significant connection with such State other than mere physical presence in such State, and (II) there is available in such State substantial evidence concerning the child's present or future care, protection, training, and personal relationships;
(C) the child is physically present in such State and (i) the child has been abandoned, or (ii) it is necessary in an emergency to protect the child because he has been subjected to or threatened with mistreatment or abuse;
(D)(i) it appears that no other State would have jurisdiction under subparagraph (A), (B), (C), or (E), or another State has declined to exercise jurisdiction on the ground that the State whose jurisdiction is in issue is the more appropriate forum to determine the custody of the child, and (ii) it is in the best interest of the child that such court assume jurisdiction; or
(E) the court has continuing jurisdiction pursuant to subsection (d) of this section.
[28 U.S.C.A. § 1738A(c)]
[4] Although not raised by the parties, a question exists concerning the effective date of 28 U.S.C.A. § 1738A. In section 2 of Pub.L.No. 96-611 it states: "The amendments made by this Act shall take effect on, and apply to services furnished on or after July 1, 1981." This issue has caused courts some difficulty. See Kumar v. Santa Clara County Superior Court, 124 Cal. App.3d 1003, 177 Cal. Rptr. 763, 767 n. 9 (1981) (date on which PKPA became effective subject to doubt); State ex rel. Valles v. Brown, N.M., 639 P.2d 1181, 1183 (1981) (although Act might appear to be effective July 1, 1981, court finds PKPA is effective when enacted); Bahr v. Bahr, 110 Misc.2d 665, 442 N.Y.S.2d 687 (Fam.Ct. 1981) (applying PKPA to decision rendered May 8, 1981); In Re Custody of Ross, 291 Or. 263, 630 P.2d 353, 362 n. 19 (1981) (PKPA effective Dec. 28, 1980).
[5] UCCJA § 3(a)(1), N.J.S.A. 2A:34-31(a)(1).
"Home state" means the state in which the child immediately preceding the time involved lived with his parents, a parent, or a person acting as parent, for at least 6 consecutive months, and in the case of a child less than 6 months old the state in which the child lived from birth with any of the persons mentioned. Periods of temporary absence of any of the named persons are counted as part of the 6-month or other period. [UCCJA § 2(5), N.J.S.A. 2A:34-30(e).] Compare 28 U.S.C.A. § 1738A(b)(4).
[6] UCCJA § 3(a)(2), N.J.S.A. 2A:34-31(a)(2), which provide:
It is in the best interest of the child that a court of this State assume jurisdiction because (i) the child and his parents, or the child and at least one contestant, have a significant connection with this State, and (ii) there is available in this State substantial evidence concerning the child's present or future care, protection, training, and personal relationships.
[7] UCCJA § 3(a)(3), N.J.S.A. 2A:34-31(a)(3), which provide:
The child is physically present in this State and (i) the child has been abandoned or (ii) it is necessary in an emergency to protect the child because he has been subjected to or threatened with mistreatment or abuse or is otherwise neglected.
[8] UCCJA § 3(a)(4), N.J.S.A. 2A:34-31(a)(4), which provide:
(i) It appears that no other state would have jurisdiction under prerequisites substantially in accordance with paragraphs (1), (2), or (3), or another state has declined to exercise jurisdiction on the ground that this State is the more appropriate forum to determine the custody of the child, and (ii) it is in the best interest of the child that this court assume jurisdiction.
[9] UCCJA § 6, N.J.S.A. 2A:34-34 provide in part:
A court of this State shall not exercise its jurisdiction under this act if at the time of filing the petition a proceeding concerning the custody of the child was pending in a court of another state exercising jurisdiction substantially in conformity with this act, unless the proceeding is stayed by the court of the other state because this State is a more appropriate forum or for other reasons.
[10] Like the UCCJA, PKPA provides for jurisdiction based on an emergency or if no State has jurisdiction and it is in the best interest of the child that the forum assume jurisdiction. Compare 28 U.S.C.A. § 1738A(c)(2)(C) & (D) with UCCJA § 3(a)(3) & (4), N.J.S.A. 2A:34-31(a)(3) & (4).
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Fluid flow control is an essential part of medical devices such as intravenous infusion pumps and enteral feeding systems. These fluid flow control systems must meet a complex and conflicting set of requirements, such as broad flow rate range, wide ranging fluid viscosity, inevitable presence of harmful amounts of gas, changing source pressure, changing patient pressure, variable patient line resistance, and a wide range of tubing configurations.
Reliability and ability to detect fault conditions are critical features of such flow control devices. Low acquisition and maintenance costs are important characteristics also.
The usability of the system is vitally important, as it impacts the workflow of caregivers, which has a strong, but indirect, impact on the quality of patient care. This usability includes ease of loading the sterile tubing set, the need for attention from the caregiver during the fluid delivery period, and attending to unnecessary alarm conditions.
Conventional fluid control or pumping mechanisms suffer from an unfavorable tradeoff between sophistication and complexity. The added complexity of many modern systems has led to a lack of reliability, resulting in product performance failures, high levels of maintenance, product recalls by regulatory agencies, and documented high rates of patient harm.
One of the earlier types of fluid pump, as marketed by Harvard Apparatus Company and as replicated in the market hundreds of times thereafter, is a syringe pump. In a syringe pump, fluid is contained within a commonly found glass or plastic syringe, manufactured with a well-specified diameter and stroke length. These are the same syringes that are used to provide manual injections of sterile fluid. The piston of the syringe is securely held and, usually with a lead screw mechanism, the piston is advanced in carefully timed steps of a motor. Each step of the motor expresses a known amount of liquid out of the syringe and into a line going to the vasculature of the patient. The syringe pump offers a very simple mechanism and an extraordinarily simple control system, consisting of a timer circuit, set by the desired fluid flow rate. Force and position sensors are often added to provide feedback regarding occlusions, misloading, and end of infusion. The syringe pump design is inherently limited, however, by the relatively small size of the syringe, in the amount of fluid infused and in the maximum fluid flow rate, so this design does not satisfy the needs of many clinical applications. Ironically, at the very small volumes and flow rates, the syringe pump suffers from a discontinuity of fluid flow, based on the high static friction of the syringe. Very small movements of the drive motor do not necessarily translate into movement of the piston and delivery of fluid; it may take multiple motor steps and multiple time intervals before the piston actually delivers fluid to the patient. Long delay periods between delivery are not desirable clinically. A further deficiency in the syringe pump is the improper impedance match with the patient's vasculature; the syringe pump motor drive is equipped with a motor that is capable of reliably meeting the maximum torque foreseen by the system. This powerful motor is also geared down such that very low displacements can be achieved, giving the pump the ability to deliver at low flow rates. The combination of the powerful motor and the gearing, however, allows the syringe drive to generate fluid pressures that are far in excess of those needed to safely infuse a fluid into the vasculature of a patient. The consequence of this potentially high pressure output is that harmful levels of fluid pressure can be applied to the patient, with deleterious effects, especially in the event of an extravasation of the infusion catheter or the creation of a bolus upon release of a temporary occlusion.
Variations of the syringe pump are to be found in the form of a reciprocating piston that can draw from a fluid bag or vented bottle. Such devices, as found with the Abbott/Hospira Plum™ infusion device, overcome the volume limitation of a syringe pump. Added complexity for valving serves to increase cost and reduce reliability. A large volume pump, because of its multiple fluid connections and air spaces, creates an environment, not found with syringe pumps, for the introduction of harmful air bubbles, which must be detected and accommodated. These reciprocating piston pumps still retain the disadvantage of impedance mismatch described above for syringe pumps.
The most common form of infusion pump is the peristaltic pump, whereupon fingers or rollers occlude a section of flexible tubing in peristaltic fashion, expressing fluid out the tube toward the patient. This mechanism provides the simplest configuration to carry the sterile fluid in the form a simple flexible tube. The peristaltic pump suffers the same impedance mismatch fate as the syringe pump, because the forces required to faithfully occlude a portion of the flexible tube are great, allowing the pump to generate harmfully high infusion pressures. This potentially high pressure can be mitigated through the use of force sensors on the tubing, adding complexity and cost. The problem with air ingress to the patient is the same as with the reciprocating piston pump described above. The peristaltic pump introduced a new problem related to fluid flow accuracy, since the amount of fluid expressed to the patient is entirely dependent on the interior diameter of the fluid tubing in its uncompressed state. In fact the surface area error is a square law function of the error in the diameter, so a 10% error in the diameter would yield an unacceptable 21% (1.12) error in the volume expressed to the patient. Unfortunately, there are two very common events that can reduce the effective diameter of the tubing: one is the fatigue of the tubing as it is repeatedly worked by the peristaltic mechanism and the other is the failure of the tubing to refill completely due to low flow from the fluid source.
There is another class of pumps providing single flow rates using a constant force spring, membrane, or gas reaction pushing fluid against a fixed, calibrated resistance. These devices do not provide the programmable variation of flow rate needed for most clinical applications.
One variation of the reciprocal piston pump was designed and marketed by FluidSense Corporation of Newburyport, Mass. It used a flexible membrane connected to a spring-loaded piston on one side and sterile fluid on the other. A low cracking pressure passive inlet valve and an actively operated momentary outlet valve provided for a pumping action if the spring loaded piston were “cocked” back to load the spring, providing a positive fluid force. A highly sensitive linear encoder was used to watch the position of the spring-loaded piston, providing information on the fluid pressure and volume. This design allowed for a simplified and more sensitive pump mechanism, but the flow was intermittent with the action of each pulse of the outlet valve and the driving pressure varied from 3 to 7 PSIg, higher than necessary for most clinical applications. It also suffered from the introduction of air bubbles, as with all large volume pumping systems.
Programmable infusion devices, as opposed to single rate delivery systems, all suffer from two effects of electromechanical complexity. First, there are usually tight mechanical tolerances which can be disturbed by shock, vibration, temperature shifts, and aging. Infusion pumps are often out of their performance specifications, sometimes intermittently, making troubleshooting very expensive and difficult. Secondly, these complex mechanisms are often difficult to disinfect. Customers have only recently become sensitized to the extremely high importance of disinfecting infusion pumps and other medical devices. Cross contamination of patients is one of the top healthcare issues in the acute care environment.
Another particular problem that patients and caregivers face with great regularly is the presence of air bubbles in the fluid path. Conventional infusion pumps observe a segment of tubing via an ultrasonic or optical detector circuit. They reliably detect bubbles with high sensitivity. Unfortunately, the specificity of these sensors is low, so false alarms are commonplace. When these bubbles are detected, three bad things happen. First, the pump goes into an alarm condition and fluid flow to the patient is halted, which can often cause harm to the patient by withholding needed medication. Second, the alarm at the bedside causes significant distress to the patient and the patient's family. Third, the alarm disrupts the nurse's workflow, taking time away from other patients and directing the nurse's attention toward the infusion pump and away from the patient.
Air eliminating filters are commonly found in infusion therapy administration sets. These filters fail to solve the problems identified above, because these filters do not function properly when exposed to negative gauge pressures if they are positioned proximal to the infusion pump. If these filters are placed below the infusion pump, then there is no way for the pump to verify that these filters are in place, so the alarms must still stay active. These filters must also incorporate hydrophilic filters, which are not compatible with certain medical fluids, such as whole blood. | {
"pile_set_name": "USPTO Backgrounds"
} |
Q:
Django-rest-framework api add SessionAuthentication as optional
Hi i'm currently have my api that use this simple-JWT package for jwt token authentication, it worked great. But now when i try to call the api from the django website app using Ajax in which is from a page user already logged in but it still required me to use the jwt access_token.
My ajax call from the page user already logged in:
$.ajax({
type: "POST",
url: "/api/add_favorite/" + property_id + "/",
beforeSend: function (xhr) {
xhr.setRequestHeader('Authorization', 'Bearer {{ refresh_token }}');
},
success: function (data) {
if (data.code == 200) {
alert('added to favorite');
replace_part_1 = '<a id="mylink2" href="#" value="' + property_id +'"><i class="fas fa-heart fa-lg" style="color: red" title="Remove from favorite"></i></a>'
$("a[value='" + property_id + "']").replaceWith(replace_part_1);
}
}
});
Now i don't want to set the header with authorization since in the page user already logged in so the session is already set.
So i tried to add Django Session authentication to the the api like so:
@api_view(['POST'])
@authentication_classes([SessionAuthentication, JWTAuthentication])
@permission_classes([IsAuthenticated])
def add_favorite(request, property_id):
if request.method == 'POST':
try:
favorite_property = Property.objects.get(pk=property_id)
if request.user.is_authenticated:
login_user = request.user
if not login_user.properties.filter(pk=property_id).exists():
login_user.properties.add(favorite_property)
return JsonResponse({'code':'200','data': favorite_property.id}, status=200)
else:
return JsonResponse({'code':'404','errors': "Property already exists in favorite"}, status=404)
except Property.DoesNotExist:
return JsonResponse({'code':'404','errors': "Property not found"}, status=404)
My Ajax after removed the header :
$.ajax({
type: "POST",
url: "/api/add_favorite/" + property_id + "/",
},
success: function (data) {
if (data.code == 200) {
alert('added to favorite');
replace_part_1 = '<a id="mylink2" href="#" value="' + property_id +'"><i class="fas fa-heart fa-lg" style="color: red" title="Remove from favorite"></i></a>'
$("a[value='" + property_id + "']").replaceWith(replace_part_1);
}
}
});
and i removed the set header from the Ajax call now i get 403 return code :
Failed to load resource: the server responded with a status of 403
(Forbidden)
My settings:
REST_FRAMEWORK = {
# Use Django's standard `django.contrib.auth` permissions,
# or allow read-only access for unauthenticated users.
'DEFAULT_PERMISSION_CLASSES': [
'rest_framework.permissions.IsAuthenticated',
],
'DEFAULT_AUTHENTICATION_CLASSES': (
'rest_framework_simplejwt.authentication.JWTAuthentication',
'rest_framework.authentication.SessionAuthentication',
),
# 'DEFAULT_FILTER_BACKENDS': ('django_filters.rest_framework.DjangoFilterBackend',)
}
I don't know why the session authentication doesn't work since the Ajax call is from the page user already logged in.
Thank for reading!
A:
Because you're adding Authentication header on your ajax requests, Django automatically use TokenAuthentication if Authentication exists on the request header. Remove it to use SessionAuthentication.
There might be a problem when you're switch to use SessionAuthentication is that Django will reject your unsafe requests if there is no CSRF token, more detail here
| {
"pile_set_name": "StackExchange"
} |
namespace nUpdate.Administration.UI.Dialogs
{
partial class StatisticsServerDialog
{
/// <summary>
/// Required designer variable.
/// </summary>
private System.ComponentModel.IContainer components = null;
/// <summary>
/// Clean up any resources being used.
/// </summary>
/// <param name="disposing">true if managed resources should be disposed; otherwise, false.</param>
protected override void Dispose(bool disposing)
{
if (disposing && (components != null))
{
components.Dispose();
}
base.Dispose(disposing);
}
#region Windows Form Designer generated code
/// <summary>
/// Required method for Designer support - do not modify
/// the contents of this method with the code editor.
/// </summary>
private void InitializeComponent()
{
this.components = new System.ComponentModel.Container();
System.ComponentModel.ComponentResourceManager resources = new System.ComponentModel.ComponentResourceManager(typeof(StatisticsServerDialog));
this.serverList = new nUpdate.Administration.UI.Controls.ServerList();
this.imageList1 = new System.Windows.Forms.ImageList(this.components);
this.toolStrip1 = new System.Windows.Forms.ToolStrip();
this.addServerButton = new System.Windows.Forms.ToolStripButton();
this.toolStripSeparator1 = new System.Windows.Forms.ToolStripSeparator();
this.editServerButton = new System.Windows.Forms.ToolStripButton();
this.toolStripSeparator2 = new System.Windows.Forms.ToolStripSeparator();
this.deleteServerButton = new System.Windows.Forms.ToolStripButton();
this.noServersLabel = new System.Windows.Forms.Label();
this.toolStrip1.SuspendLayout();
this.SuspendLayout();
//
// serverList
//
this.serverList.BorderStyle = System.Windows.Forms.BorderStyle.FixedSingle;
this.serverList.DrawMode = System.Windows.Forms.DrawMode.OwnerDrawFixed;
this.serverList.FormattingEnabled = true;
this.serverList.IntegralHeight = false;
this.serverList.ItemHeight = 60;
this.serverList.Location = new System.Drawing.Point(0, 26);
this.serverList.Name = "serverList";
this.serverList.Size = new System.Drawing.Size(479, 244);
this.serverList.TabIndex = 8;
//
// imageList1
//
this.imageList1.ImageStream = ((System.Windows.Forms.ImageListStreamer)(resources.GetObject("imageList1.ImageStream")));
this.imageList1.TransparentColor = System.Drawing.Color.Transparent;
this.imageList1.Images.SetKeyName(0, "Visualpharm-Hardware-Server.ico");
//
// toolStrip1
//
this.toolStrip1.BackColor = System.Drawing.Color.Transparent;
this.toolStrip1.Items.AddRange(new System.Windows.Forms.ToolStripItem[] {
this.addServerButton,
this.toolStripSeparator1,
this.editServerButton,
this.toolStripSeparator2,
this.deleteServerButton});
this.toolStrip1.Location = new System.Drawing.Point(0, 0);
this.toolStrip1.Name = "toolStrip1";
this.toolStrip1.RenderMode = System.Windows.Forms.ToolStripRenderMode.System;
this.toolStrip1.Size = new System.Drawing.Size(479, 25);
this.toolStrip1.TabIndex = 9;
this.toolStrip1.Text = "toolStrip1";
//
// addServerButton
//
this.addServerButton.Image = ((System.Drawing.Image)(resources.GetObject("addServerButton.Image")));
this.addServerButton.ImageTransparentColor = System.Drawing.Color.Magenta;
this.addServerButton.Name = "addServerButton";
this.addServerButton.Size = new System.Drawing.Size(92, 22);
this.addServerButton.Text = "Add a server";
this.addServerButton.Click += new System.EventHandler(this.addServerButton_Click);
//
// toolStripSeparator1
//
this.toolStripSeparator1.Name = "toolStripSeparator1";
this.toolStripSeparator1.Size = new System.Drawing.Size(6, 25);
//
// editServerButton
//
this.editServerButton.Image = ((System.Drawing.Image)(resources.GetObject("editServerButton.Image")));
this.editServerButton.ImageTransparentColor = System.Drawing.Color.Magenta;
this.editServerButton.Name = "editServerButton";
this.editServerButton.Size = new System.Drawing.Size(81, 22);
this.editServerButton.Text = "Edit server";
this.editServerButton.Click += new System.EventHandler(this.editServerButton_Click);
//
// toolStripSeparator2
//
this.toolStripSeparator2.Name = "toolStripSeparator2";
this.toolStripSeparator2.Size = new System.Drawing.Size(6, 25);
//
// deleteServerButton
//
this.deleteServerButton.Image = ((System.Drawing.Image)(resources.GetObject("deleteServerButton.Image")));
this.deleteServerButton.ImageTransparentColor = System.Drawing.Color.Magenta;
this.deleteServerButton.Name = "deleteServerButton";
this.deleteServerButton.Size = new System.Drawing.Size(94, 22);
this.deleteServerButton.Text = "Delete server";
this.deleteServerButton.Click += new System.EventHandler(this.deleteServerButton_Click);
//
// noServersLabel
//
this.noServersLabel.AutoSize = true;
this.noServersLabel.Location = new System.Drawing.Point(159, 128);
this.noServersLabel.Name = "noServersLabel";
this.noServersLabel.Size = new System.Drawing.Size(153, 13);
this.noServersLabel.TabIndex = 10;
this.noServersLabel.Text = "No statistic servers available.";
this.noServersLabel.Visible = false;
//
// StatisticsServerDialog
//
this.AutoScaleDimensions = new System.Drawing.SizeF(6F, 13F);
this.AutoScaleMode = System.Windows.Forms.AutoScaleMode.Font;
this.ClientSize = new System.Drawing.Size(479, 270);
this.Controls.Add(this.noServersLabel);
this.Controls.Add(this.toolStrip1);
this.Controls.Add(this.serverList);
this.Font = new System.Drawing.Font("Segoe UI", 8.25F, System.Drawing.FontStyle.Regular, System.Drawing.GraphicsUnit.Point, ((byte)(0)));
this.FormBorderStyle = System.Windows.Forms.FormBorderStyle.FixedDialog;
this.Icon = ((System.Drawing.Icon)(resources.GetObject("$this.Icon")));
this.KeyPreview = true;
this.MaximizeBox = false;
this.Name = "StatisticsServerDialog";
this.StartPosition = System.Windows.Forms.FormStartPosition.CenterParent;
this.Text = "Statistic servers - {0}";
this.Load += new System.EventHandler(this.StatisticsServerDialog_Load);
this.KeyDown += new System.Windows.Forms.KeyEventHandler(this.StatisticsServerDialog_KeyDown);
this.toolStrip1.ResumeLayout(false);
this.toolStrip1.PerformLayout();
this.ResumeLayout(false);
this.PerformLayout();
}
#endregion
private Controls.ServerList serverList;
private System.Windows.Forms.ImageList imageList1;
private System.Windows.Forms.ToolStrip toolStrip1;
private System.Windows.Forms.ToolStripButton addServerButton;
private System.Windows.Forms.ToolStripSeparator toolStripSeparator1;
private System.Windows.Forms.ToolStripButton editServerButton;
private System.Windows.Forms.ToolStripSeparator toolStripSeparator2;
private System.Windows.Forms.ToolStripButton deleteServerButton;
private System.Windows.Forms.Label noServersLabel;
}
} | {
"pile_set_name": "Github"
} |
---
abstract: 'The generalized decoration-iteration transformation is adopted to treat exactly a hybrid model of doubly decorated two-dimensional lattices, which have localized Ising spins at their nodal lattice sites and itinerant electrons delocalized over pairs of decorating sites. Under the assumption of a half filling of each couple of the decorating sites, the investigated model system exhibits a remarkable spontaneous antiferromagnetic long-range order with an obvious quantum reduction of the staggered magnetization. It is shown that the critical temperature of the spontaneously long-range ordered quantum antiferromagnet displays an outstanding non-monotonic dependence on a ratio between the kinetic term and the Ising-type exchange interaction.'
author:
- Jozef Strečka
- Akinori Tanaka
- Lucia Čanová
- Taras Verkholyak
title: 'Exact evidence for the spontaneous antiferromagnetic long-range order in the two-dimensional hybrid model of localized Ising spins and itinerant electrons'
---
\[sec:intro\] Introduction
==========================
Exactly solvable lattice-statistical models are of appreciable scientific interest as they bring a valuable insight into diverse aspects of quantum, cooperative, and critical phenomena.[@baxt82; @matt93; @sach99; @lavi99; @lieb04; @suth04; @diep04; @wu09] It should be mentioned, however, that sophisticated mathematical methods must be usually employed when searching for an exact treatment of even relatively simple interacting many-body systems, while an exact treatment of more realistic or more complex models is often quite unfeasible or is accompanied with a substantial increase of computational difficulties. From this point of view, the exact mapping technique based on generalized algebraic transformations [@fish59; @syoz72; @roja09] belongs to the simplest mathematical methods, which allows to obtain the exact solution of more complicated model from a precise mapping relationship with a simpler exactly solved model. Following Fisher’s ideas,[@fish59] an arbitrary statistical-mechanical system (even of quantum nature) that merely interacts with either two or three outer Ising spins may be in principle replaced by the effective interactions between the outer Ising spins through appropriately chosen decoration-iteration [@syoz51] or star-triangle [@onsa44] mapping transformations. Even although the concept based on the generalized algebraic transformations has been worked out by Fisher more than a half century ago,[@fish59] the algebraic mapping transformations were initially widely used to treat only lattice-statistical models consisting of the Ising spins (see Ref. and references cited therein) before this conceptually simple approach was finally applied to hybrid models composed of the Ising and classical Heisenberg spins,[@gonc82; @hori83; @gonc84; @gonc86; @sant86; @sant95] as well as, the Ising and quantum Heisenberg spins.[@stre02; @jasc02; @stre04; @stre06; @stre08; @yao08; @valv09; @stre09]
Another interesting application of the algebraic mapping transformations has recently been suggested by Pereira *et al*. [@pere08; @pere09] when applying the generalized decoration-iteration transformation to an intriguing diamond-chain model of interacting spin-electron system. In this diamond-chain model, the nodal lattice sites are occupied by the localized Ising spins and the mobile electrons can freely move on a couple of interstitial decorating sites symmetrically placed in between two localized Ising spins. The main aim of this work is to treat exactly an analogous two-dimensional (2D) hybrid model defined on doubly decorated planar lattices, which should provide a deeper insight into how itinerant character of the mobile electrons will influence phase transitions and critical phenomena of this interacting spin-electron system.
The outline of this paper is as follows. In Section \[sec:model\], we first provide a rather detailed description of the model under investigation together with the most crucial steps of the exact mapping method, which enables us to obtain exact closed-form expressions for the critical temperature, order parameter and other relevant thermodynamic quantities. The most interesting results for the ground state, the finite-temperature phase diagram and thermodynamics are presented and detailed discussed in Section \[sec:result\]. Finally, the summary of the most important scientific achievement is mentioned with several concluding remarks in Section \[sec:conc\].
\[sec:model\] Model and method
==============================
Let us consider a hybrid lattice-statistical model of interacting spin-electron system on doubly decorated 2D lattices, which have one localized Ising spin at each nodal lattice site and two delocalized mobile electrons at each couple of decorating sites. The magnetic structure of the model under investigation is schematically depicted in figure \[fig1\] on the particular example of the doubly decorated square lattice.
![A part of the doubly decorated square lattice, which has one localized Ising spin at each nodal lattice site (full circle) and two mobile electrons at each couple of decorating sites (empty circles). The ellipse demarcates the localized Ising spins and itinerant electrons described through the $k$th bond Hamiltonian (\[ham\]).[]{data-label="fig1"}](fig1.eps){width="8cm"}
For further convenience, the total Hamiltonian can be defined as a sum over bond Hamiltonians $\hat{\cal H} = \sum_k \hat{\cal H}_k$, where each bond Hamiltonian $\hat{\cal H}_k$ involves all the interaction terms of two itinerant electrons from the $k$th bond of the doubly decorated 2D lattice $$\begin{aligned}
\hat{\cal H}_k = \! \! \! &-& \! \! \! t \left( c^{\dagger}_{k1, \uparrow} c^{}_{k2, \uparrow}
+ c^{\dagger}_{k1, \downarrow} c^{}_{k2, \downarrow}
+ c^{\dagger}_{k2, \uparrow} c^{}_{k1, \uparrow}
+ c^{\dagger}_{k2, \downarrow} c^{}_{k1, \downarrow} \right) \nonumber \\
\! \! \! &-& \! \! \!
\frac{J}{2} \hat{\sigma}_{k1}^z \left( c^{\dagger}_{k1, \uparrow} c^{}_{k1, \uparrow}
- c^{\dagger}_{k1, \downarrow} c^{}_{k1, \downarrow} \right)
\nonumber \\
\! \! \! &-& \! \! \!
\frac{J}{2} \hat{\sigma}_{k2}^z \left( c^{\dagger}_{k2, \uparrow} c^{}_{k2, \uparrow}
- c^{\dagger}_{k2, \downarrow} c^{}_{k2, \downarrow} \right). \label{ham}\end{aligned}$$ Here, $c^{\dagger}_{k \alpha, \gamma}$ and $c^{}_{k \alpha, \gamma}$ ($\alpha = 1,2$, $\gamma = \uparrow, \downarrow$) denote usual creation and annihilation fermionic operators and $\hat{\sigma}_{k \alpha}^z$ is the standard spin-1/2 operator with the eigenvalues ${\sigma}_{k \alpha}^z = \pm 1/2$. The hopping parameter $t$ takes into account kinetic energy of the mobile electrons and the exchange integral $J$ describes the Ising-type interaction between the itinerant electrons and their nearest Ising neighbors.
A crucial step of our approach lies in the calculation of the partition function. Owing to a validity of the commutation relation between different bond Hamiltonians $[\hat{\cal H}_i, \hat{\cal H}_j] = 0$, the total partition function ${\cal Z}$ can be partially factorized into a product of the bond partition functions ${\cal Z}_k$ $$\begin{aligned}
{\cal Z} = \displaystyle \sum_{\{ \sigma_i \}} \prod_{k=1}^{Nq/2}
\mbox{Tr}_{k} \exp \left(- \beta \hat{\cal H}_k \right)
= \displaystyle \sum_{\{ \sigma_i \}} \prod_{k=1}^{Nq/2} {\cal Z}_k,
\label{pf}\end{aligned}$$ where $\beta = 1/(k_{\rm B} T)$, $k_{\rm B}$ is Boltzmann’s constant, $T$ is the absolute temperature, $N$ is the total number of the Ising spins (i.e. the nodal lattice sites) and $q$ is their coordination number (i.e. the number of nearest-neighbor decorating sites). Next, the symbol $\sum_{\{\sigma_i \}}$ denotes a summation over all possible spin configurations of the localized Ising spins and the symbol $\mbox{Tr}_{k}$ stands for a trace over degrees of freedom of two mobile electrons from the $k$th couple of decorating sites. An explicit form of the bond partition function ${\cal Z}_k$ can be subsequently acquired by a direct diagonalization of the bond Hamiltonian (\[ham\]). The matrix representation of the bond Hamiltonian $\hat{\cal H}_k$ in the orthonormal basis of states $| \psi_i \rangle = \{c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \uparrow}| 0 \rangle$, $c^{\dagger}_{k1, \downarrow} c^{\dagger}_{k2, \downarrow} | 0 \rangle$, $c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \downarrow} | 0 \rangle$, $c^{\dagger}_{k1, \downarrow} c^{\dagger}_{k2, \uparrow} | 0 \rangle$, $c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k1, \downarrow}| 0 \rangle$, $c^{\dagger}_{k2, \uparrow} c^{\dagger}_{k2, \downarrow}| 0 \rangle \}$ ($| 0 \rangle$ labels the empty state) reads
$$\begin{aligned}
\langle \psi_j | \hat{{\cal{H}}}_{k}| \psi_i \rangle = \left(
\begin{array}{cccccc}
-h_{k1} - h_{k2} & 0 & 0 & 0 & 0 & 0 \\
0 & h_{k1} + h_{k2} & 0 & 0 & 0 & 0 \\
0 & 0 & -h_{k1} + h_{k2} & 0 & -t & -t \\
0 & 0 & 0 & h_{k1} - h_{k2} & t & t \\
0 & 0 & -t & t & 0 & 0 \\
0 & 0 & -t & t & 0 & 0 \\
\end{array}
\right),
\label{matrix}\end{aligned}$$
where we have defined two new parameters $h_{k1} = J \sigma_{k1}^z/2$ and $h_{k2} = J \sigma_{k1}^z/2$ that include the Ising-type interaction between the mobile electrons and their nearest-neighbor localized Ising spins. It is noteworthy that the parameters $h_{k1}$ and $h_{k2}$ can alternatively be viewed also as generally non-uniform effective field, which is produced by the localized Ising spins on the itinerant electrons situated at the nearest-neighbor decorating sites. The straightforward diagonalization of the Hamiltonian matrix (\[matrix\]) yields six eigenenergies $$\begin{aligned}
E_{k1,k2} \! \! \! &=& \! \! \! \pm (h_{k1} + h_{k2}), \qquad E_{k3,k4} = 0, \nonumber \\
E_{k5,k6} \! \! \! &=& \! \! \! \pm \sqrt{\left(h_{k1} - h_{k2} \right)^2 + 4 t^2},
\label{eigen}\end{aligned}$$ which can be further used for the relevant calculation of the bond partition function ${\cal Z}_k$. After tracing out the degrees of freedom of the itinerant electrons, the bond partition function ${\cal Z}_k$ merely depends on spin states of two localized Ising spins and, besides, its explicit form immediately implies a possibility of performing the generalized decoration-iteration transformation [@fish59; @syoz72; @roja09] $$\begin{aligned}
\! \! \! \! \! \! \! && \! \! \! \! \! {\cal Z}_k = \sum_{i=1}^6 \exp \left( - \beta E_{ki} \right) =
2 + 2 \cosh \! \! \left[ \frac{\beta J}{2} (\sigma_{k1}^z + \sigma_{k2}^z) \right] + \nonumber \\
\! \! \! \! \! \! \! && \! \! \! \! \!
2 \cosh \! \! \left[ \frac{\beta}{2} \sqrt{J^2 (\sigma_{k1}^z - \sigma_{k2}^z)^2 + (4t)^2} \right]
= A \exp(\beta R \sigma_{k1}^z \sigma_{k2}^z). \nonumber \\
\label{dit}\end{aligned}$$ The physical meaning of the mapping transformation (\[dit\]) is to replace the bond partition function ${\cal Z}_k$ by the equivalent expression, which would contain the effective pair interaction $R$ between the localized Ising spins only. The mapping parameters $A$ and $R$ are unambiguously given by the ’self-consistency’ condition of the algebraic transformation (\[dit\]), which must hold for any combination of spin states of two Ising spins $\sigma_{k1}^z$ and $\sigma_{k2}^z$ involved therein. It can be readily proved that the decoration-iteration transformation (\[dit\]) indeed represents a set of two independent equations, which directly determine the mapping parameters $A$ and $R$ $$\begin{aligned}
A = (V_1 V_2)^{1/2}, \qquad \beta R = 2 \ln (V_1/V_2),
\label{mp} \end{aligned}$$ that are for the sake of brevity expressed in terms of the newly defined functions $V_1$ and $V_2$ $$\begin{aligned}
V_1 \!\!\! &=& \!\!\! 2 + 2 \cosh (\beta J/2) + 2 \cosh (2 \beta t), \nonumber \\
V_2 \!\!\! &=& \!\!\! 4 + 2 \cosh \left[\beta \sqrt{J^2 + (4t)^2}/2 \right].
\label{fun} \end{aligned}$$ Substituting the algebraic transformation (\[dit\]) into the factorized form of the partition function (\[pf\]), which physically corresponds to performing the decoration-iteration mapping at each bond of the doubly decorated 2D lattice, consequently leads to a simple mapping relationship between the partition function ${\cal Z}$ of the interacting spin-electron system on the doubly decorated 2D lattice and, respectively, the partition function ${\cal Z}_{{\rm IM}}$ of the simple spin-1/2 Ising model on the corresponding undecorated lattice with the effective (temperature-dependent) nearest-neighbor interaction $R$ $$\begin{aligned}
{\cal Z} (\beta, J, t) = A^{Nq/2} {\cal Z}_{{\rm IM}} (\beta, R).
\label{mr}\end{aligned}$$ The mapping relation (\[mr\]) essentially completes our exact calculation of the partition function ${\cal Z}$, since the partition function of the nearest-neighbor spin-1/2 Ising model has been precisely calculated for several 2D lattices (for reviews see Refs. ). For brevity, let us therefore merely quote the respective results for the partition functions of the spin-1/2 Ising model on the square lattice [@onsa44] $$\begin{aligned}
\lim_{N \to \infty} \!\!\!\!\! && \!\!\!\!\! \frac{1}{N} \ln {\cal Z}_{{\rm IM}} = \ln 2
+ \frac{1}{4 \pi^2} \int_0^{2 \pi} \!\!\! \int_0^{2 \pi} \!\!\! \ln [\cosh^2 \left(\beta R/2 \right) \nonumber \\
\!\!\! &-& \!\!\! \sinh \left(\beta R/2 \right) \left(\cos \theta + \cos \phi \right)]
{\rm d} \theta {\rm d} \phi
\label{pfsquare}\end{aligned}$$ and the honeycomb lattice [@hout50] $$\begin{aligned}
\!\!\!\! && \!\!\!\! \lim_{N \to \infty} \!\! \frac{1}{N} \ln {\cal Z}_{{\rm IM}} = \ln 2
+ \frac{1}{16 \pi^2} \int_0^{2 \pi} \!\!\! \int_0^{2 \pi} \!\!\! \ln [\{1 +
\cosh^3 \! \left(\beta R/2 \right) \nonumber \\
\!\!\!\! && \!\!\!\! -
\sinh^2 \left(\beta R/2 \right) \left[\cos \theta + \cos \phi + \cos(\theta + \phi) \right]\}/2]
{\rm d} \theta {\rm d} \phi.
\label{pfhoney}\end{aligned}$$ In what follows, the precise mapping relationship (\[mr\]) between the partition functions will be used as a starting point for performing a rather comprehensive analysis of the critical behavior, the order parameter, and basic thermodynamic quantities.
Critical condition
------------------
In order to locate a critical point of the investigated spin-electron system, one may take advantage of the fact that the partition function always becomes non-analytic at a critical point. It can be easily understood from Eqs. (\[mp\])–(\[mr\]) that the mapping parameter $A$ cannot cause a non-analytic behavior of the partition function ${\cal Z}$ and thus, the investigated spin-electron system becomes critical if and only if the corresponding spin-1/2 Ising model with the effective coupling $\beta R$ becomes critical as well. Accordingly, the critical points of the investigated spin-electron system can be straightforwardly obtained from a comparison of the effective temperature-dependent coupling $\beta R$ with the relevant critical point of the corresponding spin-1/2 Ising model on the undecorated lattice. However, the mathematical structure of the mapping parameter $R$ has another important consequences on a critical behavior. More specifically, one may easily prove from Eq. (\[fun\]) a general validity of the inequality $V_1<V_2$, which in compliance with the definition (\[mp\]) implies the antiferromagnetic nature of the effective interaction ($R<0$) in the spin-1/2 Ising model on the corresponding undecorated lattice. Owing to this fact, the interacting spin-electron system is always mapped on the spin-1/2 Ising model with the antiferromagnetic nearest-neighbor interaction, which has a non-zero critical temperature only on the 2D loose-packed lattices such as square [@onsa44] and honeycomb [@hout50; @temp50; @newe50; @husi50; @syoz50] lattices. As a matter of fact, it is well known dictum that the spin-1/2 Ising model with the antiferromagnetic nearest-neighbor interaction on close-packed lattices like triangular [@hout50; @syoz50; @wann50] and kagomé [@syoz51; @kano53] lattices does not exhibit a spontaneous long-range order at any finite temperature and consequently, it does not have any finite-temperature critical point that would correspond to the order-disorder transition.
Bearing all this in mind, we will consider hereafter only the interacting spin-electron system on the doubly decorated 2D loose-packed lattices. It is worthwhile to remark that the critical temperature of the antiferromagnetic spin-1/2 Ising model on the loose-packed lattices is equal to the one of the ferromagnetic model and hence, the critical points for the spin-electron system on the doubly decorated square and honeycomb lattices readily follow from the conditions $\beta_{\rm c} |R| = 2 \ln (1 + \sqrt{2})$[@onsa44] and, respectively, $\beta_{\rm c} |R| = 2 \ln(2 + \sqrt{3})$,[@hout50] where $\beta_{\rm c} = 1/(k_{\rm B} T_{\rm c})$ and $T_{\rm c}$ is the critical temperature.
Staggered magnetization
-----------------------
As a direct consequence of the mapping equivalence with the antiferromagnetic spin-1/2 Ising model on the relevant undecorated loose-packed lattice, one should anticipate predominantly antiferromagnetic character of the interacting spin-electron system on the doubly decorated 2D loose-packed lattice as well. Let us therefore calculate the staggered magnetization as the most common order parameter inherent to the antiferromagnetic spin alignment. Using the exact mapping theorems developed by Barry *et al*.,[@barr88; @khat90; @barr91; @barr95] the spontaneous staggered magnetization of the localized Ising spins can easily be calculated from the exact spin identity $$\begin{aligned}
m_i \equiv \frac{1}{2} \langle \hat{\sigma}_{k1}^z - \hat{\sigma}_{k2}^z \rangle_{t,J}
= \frac{1}{2} \langle \hat{\sigma}_{k1}^z - \hat{\sigma}_{k2}^z \rangle_{R}
\equiv m_{\rm IM} (\beta R),
\label{mi} \end{aligned}$$ where the symbols $\langle \ldots \rangle_{t,J}$ and $\langle \ldots \rangle_{R}$ denote standard canonical ensemble average performed within the interacting spin-electron model on the doubly decorated 2D lattice and, respectively, its equivalent spin-1/2 Ising model on the corresponding undecorated 2D lattice.[@acom] The exact spin identity (\[mi\]) furnishes an accurate proof that the staggered magnetization of the Ising sublattice in the interacting spin-electron model on the doubly decorated 2D lattice directly equals the staggered magnetization of the spin-1/2 Ising model on the corresponding undecorated 2D lattice with the antiferromagnetic nearest-neighbor interaction $R<0$. However, the spontaneous staggered magnetization of the antiferromagnetic spin-1/2 Ising model on the loose-packed 2D lattices precisely coincides with the spontaneous magnetization of the ferromagnetic model, i.e. the quantity, which has exactly been determined for several 2D Ising models (see Ref. and references cited therein). In this regard, the staggered magnetization of the antiferromagnetic spin-1/2 Ising model on the square [@yang52] and honeycomb [@naya54] lattices for instance read $$\begin{aligned}
m_{\rm IM} \! \! \! &=& \! \! \! \frac{1}{2} \left[ 1 - \frac{16 x^4}{(1-x^2)^4} \right]^{1/8}
\! \! \! \! \! \!,
\qquad {\rm (square)} \label{m0} \\
m_{\rm IM} \! \! \! &=& \! \! \!
\frac{1}{2} \left[ 1 - \frac{16 x^3 (1 + x^3)}{(1-x)^3(1-x^2)^3} \right]^{1/8}\! \! \! \! \! \!,
\qquad {\rm (honeycomb)} \nonumber \end{aligned}$$ where $x = \exp(- \beta R/2)$. The above formulas complete our calculation of the staggered magnetization of the localized Ising spins when substituting the exact expression (\[m0\]) with the appropriately chosen effective coupling (\[mp\])–(\[fun\]) into the exact spin identity (\[mi\]).
On the other hand, the staggered magnetization of the itinerant electrons delocalized over pairs of decorating sites can be calculated with the aid of the generalized Callen-Suzuki identity [@call63; @suzu65; @saba81; @saba85; @balc02] $$\begin{aligned}
\langle f (c^{\dagger}_{k \alpha, \gamma}, c^{}_{k \alpha, \gamma}) \rangle_{t,J}
\! = \left \langle
\frac{\mbox{Tr}_k f (c^{\dagger}_{k \alpha, \gamma}, c^{}_{k \alpha, \gamma})
\exp(- \beta \hat{\cal H}_k)}{\mbox{Tr}_k \exp(- \beta \hat{\cal H}_k)}
\right \rangle_{\! \! t,J}\! \! \! \! \! \!, \nonumber \\
\label{csi}\end{aligned}$$ where $\alpha=1,2$, $\gamma = \uparrow,\downarrow$, and $f$ is in principle an arbitrary function of the creation and annihilation fermionic operators from the $k$th bond Hamiltonian (\[ham\]). With the help of the exact identity (\[csi\]), the spontaneous staggered magnetization of the itinerant electrons can be calculated from the expression $$\begin{aligned}
m_e = \frac{1}{2} \langle (\hat{S}_{k1}^z - \hat{S}_{k2}^z) \rangle_{t,J}
\! = \left \langle \frac{1}{4 \beta {\cal Z}_k} \left( \frac{\partial {\cal Z}_k}{\partial h_{k1}} -
\frac{\partial {\cal Z}_k}{\partial h_{k2}} \right)
\right \rangle_{t,J}\! \! \! \! \! \!, \nonumber \\
\label{me}\end{aligned}$$ where $\hat{S}_{k \alpha}^z = (c^{\dagger}_{k \alpha, \uparrow} c^{}_{k \alpha, \uparrow} - c^{\dagger}_{k \alpha, \downarrow} c^{}_{k \alpha, \downarrow})/2$ marks the $z$th component of the spin operator of the mobile electron. After a straightforward calculation based on the differential operator technique $\exp(a \partial/\partial x + b \partial/\partial y) g(x,y) = g(x+a, y+b)$ [@honm79; @kane93] and the exact van der Waerden identity $\exp(c \sigma^z)
= \cosh(c/2) + 2 \sigma^z \sinh(c/2)$, the staggered magnetization of the itinerant electrons can be related to the staggered magnetization of the localized Ising spins through the precise formula $$\begin{aligned}
m_e = m_i \frac{J}{\sqrt{J^2 + (4t)^2}}
\frac{\sinh \left[\frac{\beta}{2} \sqrt{J^2 + (4t)^2} \right]}
{2 + \cosh \left[\frac{\beta}{2} \sqrt{J^2 + (4t)^2} \right]}.
\label{mag}\end{aligned}$$ Since the exact expression for the staggered magnetization of the localized Ising spins is already known from Eqs. (\[mi\])–(\[m0\]), the formula (\[mag\]) provides the relevant exact result for the staggered magnetization of the itinerant electrons hopping between the decorating sites.
Thermodynamics
--------------
Before concluding this section, it is worthy of notice that several basic thermodynamic quantities can also be easily derived from the exact mapping equivalence (\[mr\]) between the partition functions ${\cal Z}$ and ${\cal Z}_{\rm IM}$. For instance, the Helmholtz free energy $F$, the internal energy $U$, the entropy $S$, and the specific heat $C$, can directly be computed from the basic relations of thermodynamics and statistical physics such as $$\begin{aligned}
F = - k_{\rm B} T \ln {\cal Z}, \, \, \, U = - \frac{\partial \ln {\cal Z}}{\partial \beta}, \, \, \,
S = - \frac{\partial F}{\partial T}, \,\, \, C = \frac{\partial U}{\partial T}. \nonumber
\label{tsp}\end{aligned}$$
\[sec:result\] Results and discussion
=====================================
Now, let us proceed to a discussion of the most interesting results obtained for the interacting spin-electron system on the doubly decorated 2D lattices. Before doing this, however, the relations (\[mp\])–(\[fun\]) might serve in evidence that the effective nearest-neighbor interaction $R$ of the spin-1/2 Ising model on the corresponding undecorated lattice is invariant under the transformation $J \to -J$. A change of the ferromagnetic Ising interaction $J>0$ to the antiferromagnetic one $J<0$ actually causes only a rather trivial change of the mutual spin orientation of the itinerant electrons and their nearest Ising neighbors. This observation would suggest that the critical temperature as well as other thermodynamic quantities remain unchanged under the sign change $J \to -J$ and thus, one may further consider the ferromagnetic interaction $J>0$ without loss of the generality.
Ground state
------------
First, let us take a closer look at the ground-state behavior. It is quite evident that the ground state will correspond to the lowest-energy eigenvalue of the bond Hamiltonian (\[ham\]), which can be obtained from the eigenenergies (\[eigen\]) by considering four available configurations of the Ising spins $\sigma_{k1}$ and $\sigma_{k2}$ explicitly involved therein. It turns out that the lowest-energy eigenstate constitutes a peculiar four-sublattice quantum antiferromagnet, which can be characterized through the eigenvector $$\begin{aligned}
|{\rm AF} \rangle = \displaystyle \prod_{k=1}^{Nq/2} \! \! \! \! \! \! && \! \! \! \! \! \!
|\!\! \uparrow, \downarrow \rangle_{\sigma_{k1}, \sigma_{k2}} \Biggl[ \frac{1}{2} \left(1 + \frac{J}{\sqrt{J^2 + (4t)^2}} \right) c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \downarrow}
\nonumber \\
\! \! \! &-& \! \! \! \frac{1}{2} \left(1 - \frac{J}{\sqrt{J^2 + (4t)^2}} \right)
c^{\dagger}_{k1, \downarrow} c^{\dagger}_{k2, \uparrow} \label{gs} \\
\! \! \! &+& \! \! \! \frac{2t}{\sqrt{J^2 + (4t)^2}} \left(c^{\dagger}_{k1, \uparrow}
c^{\dagger}_{k1, \downarrow} + c^{\dagger}_{k2, \uparrow} c^{\dagger}_{k2, \downarrow}
\right) \Biggr] | 0 \rangle,
\nonumber\end{aligned}$$ where the product runs over all bonds of the doubly decorated 2D lattice, the former ket vector determines spin states of the localized Ising spins, and the latter one spin states of mobile electrons. Interestingly, one may also find a much simpler goniometric representation of the lowest-energy eigenstate $|{\rm AF} \rangle$ by introducing the mixing angle $\phi$ through the definition $\tan 2 \phi = 4t/J$, which yields for the particular case with $J>0$ [@note] $$\begin{aligned}
|{\rm AF} \rangle \! \! \! &=& \! \! \! \displaystyle \prod_{k=1}^{Nq/2}
|\!\! \uparrow, \downarrow \rangle_{\sigma_{k1}, \sigma_{k2}}
\Bigl[ \cos^2 \! \phi \, c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \downarrow} -
\sin^2 \! \phi \, c^{\dagger}_{k1, \downarrow} c^{\dagger}_{k2, \uparrow} \nonumber \\
\! \! \! &+& \! \! \! \sin \phi \cos \phi \left( c^{\dagger}_{k1, \uparrow}
c^{\dagger}_{k1, \downarrow} + c^{\dagger}_{k2, \uparrow} c^{\dagger}_{k2, \downarrow} \right)
\Bigr] |0 \rangle.
\label{gsg} \end{aligned}$$ Altogether, the four-sublattice quantum antiferromagnet $|{\rm AF} \rangle$ can be characterized by a perfect Néel order of the Ising spins situated at the nodal sites of some loose-packed 2D lattice, while the mobile electrons delocalized over its decorating sites rest in the entangled state composed of two intrinsic antiferromagnetic states $c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \downarrow} |0 \rangle$, $c^{\dagger}_{k1, \downarrow} c^{\dagger}_{k2, \uparrow} |0 \rangle$, and, two non-magnetic ionic states $c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k1, \downarrow} |0 \rangle$, $c^{\dagger}_{k2, \uparrow} c^{\dagger}_{k2, \downarrow} |0 \rangle$. The quantum entanglement of those four microstates arises from a virtual hopping process of the itinerant electrons, which is diagrammatically illustrated in Fig. \[fig2\]. The respective probability distribution of the four entangled microstates is displayed in Fig. \[fig3\] as a function of a relative strength of the hopping term.
![\[fig3\]The probability distribution for the four entangled microstates as a function of the ratio between the hopping term $t$ and the Ising exchange constant $J$.](fig2.eps){width="8cm"}
![\[fig3\]The probability distribution for the four entangled microstates as a function of the ratio between the hopping term $t$ and the Ising exchange constant $J$.](fig3.eps){width="8cm"}
Let us make a few comments on an origin of the remarkable four-sublattice quantum antiferromagnet emerging in $|{\rm AF} \rangle$. The hopping process of both itinerant electrons energetically favors their antiparallel spin alignment and this antiferromagnetic correlation is subsequently mediated through the Ising-type exchange interaction $J$ also on their two nearest-neighbor Ising spins (hence, the antiferromagnetic character of the effective interaction $R<0$ between the Ising spins). If a relative strength of the hopping term is sufficiently weak, the Ising spins prefer the ferromagnetic alignment with respect to their nearest-neighbor mobile electrons as it can be clearly seen from the occurrence probability of the majority microstate $c^{\dagger}_{k1, \uparrow} c^{\dagger}_{k2, \downarrow} |0 \rangle$ that converges to $p_{\uparrow,\downarrow} \to 1$ in the limit $t/J \to 0$. It is nevertheless worth mentioning that the occurrence probabilities of three minority microstates monotonically increase upon strengthening the hopping term at the expense of the occurrence probability of the majority microstate until they asymptotically reach the same value $p_{\uparrow,\downarrow} = p_{\downarrow,\uparrow} = p_{\uparrow \downarrow, 0} = p_{\downarrow \uparrow, 0} \to 1/4$ in the limit $t/J \to \infty$.
Finite-temperature phase diagram
--------------------------------
Next, let us examine critical phenomena associated with finite-temperature phase transitions of the spontaneously long-range ordered phase $|{\rm AF} \rangle$. It is worthwhile to recall that the critical temperature can easily be obtained by solving numerically the critical conditions derived in the foregoing section. The finite-temperature phase diagram in the form of the critical temperature versus the kinetic term dependence is shown in Fig. \[fig4\] for the interacting spin-electron system on doubly decorated square and honeycomb lattices. It is quite obvious from this figure that the interacting spin-electron system on any loose-packed doubly decorated 2D lattice exhibits the same general trends in the relevant dependences of the critical temperature. The critical temperature initially exhibits a relatively rapid increase from zero temperature with increasing the ratio between the hopping term $t$ and the exchange constant $J$
![The dimensionless critical temperature as a function of the relative strength of the hopping term for the interacting spin-electron system on the doubly decorated square and honeycomb lattices.[]{data-label="fig4"}](fig4.eps){width="8cm"}
until it achieves its maximum value. The critical temperature then gradually decreases upon further increase of a relative strength of the kinetic energy before it again tends to zero temperature in the other particular limit $t/J \to \infty$. In the limit $t/J \to 0$, the observed zero critical temperature can be attributed to a localization of the itinerant electrons at particular decorating sites. In fact, there does not exist any other interaction between the itinerant electrons within the tight-binding model described by the Hamiltonian (\[ham\]) except the effective interaction originating from their virtual hopping process. If the hopping process of the itinerant electrons is ignored, the interacting spin-electron system then effectively splits into independent fragments each of them having one central Ising spin coupled to the $q$ localized electrons from its nearest-neighbor decorating sites. In the other particular limit $t/J \to \infty$, the zero critical temperature results from the same probabilities of the four entangled microstates of $|{\rm AF} \rangle$ as it has been already discussed by the ground-state analysis. Owing to this fact, the decorating sites occupied by the mobile electrons have non-magnetic character, which is compatible with a disappearance of the effective interaction $R=0$ between the localized Ising spins that occurs in the particular limit $t/J \to \infty$.
Order parameter
---------------
Temperature variations of both sublattice staggered magnetizations $m_i$ and $m_e$ are depicted in Fig. \[fig5\] for three different values of a relative strength of the kinetic energy. The most obvious difference between the sublattice staggered magnetizations $m_i$ and $m_e$ pertinent to the Ising spins and itinerant electrons, respectively, lies in the quantum reduction of the latter staggered magnetization. The greater a relative strength of the hopping term is, the greater quantum reduction of the staggered magnetization $m_e$ can be observed in Fig. \[fig5\] in concordance with the relevant ground-state prediction of the lowest-energy eigenstate (\[gs\]), as well as, the zero-temperature limit of the expression (\[mag\]) both yielding $$\begin{aligned}
m_e (T=0) = \frac{1}{2} \frac{J}{\sqrt{J^2 + (4t)^2}}.
\label{maggs}\end{aligned}$$ On the other hand, the sublattice staggered magnetization $m_i$ pertinent to the Ising spins always starts from its maximum possible value that implies a perfect Néel long-range order of the localized Ising spins. For completeness, it is also worthy of notice that both sublattice staggered magnetizations tend to zero in a vicinity of the critical temperature with the critical exponent $\beta = 1/8$ from the standard Ising universality class.
![Thermal dependences of both sublattice staggered magnetizations for the interacting spin-electron system on the doubly decorated square lattice at three different values of a relative strength of the hopping term $t/J = 0.2$, $0.4$, and $1.0$.[]{data-label="fig5"}](fig5.eps){width="8cm"}
Specific heat
-------------
Finally, thermal dependences of the specific heat are plotted in Fig. \[fig6\] for the interacting spin-electron system on the doubly decorated square lattice at three different relative strengths of the kinetic term $t/J = 0.1$, $0.25$, and $0.5$. It is quite evident that the investigated model system exhibits the familiar logarithmic singularity at critical temperature of the order-disorder transition, which provides another independent confirmation of the critical behavior from the standard Ising universality class.
![Temperature variations of the specific heat for the interacting spin-electron system on the doubly decorated square lattice at three different values of a relative strength of the hopping term $t/J = 0.1$, $0.25$, and $0.5$.[]{data-label="fig6"}](fig6.eps){width="8cm"}
In addition to the logarithmic divergence observed in a close vicinity of the critical point, the specific heat also displays a round Schottky-type maximum in the high-temperature tail of the specific heat curve. This maximum is well separated from the logarithmic singularity at relatively weak hopping terms (see solid line for $t/J = 0.1$), while it becomes superimposed on a logarithmic divergence at moderate strengths of the kinetic term (see dotted line for $t/J = 0.25$). Last but not least, the round high-temperature maximum again separates from the logarithmic singularity upon further increase of a relative strength of the hopping term. The round maximum then shifts towards higher temperatures and it becomes the broader, the stronger a relative strength of the kinetic term is (see dashed line for $t/J = 0.5$).
\[sec:conc\]Concluding remarks
==============================
In this article, the hybrid lattice-statistical model of the interacting spin-electron system on doubly decorated 2D lattices has exactly been solved by the use of generalized decoration-iteration transformation under the constraint of a half-filling of each couple of the decorating sites. It has been shown that the ground state of the investigated model system defined on any doubly decorated loose-packed 2D lattice represents an interesting four-sublattice quantum antiferromagnetic phase. It is worth noticing, moreover, that this four-sublattice quantum antiferromagnet exhibits a remarkable combination of the spontaneous long-range order manifested through a non-trivial criticality at non-zero temperatures with obvious macroscopic features of quantum origin such as the quantum reduction of the staggered magnetization pertinent to the itinerant electrons. To the best of our knowledge, the model under investigation thus represents a rather rare example of the exactly solved model with such an intriguing combination of otherwise hardly compatible properties. To compare with, the interacting spin-electron system at a quarter filling (i.e. with one mobile electron per each couple of decorating sites) merely exhibits a classical ferromagnetic or ferrimagnetic spontaneous long-range order depending on whether the ferromagnetic or antiferromagnetic interaction between the localized Ising spins and itinerant electrons is assumed.[@icm] This would indicate that an existence of the four-sublattice quantum antiferromagnetic phase is closely related to a collective motion of electrons even if there does not exist any direct interaction between mobile electrons within our tight-binding model.
Besides the purely academic interest in searching exactly solvable quantum spin models, the considered model system has also been suggested in order to bring insight into a magnetism of hybrid systems consisting of both localized spins as well as mobile electrons. Among the most famous magnetic materials, which obey this specific requirement, one could mention the magnetic metal SrCo$_6$O$_{11}$ [@ishi05; @muku06; @ishi07a; @ishi07b] or the series of polymeric coordination compounds \[Ru$_2$(OOC$t$Bu)$_4$\]$_3$\[M(CN)$_6$\] (M = Fe[@yosh02; @miku06; @vos05], Cr[@vos05; @mill05]). In the latter family of magnetic materials, one and three unpaired electrons of the trivalent metal ions such as Fe$^{3+}$ ($S = 1/2$) and Cr$^{3+}$ ($S = 3/2$) are localized at the corners of a simple square lattice, whereas three unpaired electrons are delocalized over the mixed-valent dimeric unit Ru$_2^{5+}$ residing each bond of the square lattice.[@norm79] In this respect, the magnetic structure of this series of coordination compounds closely resembles the one of the suggested model system even if the electronic structure of the mixed-valent dimeric unit Ru$_2^{5+}$ would surely require more complex Hamiltonian in order to describe the double-exchange mechanism in the mixed-valent Ru$_2^{5+}$ dimeric unit. In this direction will continue our further work.
This work was supported by the Slovak Research and Development Agency under the contract LPP-0107-06. The financial support provided under the grants VEGA 1/2009/05 and VVGS 2/09-10 is also gratefully acknowledged.
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R. Honmura and T. Kaneyoshi, J. Phys. C: Solid St. Phys. [**12**]{}, 3979 (1979).
T. Kaneyoshi, Acta Phys. Pol. A [**83**]{}, 703 (1993).
The relevant eigenstate for the other particular case $J<0$ can be obtained from the eigenvector (\[gsg\]) under the reversal of all Ising spins $\sigma_{k}^z \to - \sigma_{k}^z$.
J. Strečka, A. Tanaka, M. Jaščur, presented at International Conference on Magnetism, to be held on July 27 – 31, 2009, in Karlsruhe, Germany. Submitted to J. Phys.: Conf. Ser., preprint arxiv: 0908.2880.
S. Ishiwata, D. Wang, T. Saito, and M. Takano, Chem. Mater. **17**, 2789 (2005).
H. Mukuda, Y. Kitaoka, S. Ishiwata, T. Saito, Y. Shimakawa, H. Harima, and M. Takano, J. Phys. Soc. Jpn. **75**, 094715 (2006).
S. Ishiwata, I. Terasaki, F. Ishii, N. Nagaosa, H. Mukuda, Y. Kitaoka, T. Saito, and M. Takano, Phys. Rev. Lett. **98**, 217201 (2007).
S. Ishiwata, M. Lee, Y. Onose, N.P. Ong, M. Takano, and I. Terasaki, J. Magn. Magn. Mater. **310**, 1989 (2007).
D. Yoshioka, M. Mikuriya, and M. Handa, Chem. Lett., 1044 (2002).
M. Mikuriya, D. Yoshioka, and M. Handa, Coord. Chem. Rev. **250**, 2194 (2006).
T.E. Vos and J.S. Miller, Angew. Chem. Int. Ed. **44**, 2416 (2005).
J.S. Miller, T.E. Vos, and W.W. Shum, Adv. Mater. **17**, 2251 (2005).
J.G. Norman, G.E. Renzoni, and D.A. Case, J. Am. Chem. Soc. **101**, 5256 (1979).
| {
"pile_set_name": "ArXiv"
} |
MarQueis Gray pumped his fists as he sprinted toward the sideline and shouted, "Yeah, baby!"
Tight end Drew Goodger was the reason for the excitement. The 6-foot-5, 255-pound sophomore got a bear hug and helmet slap from his senior quarterback after turning a dump pass from Gray into a 20-yard gain by hurdling safety Derrick Wells.
"I was shocked," Gray said after the University of Minnesota's first fall scrimmage Friday, Aug. 10, at TCF Bank Stadium. "We need more plays like that."
Last season, Gray rarely had the patience to wait for pass plays like that to develop. If his initial read wasn't open, he tended to tuck the ball and run. Now one of the Big Ten's most productive running quarterbacks is showing a more versatile passing game as well.
Gray, who led two touchdown drives Friday, has a better understanding of how to read defenses. He built chemistry and confidence with his receivers and tight ends during summer workouts. He also knows the offensive line is more experienced and able to give him more time to throw.
"When you're more comfortable, you can do things that you're supposed to do," Gophers offensive coordinator Matt Limegrover said. "I think that's at the point he's at. He feels more comfortable with the people around him. They're protecting him better. I think he's feeling like, 'Hey, I can get set; I can make the throws I need to make.' (If you have that,) you're always going to look better, feel better and be more comfortable and more accurate.
Advertisement
"
The scouting report on Gray last season was that he could become mistake-prone if forced to rely on his passing, which was a work in progress. Gray broke the school's rushing record for a quarterback with 966 yards, but he ranked last in the Big Ten in completion percentage (.507) and passing efficiency (114.5), while throwing for 1,495 yards and eight touchdowns, with eight interceptions.
The Gophers expect those numbers to be much improved this season, based on Gray's performance in fall camp.
"(It's) knowing where to go with the ball instead of just pulling it down and taking off running," Gray said. "That's the job of my QB coach. He made me stay in there and watch film with him, getting in those extra reps. That's the main reason why I haven't been turning the ball over in this camp so far."
The Gophers said Gray's unofficial statistics from Friday's scrimmage were 8 completions in 11 attempts for 135 yards.
A year ago in fall camp, Gray threw multiple interceptions daily and hadn't completely distanced himself from freshman Max Shortell for the starting job. Shortell had a better pocket presence than Gray, even as a true freshman, but he is clearly the backup now.
Shortell, a 6-6 sophomore, hasn't been as sharp as Gray through eight practices, but he still has an edge over freshmen Philip Nelson and Mitch Leidner for the No. 2 spot.
Leidner impressed coaches enough to open fall camp challenging Nelson for second-team snaps before the scrimmage. Nelson had an interception and fumble Friday, but he also threw two touchdown passes, including a 66-yarder to Isaac Fruechte.
Limegrover said Nelson and Leidner are "still works in progress" because they've been overwhelmed by having to learn so much so quickly. Offensively and defensively, the Gophers already have installed everything they plan to use in the Aug. 30 season opener at Nevada-Las Vegas.
"Max has just been through this all a little bit more," Limegrover said. "If Max slows down and he doesn't keep competing, they'll catch him. But if he keeps getting better as well, he's going to keep them at an arm's length." | {
"pile_set_name": "Pile-CC"
} |
Q:
Boost factor in MultiFieldQueryParser
Can I boost different fields in MultiFieldQueryParser with different factors?
Also, what is the maximum boost factor value I can assign to a field?
Thanks a ton!
Ed
A:
MultiFieldQueryParser has a [constructor][1] that accepts a map of boosts. You use it with something like this:
String[] fields = new String[] { "title", "keywords", "text" };
HashMap<String,Float> boosts = new HashMap<String,Float>();
boosts.put("title", 10);
boosts.put("keywords", 5);
MultiFieldQueryParser queryParser = new MultiFieldQueryParser(
fields,
new StandardAnalyzer(),
boosts
);
As for the maximum boost, I'm not sure, but you shouldn't think about boost in absolute terms anyway. Just use a ratio of boosts that makes sense. Also see this question.
[1]: https://lucene.apache.org/core/4_4_0/queryparser/org/apache/lucene/queryparser/classic/MultiFieldQueryParser.html#MultiFieldQueryParser(org.apache.lucene.util.Version, java.lang.String[], org.apache.lucene.analysis.Analyzer, java.util.Map)
| {
"pile_set_name": "StackExchange"
} |
---
name: Question
about: How do I... I need help with...
title: "[HELP]"
labels: ''
assignees: ''
---
**PLEASE DO NOT ASK USAGE QUESTIONS USING GITHUB "ISSUES"**
If you are pretty sure that you have identified a **BUG** in OpenImageIO,
please file a [bug report issue](https://github.com/OpenImageIO/oiio/issues/new?template=bug_report.md).
But if you are just asking a question:
* How do I...?
* I need help with...
* Am I doing something wrong?
* I can't build OpenImageIO
For anything of this nature, the best way to get help using OpenImageIO is
to ask a question on the [oiio-dev developer mail list](http://lists.openimageio.org/listinfo.cgi/oiio-dev-openimageio.org).
The [documentation](https://openimageio.readthedocs.org)
is pretty comprehensive, so please check there first; you may find the answer
more quickly than you can get your question answered on the mail list.
| {
"pile_set_name": "Github"
} |
//
// impl/write_at.hpp
// ~~~~~~~~~~~~~~~~~
//
// Copyright (c) 2003-2014 Christopher M. Kohlhoff (chris at kohlhoff dot com)
//
// Distributed under the Boost Software License, Version 1.0. (See accompanying
// file LICENSE_1_0.txt or copy at http://www.boost.org/LICENSE_1_0.txt)
//
#ifndef BOOST_ASIO_IMPL_WRITE_AT_HPP
#define BOOST_ASIO_IMPL_WRITE_AT_HPP
#if defined(_MSC_VER) && (_MSC_VER >= 1200)
# pragma once
#endif // defined(_MSC_VER) && (_MSC_VER >= 1200)
#include <boost/asio/buffer.hpp>
#include <boost/asio/completion_condition.hpp>
#include <boost/asio/detail/array_fwd.hpp>
#include <boost/asio/detail/base_from_completion_cond.hpp>
#include <boost/asio/detail/bind_handler.hpp>
#include <boost/asio/detail/consuming_buffers.hpp>
#include <boost/asio/detail/dependent_type.hpp>
#include <boost/asio/detail/handler_alloc_helpers.hpp>
#include <boost/asio/detail/handler_cont_helpers.hpp>
#include <boost/asio/detail/handler_invoke_helpers.hpp>
#include <boost/asio/detail/handler_type_requirements.hpp>
#include <boost/asio/detail/throw_error.hpp>
#include <boost/asio/detail/push_options.hpp>
namespace boost {
namespace asio {
template <typename SyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition>
std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
CompletionCondition completion_condition, boost::system::error_code& ec)
{
ec = boost::system::error_code();
boost::asio::detail::consuming_buffers<
const_buffer, ConstBufferSequence> tmp(buffers);
std::size_t total_transferred = 0;
tmp.prepare(detail::adapt_completion_condition_result(
completion_condition(ec, total_transferred)));
while (tmp.begin() != tmp.end())
{
std::size_t bytes_transferred = d.write_some_at(
offset + total_transferred, tmp, ec);
tmp.consume(bytes_transferred);
total_transferred += bytes_transferred;
tmp.prepare(detail::adapt_completion_condition_result(
completion_condition(ec, total_transferred)));
}
return total_transferred;
}
template <typename SyncRandomAccessWriteDevice, typename ConstBufferSequence>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers)
{
boost::system::error_code ec;
std::size_t bytes_transferred = write_at(
d, offset, buffers, transfer_all(), ec);
boost::asio::detail::throw_error(ec, "write_at");
return bytes_transferred;
}
template <typename SyncRandomAccessWriteDevice, typename ConstBufferSequence>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
boost::system::error_code& ec)
{
return write_at(d, offset, buffers, transfer_all(), ec);
}
template <typename SyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
CompletionCondition completion_condition)
{
boost::system::error_code ec;
std::size_t bytes_transferred = write_at(
d, offset, buffers, completion_condition, ec);
boost::asio::detail::throw_error(ec, "write_at");
return bytes_transferred;
}
#if !defined(BOOST_ASIO_NO_IOSTREAM)
template <typename SyncRandomAccessWriteDevice, typename Allocator,
typename CompletionCondition>
std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b,
CompletionCondition completion_condition, boost::system::error_code& ec)
{
std::size_t bytes_transferred = write_at(
d, offset, b.data(), completion_condition, ec);
b.consume(bytes_transferred);
return bytes_transferred;
}
template <typename SyncRandomAccessWriteDevice, typename Allocator>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b)
{
boost::system::error_code ec;
std::size_t bytes_transferred = write_at(d, offset, b, transfer_all(), ec);
boost::asio::detail::throw_error(ec, "write_at");
return bytes_transferred;
}
template <typename SyncRandomAccessWriteDevice, typename Allocator>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b,
boost::system::error_code& ec)
{
return write_at(d, offset, b, transfer_all(), ec);
}
template <typename SyncRandomAccessWriteDevice, typename Allocator,
typename CompletionCondition>
inline std::size_t write_at(SyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b,
CompletionCondition completion_condition)
{
boost::system::error_code ec;
std::size_t bytes_transferred = write_at(
d, offset, b, completion_condition, ec);
boost::asio::detail::throw_error(ec, "write_at");
return bytes_transferred;
}
#endif // !defined(BOOST_ASIO_NO_IOSTREAM)
namespace detail
{
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
class write_at_op
: detail::base_from_completion_cond<CompletionCondition>
{
public:
write_at_op(AsyncRandomAccessWriteDevice& device,
uint64_t offset, const ConstBufferSequence& buffers,
CompletionCondition completion_condition, WriteHandler& handler)
: detail::base_from_completion_cond<
CompletionCondition>(completion_condition),
device_(device),
offset_(offset),
buffers_(buffers),
start_(0),
total_transferred_(0),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_op(const write_at_op& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(other.handler_)
{
}
write_at_op(write_at_op&& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
std::size_t bytes_transferred, int start = 0)
{
switch (start_ = start)
{
case 1:
buffers_.prepare(this->check_for_completion(ec, total_transferred_));
for (;;)
{
device_.async_write_some_at(
offset_ + total_transferred_, buffers_,
BOOST_ASIO_MOVE_CAST(write_at_op)(*this));
return; default:
total_transferred_ += bytes_transferred;
buffers_.consume(bytes_transferred);
buffers_.prepare(this->check_for_completion(ec, total_transferred_));
if ((!ec && bytes_transferred == 0)
|| buffers_.begin() == buffers_.end())
break;
}
handler_(ec, static_cast<const std::size_t&>(total_transferred_));
}
}
//private:
AsyncRandomAccessWriteDevice& device_;
uint64_t offset_;
boost::asio::detail::consuming_buffers<
const_buffer, ConstBufferSequence> buffers_;
int start_;
std::size_t total_transferred_;
WriteHandler handler_;
};
template <typename AsyncRandomAccessWriteDevice,
typename CompletionCondition, typename WriteHandler>
class write_at_op<AsyncRandomAccessWriteDevice,
boost::asio::mutable_buffers_1, CompletionCondition, WriteHandler>
: detail::base_from_completion_cond<CompletionCondition>
{
public:
write_at_op(AsyncRandomAccessWriteDevice& device,
uint64_t offset, const boost::asio::mutable_buffers_1& buffers,
CompletionCondition completion_condition,
WriteHandler& handler)
: detail::base_from_completion_cond<
CompletionCondition>(completion_condition),
device_(device),
offset_(offset),
buffer_(buffers),
start_(0),
total_transferred_(0),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_op(const write_at_op& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffer_(other.buffer_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(other.handler_)
{
}
write_at_op(write_at_op&& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffer_(other.buffer_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
std::size_t bytes_transferred, int start = 0)
{
std::size_t n = 0;
switch (start_ = start)
{
case 1:
n = this->check_for_completion(ec, total_transferred_);
for (;;)
{
device_.async_write_some_at(offset_ + total_transferred_,
boost::asio::buffer(buffer_ + total_transferred_, n),
BOOST_ASIO_MOVE_CAST(write_at_op)(*this));
return; default:
total_transferred_ += bytes_transferred;
if ((!ec && bytes_transferred == 0)
|| (n = this->check_for_completion(ec, total_transferred_)) == 0
|| total_transferred_ == boost::asio::buffer_size(buffer_))
break;
}
handler_(ec, static_cast<const std::size_t&>(total_transferred_));
}
}
//private:
AsyncRandomAccessWriteDevice& device_;
uint64_t offset_;
boost::asio::mutable_buffer buffer_;
int start_;
std::size_t total_transferred_;
WriteHandler handler_;
};
template <typename AsyncRandomAccessWriteDevice,
typename CompletionCondition, typename WriteHandler>
class write_at_op<AsyncRandomAccessWriteDevice, boost::asio::const_buffers_1,
CompletionCondition, WriteHandler>
: detail::base_from_completion_cond<CompletionCondition>
{
public:
write_at_op(AsyncRandomAccessWriteDevice& device,
uint64_t offset, const boost::asio::const_buffers_1& buffers,
CompletionCondition completion_condition,
WriteHandler& handler)
: detail::base_from_completion_cond<
CompletionCondition>(completion_condition),
device_(device),
offset_(offset),
buffer_(buffers),
start_(0),
total_transferred_(0),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_op(const write_at_op& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffer_(other.buffer_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(other.handler_)
{
}
write_at_op(write_at_op&& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffer_(other.buffer_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
std::size_t bytes_transferred, int start = 0)
{
std::size_t n = 0;
switch (start_ = start)
{
case 1:
n = this->check_for_completion(ec, total_transferred_);
for (;;)
{
device_.async_write_some_at(offset_ + total_transferred_,
boost::asio::buffer(buffer_ + total_transferred_, n),
BOOST_ASIO_MOVE_CAST(write_at_op)(*this));
return; default:
total_transferred_ += bytes_transferred;
if ((!ec && bytes_transferred == 0)
|| (n = this->check_for_completion(ec, total_transferred_)) == 0
|| total_transferred_ == boost::asio::buffer_size(buffer_))
break;
}
handler_(ec, static_cast<const std::size_t&>(total_transferred_));
}
}
//private:
AsyncRandomAccessWriteDevice& device_;
uint64_t offset_;
boost::asio::const_buffer buffer_;
int start_;
std::size_t total_transferred_;
WriteHandler handler_;
};
template <typename AsyncRandomAccessWriteDevice, typename Elem,
typename CompletionCondition, typename WriteHandler>
class write_at_op<AsyncRandomAccessWriteDevice, boost::array<Elem, 2>,
CompletionCondition, WriteHandler>
: detail::base_from_completion_cond<CompletionCondition>
{
public:
write_at_op(AsyncRandomAccessWriteDevice& device,
uint64_t offset, const boost::array<Elem, 2>& buffers,
CompletionCondition completion_condition, WriteHandler& handler)
: detail::base_from_completion_cond<
CompletionCondition>(completion_condition),
device_(device),
offset_(offset),
buffers_(buffers),
start_(0),
total_transferred_(0),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_op(const write_at_op& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(other.handler_)
{
}
write_at_op(write_at_op&& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
std::size_t bytes_transferred, int start = 0)
{
typename boost::asio::detail::dependent_type<Elem,
boost::array<boost::asio::const_buffer, 2> >::type bufs = {{
boost::asio::const_buffer(buffers_[0]),
boost::asio::const_buffer(buffers_[1]) }};
std::size_t buffer_size0 = boost::asio::buffer_size(bufs[0]);
std::size_t buffer_size1 = boost::asio::buffer_size(bufs[1]);
std::size_t n = 0;
switch (start_ = start)
{
case 1:
n = this->check_for_completion(ec, total_transferred_);
for (;;)
{
bufs[0] = boost::asio::buffer(bufs[0] + total_transferred_, n);
bufs[1] = boost::asio::buffer(
bufs[1] + (total_transferred_ < buffer_size0
? 0 : total_transferred_ - buffer_size0),
n - boost::asio::buffer_size(bufs[0]));
device_.async_write_some_at(offset_ + total_transferred_,
bufs, BOOST_ASIO_MOVE_CAST(write_at_op)(*this));
return; default:
total_transferred_ += bytes_transferred;
if ((!ec && bytes_transferred == 0)
|| (n = this->check_for_completion(ec, total_transferred_)) == 0
|| total_transferred_ == buffer_size0 + buffer_size1)
break;
}
handler_(ec, static_cast<const std::size_t&>(total_transferred_));
}
}
//private:
AsyncRandomAccessWriteDevice& device_;
uint64_t offset_;
boost::array<Elem, 2> buffers_;
int start_;
std::size_t total_transferred_;
WriteHandler handler_;
};
#if defined(BOOST_ASIO_HAS_STD_ARRAY)
template <typename AsyncRandomAccessWriteDevice, typename Elem,
typename CompletionCondition, typename WriteHandler>
class write_at_op<AsyncRandomAccessWriteDevice, std::array<Elem, 2>,
CompletionCondition, WriteHandler>
: detail::base_from_completion_cond<CompletionCondition>
{
public:
write_at_op(AsyncRandomAccessWriteDevice& device,
uint64_t offset, const std::array<Elem, 2>& buffers,
CompletionCondition completion_condition, WriteHandler& handler)
: detail::base_from_completion_cond<
CompletionCondition>(completion_condition),
device_(device),
offset_(offset),
buffers_(buffers),
start_(0),
total_transferred_(0),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_op(const write_at_op& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(other.handler_)
{
}
write_at_op(write_at_op&& other)
: detail::base_from_completion_cond<CompletionCondition>(other),
device_(other.device_),
offset_(other.offset_),
buffers_(other.buffers_),
start_(other.start_),
total_transferred_(other.total_transferred_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
std::size_t bytes_transferred, int start = 0)
{
typename boost::asio::detail::dependent_type<Elem,
std::array<boost::asio::const_buffer, 2> >::type bufs = {{
boost::asio::const_buffer(buffers_[0]),
boost::asio::const_buffer(buffers_[1]) }};
std::size_t buffer_size0 = boost::asio::buffer_size(bufs[0]);
std::size_t buffer_size1 = boost::asio::buffer_size(bufs[1]);
std::size_t n = 0;
switch (start_ = start)
{
case 1:
n = this->check_for_completion(ec, total_transferred_);
for (;;)
{
bufs[0] = boost::asio::buffer(bufs[0] + total_transferred_, n);
bufs[1] = boost::asio::buffer(
bufs[1] + (total_transferred_ < buffer_size0
? 0 : total_transferred_ - buffer_size0),
n - boost::asio::buffer_size(bufs[0]));
device_.async_write_some_at(offset_ + total_transferred_,
bufs, BOOST_ASIO_MOVE_CAST(write_at_op)(*this));
return; default:
total_transferred_ += bytes_transferred;
if ((!ec && bytes_transferred == 0)
|| (n = this->check_for_completion(ec, total_transferred_)) == 0
|| total_transferred_ == buffer_size0 + buffer_size1)
break;
}
handler_(ec, static_cast<const std::size_t&>(total_transferred_));
}
}
//private:
AsyncRandomAccessWriteDevice& device_;
uint64_t offset_;
std::array<Elem, 2> buffers_;
int start_;
std::size_t total_transferred_;
WriteHandler handler_;
};
#endif // defined(BOOST_ASIO_HAS_STD_ARRAY)
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
inline void* asio_handler_allocate(std::size_t size,
write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, WriteHandler>* this_handler)
{
return boost_asio_handler_alloc_helpers::allocate(
size, this_handler->handler_);
}
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
inline void asio_handler_deallocate(void* pointer, std::size_t size,
write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, WriteHandler>* this_handler)
{
boost_asio_handler_alloc_helpers::deallocate(
pointer, size, this_handler->handler_);
}
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
inline bool asio_handler_is_continuation(
write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, WriteHandler>* this_handler)
{
return this_handler->start_ == 0 ? true
: boost_asio_handler_cont_helpers::is_continuation(
this_handler->handler_);
}
template <typename Function, typename AsyncRandomAccessWriteDevice,
typename ConstBufferSequence, typename CompletionCondition,
typename WriteHandler>
inline void asio_handler_invoke(Function& function,
write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, WriteHandler>* this_handler)
{
boost_asio_handler_invoke_helpers::invoke(
function, this_handler->handler_);
}
template <typename Function, typename AsyncRandomAccessWriteDevice,
typename ConstBufferSequence, typename CompletionCondition,
typename WriteHandler>
inline void asio_handler_invoke(const Function& function,
write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, WriteHandler>* this_handler)
{
boost_asio_handler_invoke_helpers::invoke(
function, this_handler->handler_);
}
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
inline write_at_op<AsyncRandomAccessWriteDevice,
ConstBufferSequence, CompletionCondition, WriteHandler>
make_write_at_op(AsyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
CompletionCondition completion_condition, WriteHandler handler)
{
return write_at_op<AsyncRandomAccessWriteDevice,
ConstBufferSequence, CompletionCondition, WriteHandler>(
d, offset, buffers, completion_condition, handler);
}
} // namespace detail
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename CompletionCondition, typename WriteHandler>
inline BOOST_ASIO_INITFN_RESULT_TYPE(WriteHandler,
void (boost::system::error_code, std::size_t))
async_write_at(AsyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
CompletionCondition completion_condition,
BOOST_ASIO_MOVE_ARG(WriteHandler) handler)
{
// If you get an error on the following line it means that your handler does
// not meet the documented type requirements for a WriteHandler.
BOOST_ASIO_WRITE_HANDLER_CHECK(WriteHandler, handler) type_check;
detail::async_result_init<
WriteHandler, void (boost::system::error_code, std::size_t)> init(
BOOST_ASIO_MOVE_CAST(WriteHandler)(handler));
detail::write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
CompletionCondition, BOOST_ASIO_HANDLER_TYPE(
WriteHandler, void (boost::system::error_code, std::size_t))>(
d, offset, buffers, completion_condition, init.handler)(
boost::system::error_code(), 0, 1);
return init.result.get();
}
template <typename AsyncRandomAccessWriteDevice, typename ConstBufferSequence,
typename WriteHandler>
inline BOOST_ASIO_INITFN_RESULT_TYPE(WriteHandler,
void (boost::system::error_code, std::size_t))
async_write_at(AsyncRandomAccessWriteDevice& d,
uint64_t offset, const ConstBufferSequence& buffers,
BOOST_ASIO_MOVE_ARG(WriteHandler) handler)
{
// If you get an error on the following line it means that your handler does
// not meet the documented type requirements for a WriteHandler.
BOOST_ASIO_WRITE_HANDLER_CHECK(WriteHandler, handler) type_check;
detail::async_result_init<
WriteHandler, void (boost::system::error_code, std::size_t)> init(
BOOST_ASIO_MOVE_CAST(WriteHandler)(handler));
detail::write_at_op<AsyncRandomAccessWriteDevice, ConstBufferSequence,
detail::transfer_all_t, BOOST_ASIO_HANDLER_TYPE(
WriteHandler, void (boost::system::error_code, std::size_t))>(
d, offset, buffers, transfer_all(), init.handler)(
boost::system::error_code(), 0, 1);
return init.result.get();
}
#if !defined(BOOST_ASIO_NO_IOSTREAM)
namespace detail
{
template <typename Allocator, typename WriteHandler>
class write_at_streambuf_op
{
public:
write_at_streambuf_op(
boost::asio::basic_streambuf<Allocator>& streambuf,
WriteHandler& handler)
: streambuf_(streambuf),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(handler))
{
}
#if defined(BOOST_ASIO_HAS_MOVE)
write_at_streambuf_op(const write_at_streambuf_op& other)
: streambuf_(other.streambuf_),
handler_(other.handler_)
{
}
write_at_streambuf_op(write_at_streambuf_op&& other)
: streambuf_(other.streambuf_),
handler_(BOOST_ASIO_MOVE_CAST(WriteHandler)(other.handler_))
{
}
#endif // defined(BOOST_ASIO_HAS_MOVE)
void operator()(const boost::system::error_code& ec,
const std::size_t bytes_transferred)
{
streambuf_.consume(bytes_transferred);
handler_(ec, bytes_transferred);
}
//private:
boost::asio::basic_streambuf<Allocator>& streambuf_;
WriteHandler handler_;
};
template <typename Allocator, typename WriteHandler>
inline void* asio_handler_allocate(std::size_t size,
write_at_streambuf_op<Allocator, WriteHandler>* this_handler)
{
return boost_asio_handler_alloc_helpers::allocate(
size, this_handler->handler_);
}
template <typename Allocator, typename WriteHandler>
inline void asio_handler_deallocate(void* pointer, std::size_t size,
write_at_streambuf_op<Allocator, WriteHandler>* this_handler)
{
boost_asio_handler_alloc_helpers::deallocate(
pointer, size, this_handler->handler_);
}
template <typename Allocator, typename WriteHandler>
inline bool asio_handler_is_continuation(
write_at_streambuf_op<Allocator, WriteHandler>* this_handler)
{
return boost_asio_handler_cont_helpers::is_continuation(
this_handler->handler_);
}
template <typename Function, typename Allocator, typename WriteHandler>
inline void asio_handler_invoke(Function& function,
write_at_streambuf_op<Allocator, WriteHandler>* this_handler)
{
boost_asio_handler_invoke_helpers::invoke(
function, this_handler->handler_);
}
template <typename Function, typename Allocator, typename WriteHandler>
inline void asio_handler_invoke(const Function& function,
write_at_streambuf_op<Allocator, WriteHandler>* this_handler)
{
boost_asio_handler_invoke_helpers::invoke(
function, this_handler->handler_);
}
template <typename Allocator, typename WriteHandler>
inline write_at_streambuf_op<Allocator, WriteHandler>
make_write_at_streambuf_op(
boost::asio::basic_streambuf<Allocator>& b, WriteHandler handler)
{
return write_at_streambuf_op<Allocator, WriteHandler>(b, handler);
}
} // namespace detail
template <typename AsyncRandomAccessWriteDevice, typename Allocator,
typename CompletionCondition, typename WriteHandler>
inline BOOST_ASIO_INITFN_RESULT_TYPE(WriteHandler,
void (boost::system::error_code, std::size_t))
async_write_at(AsyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b,
CompletionCondition completion_condition,
BOOST_ASIO_MOVE_ARG(WriteHandler) handler)
{
// If you get an error on the following line it means that your handler does
// not meet the documented type requirements for a WriteHandler.
BOOST_ASIO_WRITE_HANDLER_CHECK(WriteHandler, handler) type_check;
detail::async_result_init<
WriteHandler, void (boost::system::error_code, std::size_t)> init(
BOOST_ASIO_MOVE_CAST(WriteHandler)(handler));
async_write_at(d, offset, b.data(), completion_condition,
detail::write_at_streambuf_op<Allocator, BOOST_ASIO_HANDLER_TYPE(
WriteHandler, void (boost::system::error_code, std::size_t))>(
b, init.handler));
return init.result.get();
}
template <typename AsyncRandomAccessWriteDevice, typename Allocator,
typename WriteHandler>
inline BOOST_ASIO_INITFN_RESULT_TYPE(WriteHandler,
void (boost::system::error_code, std::size_t))
async_write_at(AsyncRandomAccessWriteDevice& d,
uint64_t offset, boost::asio::basic_streambuf<Allocator>& b,
BOOST_ASIO_MOVE_ARG(WriteHandler) handler)
{
// If you get an error on the following line it means that your handler does
// not meet the documented type requirements for a WriteHandler.
BOOST_ASIO_WRITE_HANDLER_CHECK(WriteHandler, handler) type_check;
detail::async_result_init<
WriteHandler, void (boost::system::error_code, std::size_t)> init(
BOOST_ASIO_MOVE_CAST(WriteHandler)(handler));
async_write_at(d, offset, b.data(), transfer_all(),
detail::write_at_streambuf_op<Allocator, BOOST_ASIO_HANDLER_TYPE(
WriteHandler, void (boost::system::error_code, std::size_t))>(
b, init.handler));
return init.result.get();
}
#endif // !defined(BOOST_ASIO_NO_IOSTREAM)
} // namespace asio
} // namespace boost
#include <boost/asio/detail/pop_options.hpp>
#endif // BOOST_ASIO_IMPL_WRITE_AT_HPP
| {
"pile_set_name": "Github"
} |
Luminescence properties of Tb(3+)-doped borosilicate scintillating glass under UV excitation.
Transparent Li₂O-BaO-La₂O₃-Al₂O₃-B₂O₃-SiO₂ glasses doped with Tb(3+) ion were prepared by high temperature melting method. Luminescence properties of Tb(3+)-doped borosilicate glasses have been investigated by transmission, excitation, emission and luminescence decay measurements. The transmission spectrum shows the glass has good transmittance in the visible region. Under the 236 nm UV excitation the intense green emission from (5)D₄ level is observed in Tb(3+)-doped borosilicate glass, comparable in intensity to the violet-blue emission starting from the (5)D₃ level. The green emission intensity of Tb(3+) ion firstly increases and then decreases with the decreasing B₂O₃/SiO₂ ratio in glass matrix. (5)D₄→(7)FJ (J=6, 5, 4 and 3) transitions of Tb(3+) ion in borosilicate glass are greatly enhanced with increasing concentration of Tb(3+) through the cross relaxation [Tb(3+) ((5)D₃)+Tb(3+) ((7)F6)→Tb(3+) ((5)D₄)+Tb(3+) ((7)F₀)] between two Tb(3+) ions. Luminescence decay time of 2.13 ms is obtained for the emission transitions starting from (5)D₄ level in 2.5Li₂O-20BaO-20La₂O₃-2.5Al₂O₃-20B₂O₃-35SiO₂-0.5Tb₄O₇ glass. The results show that Tb(3+)-doped borosilicate glasses would be potential candidates for scintillating material for static X-ray imaging. | {
"pile_set_name": "PubMed Abstracts"
} |
8. Gregory S. Kealey, "The Early Years of State Surveillance
of Labour and Left in Canada: The Institutional Framework of the Royal
Canadian Mounted Police Security and Intelligence Apparatus, 1918-26,"
pp. 129-148.
This issue of Intelligence and National Security was also published in
book form: See Wesley K. Wark, ed., Espionage: Past, Present, Future?
Studies in Intelligence series (London: Frank Cass, 1994).
Surveillant 3.6 notes
that these are essays "from an international conference held at the
University of Toronto devoted to the contemporary state of intelligence
studies." The diversity of the articles "provides an indication
of the richness of the field." | {
"pile_set_name": "Pile-CC"
} |
Submissionist was the term used by southern secessionists in the year preceding the American Civil War to describe southerners who wanted to preserve the Union .
| {
"pile_set_name": "Github"
} |
[Assessment of brain protection by means of cerebral oximetry incarotid endarterectomy].
Presented herein are the results of cerebral oximetry in the assessment of the indication for brain protection during operations of carotid endarterectomy in a total of forty-eight patients presenting with carotid artery stenoses. It was determined that cerebral oximetry gives an insight into the degree of efficacy of the collateral blood flow along both hemispheres, and by virtue of its integral approach to the assessment of cerebral blood flow is an important criterion in determining the indications for brain protection during carotid endarterectomy. | {
"pile_set_name": "PubMed Abstracts"
} |
"use strict";
const lua = require('../../src/lua.js');
const lauxlib = require('../../src/lauxlib.js');
const lualib = require('../../src/lualib.js');
const {to_luastring} = require("../../src/fengaricore.js");
const ltests = require('./ltests.js');
test("[test-suite] events: testing metatable", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
X = 20; B = 30
_ENV = setmetatable({}, {__index=_G})
--collectgarbage()
X = X+10
assert(X == 30 and _G.X == 20)
B = false
assert(B == false)
B = nil
assert(B == 30)
assert(getmetatable{} == nil)
assert(getmetatable(4) == nil)
assert(getmetatable(nil) == nil)
a={name = "NAME"}; setmetatable(a, {__metatable = "xuxu",
__tostring=function(x) return x.name end})
assert(getmetatable(a) == "xuxu")
assert(tostring(a) == "NAME")
-- cannot change a protected metatable
assert(pcall(setmetatable, a, {}) == false)
a.name = "gororoba"
assert(tostring(a) == "gororoba")
local a, t = {10,20,30; x="10", y="20"}, {}
assert(setmetatable(a,t) == a)
assert(getmetatable(a) == t)
assert(setmetatable(a,nil) == a)
assert(getmetatable(a) == nil)
assert(setmetatable(a,t) == a)
function f (t, i, e)
assert(not e)
local p = rawget(t, "parent")
return (p and p[i]+3), "dummy return"
end
t.__index = f
a.parent = {z=25, x=12, [4] = 24}
assert(a[1] == 10 and a.z == 28 and a[4] == 27 and a.x == "10")
--collectgarbage()
a = setmetatable({}, t)
function f(t, i, v) rawset(t, i, v-3) end
setmetatable(t, t) -- causes a bug in 5.1 !
t.__newindex = f
a[1] = 30; a.x = "101"; a[5] = 200
assert(a[1] == 27 and a.x == 98 and a[5] == 197)
do -- bug in Lua 5.3.2
local mt = {}
mt.__newindex = mt
local t = setmetatable({}, mt)
t[1] = 10 -- will segfault on some machines
assert(mt[1] == 10)
end
local c = {}
a = setmetatable({}, t)
t.__newindex = c
a[1] = 10; a[2] = 20; a[3] = 90
assert(c[1] == 10 and c[2] == 20 and c[3] == 90)
do
local a;
a = setmetatable({}, {__index = setmetatable({},
{__index = setmetatable({},
{__index = function (_,n) return a[n-3]+4, "lixo" end})})})
a[0] = 20
for i=0,10 do
assert(a[i*3] == 20 + i*4)
end
end
do -- newindex
local foi
local a = {}
for i=1,10 do a[i] = 0; a['a'..i] = 0; end
setmetatable(a, {__newindex = function (t,k,v) foi=true; rawset(t,k,v) end})
foi = false; a[1]=0; assert(not foi)
foi = false; a['a1']=0; assert(not foi)
foi = false; a['a11']=0; assert(foi)
foi = false; a[11]=0; assert(foi)
foi = false; a[1]=nil; assert(not foi)
foi = false; a[1]=nil; assert(foi)
end
setmetatable(t, nil)
function f (t, ...) return t, {...} end
t.__call = f
do
local x,y = a(table.unpack{'a', 1})
assert(x==a and y[1]=='a' and y[2]==1 and y[3]==nil)
x,y = a()
assert(x==a and y[1]==nil)
end
local b = setmetatable({}, t)
setmetatable(b,t)
function f(op)
return function (...) cap = {[0] = op, ...} ; return (...) end
end
t.__add = f("add")
t.__sub = f("sub")
t.__mul = f("mul")
t.__div = f("div")
t.__idiv = f("idiv")
t.__mod = f("mod")
t.__unm = f("unm")
t.__pow = f("pow")
t.__len = f("len")
t.__band = f("band")
t.__bor = f("bor")
t.__bxor = f("bxor")
t.__shl = f("shl")
t.__shr = f("shr")
t.__bnot = f("bnot")
assert(b+5 == b)
assert(cap[0] == "add" and cap[1] == b and cap[2] == 5 and cap[3]==nil)
assert(b+'5' == b)
assert(cap[0] == "add" and cap[1] == b and cap[2] == '5' and cap[3]==nil)
assert(5+b == 5)
assert(cap[0] == "add" and cap[1] == 5 and cap[2] == b and cap[3]==nil)
assert('5'+b == '5')
assert(cap[0] == "add" and cap[1] == '5' and cap[2] == b and cap[3]==nil)
b=b-3; assert(getmetatable(b) == t)
assert(5-a == 5)
assert(cap[0] == "sub" and cap[1] == 5 and cap[2] == a and cap[3]==nil)
assert('5'-a == '5')
assert(cap[0] == "sub" and cap[1] == '5' and cap[2] == a and cap[3]==nil)
assert(a*a == a)
assert(cap[0] == "mul" and cap[1] == a and cap[2] == a and cap[3]==nil)
assert(a/0 == a)
assert(cap[0] == "div" and cap[1] == a and cap[2] == 0 and cap[3]==nil)
assert(a%2 == a)
assert(cap[0] == "mod" and cap[1] == a and cap[2] == 2 and cap[3]==nil)
assert(a // (1/0) == a)
assert(cap[0] == "idiv" and cap[1] == a and cap[2] == 1/0 and cap[3]==nil)
assert(a & "hi" == a)
assert(cap[0] == "band" and cap[1] == a and cap[2] == "hi" and cap[3]==nil)
assert(a | "hi" == a)
assert(cap[0] == "bor" and cap[1] == a and cap[2] == "hi" and cap[3]==nil)
assert("hi" ~ a == "hi")
assert(cap[0] == "bxor" and cap[1] == "hi" and cap[2] == a and cap[3]==nil)
assert(-a == a)
assert(cap[0] == "unm" and cap[1] == a)
assert(a^4 == a)
assert(cap[0] == "pow" and cap[1] == a and cap[2] == 4 and cap[3]==nil)
assert(a^'4' == a)
assert(cap[0] == "pow" and cap[1] == a and cap[2] == '4' and cap[3]==nil)
assert(4^a == 4)
assert(cap[0] == "pow" and cap[1] == 4 and cap[2] == a and cap[3]==nil)
assert('4'^a == '4')
assert(cap[0] == "pow" and cap[1] == '4' and cap[2] == a and cap[3]==nil)
assert(#a == a)
assert(cap[0] == "len" and cap[1] == a)
assert(~a == a)
assert(cap[0] == "bnot" and cap[1] == a)
assert(a << 3 == a)
assert(cap[0] == "shl" and cap[1] == a and cap[2] == 3)
assert(1.5 >> a == 1.5)
assert(cap[0] == "shr" and cap[1] == 1.5 and cap[2] == a)
`;
lualib.luaL_openlibs(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: test for rawlen", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
t = setmetatable({1,2,3}, {__len = function () return 10 end})
assert(#t == 10 and rawlen(t) == 3)
assert(rawlen"abc" == 3)
assert(not pcall(rawlen, io.stdin))
assert(not pcall(rawlen, 34))
assert(not pcall(rawlen))
-- rawlen for long strings
assert(rawlen(string.rep('a', 1000)) == 1000)
`;
lualib.luaL_openlibs(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: test comparison", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
t = {}
t.__lt = function (a,b,c)
--collectgarbage()
assert(c == nil)
if type(a) == 'table' then a = a.x end
if type(b) == 'table' then b = b.x end
return a<b, "dummy"
end
function Op(x) return setmetatable({x=x}, t) end
local function test ()
assert(not(Op(1)<Op(1)) and (Op(1)<Op(2)) and not(Op(2)<Op(1)))
assert(not(1 < Op(1)) and (Op(1) < 2) and not(2 < Op(1)))
assert(not(Op('a')<Op('a')) and (Op('a')<Op('b')) and not(Op('b')<Op('a')))
assert(not('a' < Op('a')) and (Op('a') < 'b') and not(Op('b') < Op('a')))
assert((Op(1)<=Op(1)) and (Op(1)<=Op(2)) and not(Op(2)<=Op(1)))
assert((Op('a')<=Op('a')) and (Op('a')<=Op('b')) and not(Op('b')<=Op('a')))
assert(not(Op(1)>Op(1)) and not(Op(1)>Op(2)) and (Op(2)>Op(1)))
assert(not(Op('a')>Op('a')) and not(Op('a')>Op('b')) and (Op('b')>Op('a')))
assert((Op(1)>=Op(1)) and not(Op(1)>=Op(2)) and (Op(2)>=Op(1)))
assert((1 >= Op(1)) and not(1 >= Op(2)) and (Op(2) >= 1))
assert((Op('a')>=Op('a')) and not(Op('a')>=Op('b')) and (Op('b')>=Op('a')))
assert(('a' >= Op('a')) and not(Op('a') >= 'b') and (Op('b') >= Op('a')))
end
test()
t.__le = function (a,b,c)
assert(c == nil)
if type(a) == 'table' then a = a.x end
if type(b) == 'table' then b = b.x end
return a<=b, "dummy"
end
test() -- retest comparisons, now using both 'lt' and 'le'
`;
lualib.luaL_openlibs(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: test 'partial order'", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
t = {}
local function rawSet(x)
local y = {}
for _,k in pairs(x) do y[k] = 1 end
return y
end
local function Set(x)
return setmetatable(rawSet(x), t)
end
t.__lt = function (a,b)
for k in pairs(a) do
if not b[k] then return false end
b[k] = nil
end
return next(b) ~= nil
end
t.__le = nil
assert(Set{1,2,3} < Set{1,2,3,4})
assert(not(Set{1,2,3,4} < Set{1,2,3,4}))
assert((Set{1,2,3,4} <= Set{1,2,3,4}))
assert((Set{1,2,3,4} >= Set{1,2,3,4}))
assert((Set{1,3} <= Set{3,5})) -- wrong!! model needs a 'le' method ;-)
t.__le = function (a,b)
for k in pairs(a) do
if not b[k] then return false end
end
return true
end
assert(not (Set{1,3} <= Set{3,5})) -- now its OK!
assert(not(Set{1,3} <= Set{3,5}))
assert(not(Set{1,3} >= Set{3,5}))
t.__eq = function (a,b)
for k in pairs(a) do
if not b[k] then return false end
b[k] = nil
end
return next(b) == nil
end
local s = Set{1,3,5}
assert(s == Set{3,5,1})
assert(not rawequal(s, Set{3,5,1}))
assert(rawequal(s, s))
assert(Set{1,3,5,1} == rawSet{3,5,1})
assert(rawSet{1,3,5,1} == Set{3,5,1})
assert(Set{1,3,5} ~= Set{3,5,1,6})
-- '__eq' is not used for table accesses
t[Set{1,3,5}] = 1
assert(t[Set{1,3,5}] == nil)
`;
lualib.luaL_openlibs(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: __eq between userdata", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
T = require('T')
local u1 = T.newuserdata(0)
local u2 = T.newuserdata(0)
local u3 = T.newuserdata(0)
assert(u1 ~= u2 and u1 ~= u3)
debug.setuservalue(u1, 1);
debug.setuservalue(u2, 2);
debug.setuservalue(u3, 1);
debug.setmetatable(u1, {__eq = function (a, b)
return debug.getuservalue(a) == debug.getuservalue(b)
end})
debug.setmetatable(u2, {__eq = function (a, b)
return true
end})
assert(u1 == u3 and u3 == u1 and u1 ~= u2)
assert(u2 == u1 and u2 == u3 and u3 == u2)
assert(u2 ~= {}) -- different types cannot be equal
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: concat", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
t = {}
t.__concat = function (a,b,c)
assert(c == nil)
if type(a) == 'table' then a = a.val end
if type(b) == 'table' then b = b.val end
if A then return a..b
else
return setmetatable({val=a..b}, t)
end
end
c = {val="c"}; setmetatable(c, t)
d = {val="d"}; setmetatable(d, t)
A = true
assert(c..d == 'cd')
assert(0 .."a".."b"..c..d.."e".."f"..(5+3).."g" == "0abcdef8g")
A = false
assert((c..d..c..d).val == 'cdcd')
x = c..d
assert(getmetatable(x) == t and x.val == 'cd')
x = 0 .."a".."b"..c..d.."e".."f".."g"
assert(x.val == "0abcdefg")
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: concat metamethod x numbers (bug in 5.1.1)", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
c = {}
local x
setmetatable(c, {__concat = function (a,b)
assert(type(a) == "number" and b == c or type(b) == "number" and a == c)
return c
end})
assert(c..5 == c and 5 .. c == c)
assert(4 .. c .. 5 == c and 4 .. 5 .. 6 .. 7 .. c == c)
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: test comparison compatibilities", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
local t1, t2, c, d
t1 = {}; c = {}; setmetatable(c, t1)
d = {}
t1.__eq = function () return true end
t1.__lt = function () return true end
setmetatable(d, t1)
assert(c == d and c < d and not(d <= c))
t2 = {}
t2.__eq = t1.__eq
t2.__lt = t1.__lt
setmetatable(d, t2)
assert(c == d and c < d and not(d <= c))
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: test for several levels of callstest for several levels of calls", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
local i
local tt = {
__call = function (t, ...)
i = i+1
if t.f then return t.f(...)
else return {...}
end
end
}
local a = setmetatable({}, tt)
local b = setmetatable({f=a}, tt)
local c = setmetatable({f=b}, tt)
i = 0
x = c(3,4,5)
assert(i == 3 and x[1] == 3 and x[3] == 5)
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: __index on _ENV", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
local _g = _G
_ENV = setmetatable({}, {__index=function (_,k) return _g[k] end})
a = {}
rawset(a, "x", 1, 2, 3)
assert(a.x == 1 and rawget(a, "x", 3) == 1)
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: testing metatables for basic types", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
mt = {__index = function (a,b) return a+b end,
__len = function (x) return math.floor(x) end}
debug.setmetatable(10, mt)
assert(getmetatable(-2) == mt)
assert((10)[3] == 13)
assert((10)["3"] == 13)
assert(#3.45 == 3)
debug.setmetatable(23, nil)
assert(getmetatable(-2) == nil)
debug.setmetatable(true, mt)
assert(getmetatable(false) == mt)
mt.__index = function (a,b) return a or b end
assert((true)[false] == true)
assert((false)[false] == false)
debug.setmetatable(false, nil)
assert(getmetatable(true) == nil)
debug.setmetatable(nil, mt)
assert(getmetatable(nil) == mt)
mt.__add = function (a,b) return (a or 0) + (b or 0) end
assert(10 + nil == 10)
assert(nil + 23 == 23)
assert(nil + nil == 0)
debug.setmetatable(nil, nil)
assert(getmetatable(nil) == nil)
debug.setmetatable(nil, {})
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: loops in delegation", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
a = {}; setmetatable(a, a); a.__index = a; a.__newindex = a
assert(not pcall(function (a,b) return a[b] end, a, 10))
assert(not pcall(function (a,b,c) a[b] = c end, a, 10, true))
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
test("[test-suite] events: bug in 5.1", () => {
let L = lauxlib.luaL_newstate();
if (!L) throw Error("failed to create lua state");
let luaCode = `
T, K, V = nil
grandparent = {}
grandparent.__newindex = function(t,k,v) T=t; K=k; V=v end
parent = {}
parent.__newindex = parent
setmetatable(parent, grandparent)
child = setmetatable({}, parent)
child.foo = 10 --> CRASH (on some machines)
assert(T == parent and K == "foo" and V == 10)
`;
lualib.luaL_openlibs(L);
ltests.luaopen_tests(L);
if (lauxlib.luaL_loadstring(L, to_luastring(luaCode)) === lua.LUA_ERRSYNTAX)
throw new SyntaxError(lua.lua_tojsstring(L, -1));
lua.lua_call(L, 0, 0);
});
| {
"pile_set_name": "Github"
} |
Q:
Is there a way to call a function defined using `val` in Scala with the whole curly brace block as an argument and not the final result of that block?
I know that if we want to pass a block of code in curly braces as an argument to functions defined using def, we can write:
def run(func: => Unit) {
func
}
run {
print(1)
println(2)
} // prints 12
But is there a way to achieve the same style with an anonymous function?
I have tried the following:
val v: (()=>Unit) => Unit = ( w: ()=> Unit) => { w() }
v( () => { println(1); println(2) } ) // Works as expected. Prints 12
v { println(1); println(2) } // error: type mismatch
Correction:
()=>Unit doesn't translate to a function that has a by-name parameter which would allow it to accept code enclosed by curly braces as a parameter. So my question's second part was incorrect.
Alexey Romanov's answer works perfectly if we don't re-specify the argument type in function literal, but if we re-specify the argument type in the function literal which matches the type of variable exactly, it is seen as an error.
For example, if we write
val v: (=>Unit) => Unit = (w) => { println(0); w } // works
val v: (=>Unit) => Unit = (w:=>Unit) => { println(0); w } // error
val v: (Int => Int) = (w) => 43 // works
val v: (Int => Int) = (w:Int) => 43 // works as well
A:
val v: (=>Unit) => Unit = w => { println(0); w }
v { println(1); println(2) }
println(0) inserted purely so you can see this is really a by-name parameter: 0 is printed before 1 and 2.
| {
"pile_set_name": "StackExchange"
} |
Biden to face anti-war Democrats at Iowa picnic
FILE - In this Jan. 3, 2008, file photo then-Democratic presidential hopeful, Sen. Joe Biden, D-Del., talks to supporters during a rally in Dubuque, Iowa, on the day of the Iowa caucus. Biden is heading to Iowa Sunday, Sept. 15, 2013, straight into the belly of Democratic anti-war opposition, the first steps by the vice president or the president outside Washington or the diplomatic bubble since President Barack Obama endorsed a possible military strike on Syria. There Biden is scheduled to headline a fundraiser for Democratic Sen. Tom Harkin, an annual steak picnic for the senator who is popular with anti-war Democrats. (AP Photo/Mark Hirsch, File)
DES MOINES, Iowa (AP) — Vice President Joe Biden is heading into the belly of Democrats' anti-war opposition, venturing into a politically influential heartland state for the first time since President Barack Obama publicly endorsed a possible military strike on Syria.
Biden is scheduled to headline a fundraiser in Iowa Sunday for Democratic Sen. Tom Harkin, an annual steak picnic for the senator who is popular with anti-war Democrats.
Even if Biden sidesteps talk of Syria, the issue will be as much a part of the backdrop as the bales of hay and smoke from the grilling steaks, and in a place where he will have to plant his flag should he seek the presidency in 2016.
"That's going to be a little sensitive," said eastern Iowa Democrat Richard Machacek, an Obama delegate in 2008, referring to possible military action against Syria. "It flies in the face of what the president campaigned on here."
Obama rode an anti-war wave to victory in Iowa's 2008 presidential caucuses. He had proposed limited air strikes in Syria in response to a chemical weapons attack last month against more than 1,400 people in a Damascus suburb. The administration says Syrian President Bashar al-Assad's government was behind the attack.
On Saturday Secretary of State John Kerry announced that he and Russia's foreign minister had reached an agreement to rid Syria of its chemical stockpile. Obama said in a statement the agreement was welcome news, but added that "if diplomacy fails, the United States remains prepared to act."
His own party remains cool at best to a military strike. Obama has struggled to win support from members of Congress, including Democrats, whose constituents have endured more than a decade of war.
An Associated Press poll taken Sept. 6-8 showed 34 percent of Democrats said they wanted Congress to back military action. And more than three-fourths of Democrats said they thought any military action in Syria was at least somewhat likely to turn into a long-term commitment of forces, including 44 percent who said it was extremely likely.
The poll was taken before Obama pledged not to deploy ground troops in Syria.
Cedar Falls Democrat David Kabel, an early and devout Obama supporter, is skeptical, even after Obama's speech. "I just don't know that you can reel it in once you get started," he said.
The reaction to anything Biden says about Syria will be closely watched and noted. He is weighing another run for the White House in 2016, and the crowd he mingles with Sunday -- many of them familiar with the two-time presidential candidate -- will have the opening say during the caucuses.
Including Harkin.
Harkin has said that he was leaning against supporting a military strike, though a vote has been postponed to allow the diplomatic option to develop.
While Harkin supported limited strikes in Kosovo in 1997 and Libya in 2012 under Democratic presidents, Harkin has largely opposed recent wars under Republican presidents, endearing him to his party's left.
He voted against the 1991 Gulf War resolution under President George H. W. Bush. And while he voted for the resolution ahead of the 2003 Iraq war under President George W. Bush, he later called the vote a mistake and endorsed anti-war candidate Howard Dean in Iowa's 2004 presidential caucuses.
Obama made a special appeal during Tuesday's speech to "my friends on the left," asking them to consider the images of the hundreds of children who died in the August 21 gas attack. "Sometimes resolutions and statements of condemnation are simply not enough.
He may as well have been speaking directly to those Iowa Democrats who were drawn to his vocal opposition to the war in Iraq, a position that set him apart from chief rival Hillary Clinton and on the path to winning the White House.
Harkin aides and supporters play down any possible outward hostility toward Biden, as he strolls the Warren County fairgrounds south of Des Moines, flips a few steaks for the cameras and speaks Sunday afternoon.
"People will be polite," Lipsman said.
___
Associated Press Director of Polling Jennifer Agiesta in Washington contributed to this report. | {
"pile_set_name": "Pile-CC"
} |
Characterization of latent membrane protein 2 specificity in CTL lines from patients with EBV-positive nasopharyngeal carcinoma and lymphoma.
Viral proteins expressed by EBV-associated tumors provide target Ags for immunotherapy. Adoptive T cell therapy has proven effective for posttransplant EBV-associated lymphoma in which all EBV latent Ags are expressed (type III latency). Application of immunotherapeutic strategies to tumors such as nasopharyngeal carcinoma and Hodgkin's lymphoma that have a restricted pattern of EBV Ag expression (type II latency) is under investigation. Potential EBV Ag targets for T cell therapy expressed by these tumors include latent membrane proteins (LMP) 1 and 2. A broad panel of epitopes must be identified from these target Ags to optimize vaccination strategies and facilitate monitoring of tumor-specific T cell populations after immunotherapeutic interventions. To date, LMP2 epitopes have been identified for only a limited number of HLA alleles. Using a peptide library spanning the entire LMP2 sequence, 25 CTL lines from patients with EBV-positive malignancies expressing type II latency were screened for the presence of LMP2-specific T cell populations. In 21 of 25 lines, T cell responses against one to five LMP2 epitopes were identified. These included responses to previously described epitopes as well as to newly identified HLA-A*0206-, A*0204/17-, A29-, A68-, B*1402-, B27-, B*3501-, B53-, and HLA-DR-restricted epitopes. Seven of the nine newly identified epitopes were antigenically conserved among virus isolates from nasopharyngeal carcinoma tumors. These new LMP2 epitopes broaden the diversity of HLA alleles with available epitopes, and, in particular, those epitopes conserved between EBV strains provide valuable tools for immunotherapy and immune monitoring. | {
"pile_set_name": "PubMed Abstracts"
} |
Why MFA Programs Matter
08/17/2011 11:39 am ETUpdated
Oct 17, 2011
The love-hate relationship between creative writing MFA programs and writers has not changed much since Kurt Vonnegut was playfully piqued by the emerging phenomenon of writing programs in the 1960s. He liked the attention and money, but doubted that writing fiction could be taught. With intense changes in publishing, though, the normally fraught relationship between writer and academy seems more rocky than usual, perhaps even broken.
Last year, N+1 Magazine persuasively schematized the path to publishing a novel as either "live in New York" or "get an MFA" and argued that, despite the cost in tuition and a powerful place in the publishing ecosystem, MFA programs have little effect on the quality of writing a student produces. An opposing opinion states that MFA programs have too much of an effect on writing, and produce a consistently polished and boring "McLiterature." Some consider it an outright shuck.
Despite sounding like he's singing a blues song about the disappointing seats in his new Jaguar, an MFA grad does have the right to question and critique the value of his expensive education. Yet, when you question the intrinsic value of an arts education for everyone else, the cynical attitude is revealed to be very close to the neo-con belief that the arts don't pay so there should be no arts education. Of course, success being relative, it's always difficult to quantify the value of the arts. If, as its publisher claims, Jonathan Franzen's "The Corrections" sold 3 million copies, then it netted no more money than "Saw 3D." Now, according to the theory that only things that make lots of money should exist, and because the most critically discussed literary novel of the last decade--by an author with no MFA at that--only made as much money as an underperforming 3D sequel, we should rethink this whole MFA thing.
There was a time, before bookstores went big box in the 1980s and 1990s, when young authors didn't have expectations of seven-figure success from writing literary fiction. The industry's growth did necessitate a commensurate increase in published books and, as part of that growth, MFA programs did become a college draft of sorts for agents to pick over and that worked well, for a while. As the corporate model of publishing struggles to turn itself around amid the total collapse of bookstore floor space and volatile new digital markets, does the need for MFA programs also diminish in tandem?
More than giving employment to a few hundred writers as instructors, and teaching basic composition lessons like "show, don't tell," MFA programs have created a culture of connoisseurship in readers and practitioners, and this has kept literary fiction alive. This is what arts education does better than anything else: it protects traditions from suffering market fluctuations, challenges forms with new traditions and constructs large buildings named after dead people and equipped with ace sound systems, in which to debate and perform. To bury this living database with a flat-out incorrect argument that there is no effective post graduation job market is a sock in the gut to language itself. It's also disingenuous to hold the sciences up for comparison as many branches of the sciences struggle--and chase funding--just as much as modern dance departments do. To be anti-arts education is to be anti-education under the cover of sophistry and taste.
I don't have an MFA. I came to writing through visual arts and the unfinished tatters of a BA. Despite what some claim about MFA culture colonizing all fiction, many authors still come to book writing from strange places, as well as not-so-strange places like journalism, philosophy, starring on "The Hills" or plain dumb luck. So why am I arguing for MFA programs? No matter what the resume says under the heading "education," all authors benefit from the existence of MFA programs, either directly by being a student or indirectly. My life as a writer and a publisher at Joyland is affected by MFA culture every day and wouldn't be the same without it. There are students who buy my books, instructors who teach my books, and the comradeship and advice of the editors who work at Joyland, several of whom hold creative writing degrees.
As for the argument that MFA programs produce a generically polished "McLiterature," I know, down to statistics of my in-box, that is not the case. Programs are too diverse and writers are too diverse to fall into anything other than short-lived trends and tropes. Every month at Joyland, we look at over a hundred submissions. Not all the best and most original work comes from MFA grads, but a lot of it does. While it's true that there was one week where we received three submissions from MFA grads from across the country all featuring amputee characters, you could blame the "Saw" films as much as instructors teaching Flannery O'Connor's "The Life You Save May Be Your Own." We still published one of the stories because it was great.
I also spent this summer mentoring an MFA student, and I know firsthand now what it means for a student to grow in a workshop setting. As much as the experience proved to me the value of such programs, I understand that the thwarted expectations of those who pay for postgraduate education can run counter to everything the middle class believes about upward mobility. I can imagine what it's like to have paid a lot of money for a creative writing MFA and then not publish anything, but if you thought a National Book Award would be handed over to you after cutting a tuition check, the problem isn't the programs; it's the expectations.
The critics of programs are far from wrong on a few issues though, and the creative writing schools must change, especially with publishing evolving so quickly. As creative writing instructor Cathy Day and the N+1 article both point out, avoiding the easy trap of short story teaching would help. Also, diversifying with more commercial applications of creative writing would balance practical skills with the no less important art of completely impractical, clever and beautifully unmarketable literary fiction writing. I'd suggest including screenwriting, as some programs already do, or adding more new media courses. How about courses that prepare MFA grads for ghostwriting an unauthorized Hugh Laurie biography, one that earns them enough money to pay rent for a year so they can work on a novel?
School can't prepare writers for everything in life, but that doesn't take away what a good program does give writers and readers, or the protected habitat for fiction that it provides. | {
"pile_set_name": "Pile-CC"
} |
SPID#: 23 Despite almost 13 years of research on HIV and its role as the etiologic agent of AIDS, the mechanisms of pathogenesis remain mostly unknown. Specific in vitro effects have been identified that may contribute to the overall course of disease development. These include direct cell killing by HIV (syncytia formation); the induction of apoptosis; and the development of autoimmune responses; among others. While all of these effects have been observed in vitro and in vivo, the only mechanism consistently identified in vivo has been apoptosis. Because the exact time of infection can only be estimated in HIV-infected patients, a majority of the studies involving pathogenesis have been conducted during middle or late stage disease, at the least, following seroconversion. While much research has shown that a number of changes, including viral tropism changes, occur late, the early stages of infection may be as (or more) important in pathogenesis. The initial stages of infection involve viral amplification and seeding of lymphoid tissues, and can possibly dictate later effects, i.e. rapid or slow progression to disease. The SIV/macaque model represents the best system currently available to study AIDS pathogenesis, due to the striking genetic and biologic similarities. This model provides an excellent mechanism to investigate early pathogenesis of lentiviral infection. A recently characterized SIV isolate from a sooty mangabey (SIVsmmFGb) displays varied pathogenesis in pig-tailed and rhesus macaques. In pig-tailed macaques, this virus rapidly induces AIDS, whereas in rhesus macaques, disease progresses at a typically slower rate. The progression in pig-tailed macaques is associated with a high plasma viral load (as measured by p27 assay) an insufficient immune response (no anti-SIV antibody detected in most cases). In contrast, the rhesus macaques show a lower viral load, and make high levels of anti-SIV antibody. The pig-tailed macaques all succumbed to AIDS by 9 months post infection. In all cases, SIV- encephalitis was detected, illustrating the neurotropism of this virus. The differences in pathogenesis of this virus between rhesus and pig- tailed macaques should provide an excellent system for investigating determinants of AIDS pathogenesis. | {
"pile_set_name": "NIH ExPorter"
} |
For example, in a conventional three-position switch operating mechanism, a shutter for switching the operation between a disconnecting switch operating part and an earthing switch operating part is rotated by rotating a rotation shaft of the shutter using a special shutter operating lever to be attached to the rotation shaft. | {
"pile_set_name": "USPTO Backgrounds"
} |
SpaceX revealed the plans in a filing with the Federal Communications Commission (FCC). The company is requesting that the FCC allocate radio frequencies, so it can communicate with the vehicle during the test flight -- that filing is standard practice. As The Verge notes, the test is meant to prove that the Starship rocket can be reused and potentially touch down on the moon or Mars.
SpaceX began constructing the next generation of its Starship rockets late last year. At the time, we learned that SpaceX was building one of three next-gen Starships at its facility in Boca Chica, and CEO Elon Musk said the company's plan was to begin suborbital testing within one or two months. That timeline was ambitious, and one month later, the original Starship model popped open during a "pressure test," which may be one reason the suborbital test flight is now scheduled for later this year. | {
"pile_set_name": "OpenWebText2"
} |
Allen Tate
Allen Tate has taught both here and abroad, lectured at over 100 American universities, and published 20 books during his career as one of America's most distinguished men of letters. Tate's honors include a grant from the National Institute of Arts and Letters, the Bollingen Prize for Poetry, and the Brandeis Medal Award. He was the first consultant in poetry to the Library of Congress and in 1968 served as president of the National Institute of Arts and Letters.
The Fathers is the powerful novel by the poet and critic recognized as one of the great men of letters of our time. Old Major Buchan of Pleasant Hill, Fairfax County, Virginia, lived by a gentlemen's agreement to ignore what was base or rude, to live a life which was gentle and comfortable because it was formal.
Lincoln, Congress, and Emancipation“When Lincoln took office, in March 1861, the national government had no power to touch slavery in the states where it existed. Lincoln understood this, and said as much in his first inaugural address, noting: ‘I have no purpose, directly or indirectly, to interfere with the institution of slavery in the States where it exists.’”
The Crisis of Meaning and the Life-WorldHusserl, Heidegger, Arendt, PatočkaUčník examines the existential conflict that formed the focus of Edmund Husserl’s final work: how to reconcile scientific rationality with the meaning of human existence. To investigate this conundrum, she places Husserl in dialogue with three of his most important successors: Martin Heidegger, Hannah Arendt, and Jan Patočka.
Driven toward MadnessThe Fugitive Slave Margaret Garner and Tragedy on the OhioThe story of Margaret Garner—the runaway slave who, when confronted with capture, slit the throat of her toddler daughter rather than have her face a life in slavery—has inspired Toni Morrison’s Beloved, a film based on the novel starring Oprah Winfrey, and an opera.
Drawing on the VictoriansThe Palimpsest of Victorian and Neo-Victorian Graphic TextsLate nineteenth-century Britain experienced an unprecedented explosion of visual print culture and a simultaneous rise in literacy across social classes. New printing technologies facilitated quick and cheap dissemination of images—illustrated books, periodicals, cartoons, comics, and ephemera—to a mass readership.
Winter of ArtificeThree NovelettesSwallow Press’s reissue of Winter of Artifice, with a new introduction by Laura Frost, presents an important opportunity to consider anew the work of Anaïs Nin who laid the groundwork for later writers, but whom critics frequently dismiss as solipsistic or overblown. | {
"pile_set_name": "Pile-CC"
} |
Pages
Wednesday, 27 February 2013
It's time for another food review and this time I cooked Sainsbury's Spicy Bean Quarterpounders. Once again Sainsbury's have created another vegan friendly food which is labelled suitable for vegans. The product description states "with red kidney beans and vegetables, mildly spiced and covered in a crispy crumb." Now you all know by now, that hubby is an avid meat eater and would NEVER EVER consider turning vegetarian let alone vegan, but even he ate and enjoyed these!
As you can see from the photo I served mine on a bun with cherry tomatoes, spring onion and mixed leaves on the bottom and tomato sauce on the top. Hubby doesn't take kindly to anything green (unless its hidden!) so he ate his on baps with sweet chilli sauce. Both of us thoroughly enjoyed them. The quarterpounders had a good crumb on the outside and were 'beany' and full of texture on the inside. The only downside they crumbled ☹Would we eat them again - most definately! ☺
Tuesday, 26 February 2013
I was ravenous when I got home tonight and I needed something fast, easy and most importantly tasty! On opening up the fridge I had some Redwood Cheezly that I'd used sometime back and needed using up and in my crisper box was an odd courgette, a red pepper, a couple of mushrooms. I also had 2 pitta breads that needed using up. The others had been filled with houmous, falafel and salad for lunches. And so pitta bread pizza was born purely out of hunger!Ingredients2 Pitta BreadsTomato passata½ Courgette½ Red Pepper½ Onion3 Mushrooms2 tsp Mixed herbsMethodCoat one side of each pitta with the tomato passata. Finely slice the onion, courgette, red pepper and mushrooms and layer them on to the tomato passata in that order. Grate the vegan cheese of your choice over the vegetables and sprinkle with the mixed herbs. Bake in an oven until the 'cheese' has 'melted'. Careful not to bake for too long as the pitta breads have a tendency of going hard and therefore difficult to cut saw through!
Monday, 25 February 2013
For the first time in ages I had not prepared my lunch and snacks to take to work today and as luck would have it I overslept too! Normally in the morning I have just enough time to walk Marco, get showered and dressed and pick up my work lunch and snacks before heading off out the door. If I'm lucky I manage to grab some marmite on toast but more times than not my breakfast is prepared the night before and eaten when I first get to work.Today I had not prepared my lunch, snacks or breakfast and I had got up late! What is a girl to do apart from panic as we all know how hard it is to find vegan food on the go. Especially in my home town, you have to be super organised.Thankfully I had prepared a big bowl of fruit salad a couple of days ago and some of that was left so that was packed up for breakfast. I had a couple of tortilla wraps that needed using up so they were an obvious choice. I had no houmous, pesto, falafels or ready to heat filing for the wraps so my trusty food cupboard was raided. Woohoo! I had a small tin of refried beans. I spread this over the tortillas and topped with salad leaves, sliced cherry tomatoes and cucumber. Before folding in the sides and wrapping I drizzled some sweet chilli sauce over the top. I didn't have time to photograph the finished result before leaving for work so I took a photo at work at my desk, my colleague wondered what I was doing!
Sunday, 24 February 2013
So, what do you cook, when you’ve still not gone shopping and your cupboards are bare and the only thing in the kitchen is laying at the bottom of the fridge forgotten about: Celery, Celeriac, Swede, Parsnip and Carrot. After what seemed many minutes of contemplation I came up with the idea of minestrone pasties. I made a basic vegan pastry and filled it with the vegetables I found in the bottom of our fridge! Now the only vegetables hubby likes are carrot, cauliflower, potato, onion and green pepper, but when dining out he has been known to have minestrone soup, strange but true. For this reason only, I called them minestrone pasties and served them with gravy. Now everyone knows how to make pastry right? I just substituted the fat with Vitalite (a vegan friendly margarine). For the filling this is what I did:
METHODCook diced mixed vegetables in a saucepan of boiling water (salted if desired) and boil until soft and still keeping their shape. Drain and rinse with cold water to stop cooking process and drain once more.
Fry the diced onion, celery and garlic in the olive oil until translucent, add the stock in batches and reduce each time.
Sprinkle over the herbs and flour and stir until all combined and cook through over a low heat for a minute.
Add the soy milk stirring constantly, the mixture will thicken. Once the mixture is to your desired consistency add the drained vegetables and stir until all is combined.
Leave the mixture to cool a little before adding to the pastry. I cut out discs using an upturned bowl and added a little filling to the middle before folding the pastry over to form a pasty shape. Wet the edges with a little soy milk to help them stick and press a fork into the edge to make a pretty indentation.
Bake in an oven about 180°C for about 20-25 minutes or until golden brown.* I didn't weigh the vegetables (doh!) but I reckon there were about 4 cups worth.The verdict – Hubby had one and asked for another – unbelievable!
Saturday, 23 February 2013
The other day I posted the recipe for Get Well Soon Stroganoff and I said I would post my Mushroom Stroganoff recipe as I still had some soy cream left. So true to my word, here it is! I don't think I'll ever get tired of eating this. I hope you enjoy it as much as I do.Ingredients1 onion1 clove garlic750g mushroomsSoy sauceSlug of brandy2 tsp paprika1 tsp dried thymeSoy creamSalt and black pepper to tasteMethodFinely chop the onion and garlic and saute in a little olive oil until the onion is translucent. Slice the mushrooms and add to the pan with a little soy sauce to prevent them from sticking. Once the mushrooms have released their liquid add the paprika and thyme and stir to combine. Next pour in a glug of brandy and if you're feeling professional tilt your pan and set the alcohol alight! Or, if you're a danger in the kitchen, continue to cook the mushroom mixture until the liquid has reduced. Add a little water if the mixture starts sticking, and continue to saute until the mushrooms are cooked. Add salt and black pepper to taste. Slowly add the soy cream until you reach your desired consistency. I used about ½ a carton and heat through, do not boil else the soy cream may split. Serve over rice or pasta. Or if you're feeling extravagant serve in a bowl with sides of french fries and peas. Enjoy!
Friday, 22 February 2013
This month was my first vegan swap box which the to happy vegans organise every month. I was super excited at sending a swap box and even more excited to see what I would receive.The person I sent to was Bindy, who told me that this was the first and last time she would be able to take part in the vegan swap box, as she was moving away from the UK at the end of the month. So I put my thinking cap on and thought the best thing to send her was snack foods, naughty but nice! Here is what I sent her:
I ordered a graze box to send and this was made up with a sachet of lightly salted popping corn, lightly toasted pistachios, seedsational (roasted sunflower and pumpkin seeds roasted with soy sauce) and lost army (a classic rice and peanut cracker mix). When I first went vegan I had a mentor that was set up by the vegan society and she told me that original hobnobs were vegan. I was amazed and I always have a packet at hand for those emergencies! Another good stand by is the packet of savoury snack mix.I also included two "9bars"; original and flax as well as 3 "nakd" bars; cocoa and orange, pecan pie and cashew cookie. My favourite is the cocoa and orange version which I am going to have a go at making myself sometime soon.To top off the naughty but nice I included a packet of little love heart sweets and ASDA free from choc and orange bar.To balance all the naughtiness out, I added a carton of rice dream, a milk alternative that I use quite a bit in my cooking and 2 earl grey and 2 green tea with lemon tea bags. I hope Bindy enjoys the swap box, I enjoyed putting it together.
Thursday, 21 February 2013
Yesterday I posted the Get Well Soon Stroganoff I made, and today I enjoyed some leftovers over a baked potato. It tasted even better today and was a fine accompaniment to the spud!
I still have some soy cream left over and need to use it up so in a day or so I will post my Mushroom Stroganoff recipe, it tastes divine even if I say so myself!I remember one of the first meals I had out in a restaurant when I turned vegetarian at 15 was Mushroom Stroganoff. I'll never forget that first mouthful it blew me away. I just knew I had to veganise it as it was one recipe that I couldn't do without. I honestly think mushrooms are my favourite food. What are your favourites?
Wednesday, 20 February 2013
After two weeks of going to hospital and mixing with all the bugs flying around I was bound to fall ill, wasn't I? I was tired from trying to fit work in after an 8 hour shift at the hospital and then organise and cook tea for two people who eat at differing ends of the spectrum! Don't get me wrong friends had offered to help with shopping, cooking, cleaning and dog walking, but I thought I was Wonderwoman and tried to do everything. The result was falling flat on my face with a cold and chest infection! I didn't want to surrender to it but there was no way I could carry on visiting S while I felt this poorly and besides I didn't want to pass on the illness to S, she has enough on her plate at the moment fighting Guillain Barre Syndrome.I figured I needed some good honest healthy vegetables and herbs and put together Get Well Soon Stroganoff.Ingredients1 onion1 clove garlic1 packet green beans1 packet spinach1 red pepper500g mushroomsSoy sauce2 tsp paprika1 tsp dried thymeSoy creamSalt and black pepper to tasteMethodFinely chop the onion and garlic and saute in a little olive oil until the onion is translucent. Finely chop the green beans and add to the pan, saute for another 5 minutes stirring all the time. Finely chop the red pepper and add to the pan, with a little soy sauce to prevent the vegetables from sticking. Add the paprika and thyme and stir to combine. Add a little water if the mixture starts sticking, slice the mushrooms and add to the pan and continue to saute until the mushrooms are cooked and the green beans are al dente. Shred the spinach and add to the pan, stir through the vegetable mixture until the spinach wilts. Add salt and black pepper to taste. Slowly add the soy cream until you reach your desired consistency. I used about ½ a carton and heat through, do not boil else the soy cream may split. Serve over rice or pasta. I enjoyed mine in a bowl on its own, the flavour of the vegetables worked really well together, with the herbs and soy cream.I decided not to post about the vegan swap box that I sent to Bindy as she has yet to collect the parcel from the post office and I didn't want to spoil her surprise.
Tuesday, 19 February 2013
I was so excited to see that my vegan swap box had arrived, and I couldn't wait to open it to see all the goodies. But first I put the kettle on, you never know there might be something I can dunk!I wasn't let down! Caroline from Tea and Sympatico had sent me a fabulous box full of goodies and I shouldn't have put the kettle on as the parcel even contained tea bags! It brightened up my day no end, thank you Caroline!
The picture doesn't give the goodies justice so as I write about each of the items I have more photos, so you can see how much time and effort went into this swap box.The first thing to go was the chocolate mints, similar to after eight mints but vegan, although under the ingredient list it did state that there may be a contamination risk as they were made in a factory that uses milk. They lasted about 10 minutes! Hubby and I gorged our way through them whilst watching a film!The next thing to go was the choco wafers and I am just eating the last one whilst I am writing up this blog. They are very much like Kitkats without the chocolate round the outside. They are extremely tasty, you just have to keep going back for more! And yep hubby helped me eat these too!In fact its given me an idea I might try cooking with fake meats for his tea, he probably won't know the difference. I'm not one however to indulge in the fake meats as I don't want to be reminded of what I gave up by choice. But everyone is different and cooking with fake meat will be better than what I do at the moment for him!Next to be demolished was the Fry's Orange Cream and I enjoyed every mouthfull! It was pure heaven, I can't believe it's vegan. This is going to be dangerous as soon as I find somewhere that sells these I'm buying boxes of them!The mini rice cakes were also nice, not something I would have considered before but this is the good thing about the swap box system you get to try things that you wouldn't normally. I got into quite a bit of mess eating these and lots of rice crumbs were hoovered up by Marco! I think he enjoyed them more than me and he didn't have the chocolate bits!
I've yet to try the jalapeno pepper crisps, but reading the ingredients, they're going to be hot! No doubt I'll tuck into the soya beans & gourmet nuts sometime soon.I've never heard of some of these makes and never seen anything like it in our small home town. Next time I'm in one of the 3 supermarkets in our town I'll start reading the ingredient labels on a heap load of more foods!
I'm guessing the "Mr Tom" Peanut bars taste a bit like a snickers without the chocolate!The Original Caramelised Biscuit by Lotus looks like a good dunker!One Morning soon I'll try out the porridge and I'm not quite sure what to do with the fruit hearts yet. The packet says they are ideal for baking, I'll have to get my thinking cap on with this item. Or I could just eat straight from the packet when I need something a little sweet!Caroline had written a lovely message on 'Cake Liberation' postcard, which she is a member. They meet every couple of months in Manchester, go check out their website. The group is for anyone baking or cooking without animal ingredients and when they get together they swap recipes and sample each others food. Sounds like a great get together if you ask me! I wish I lived nearer!
The last two items (not including the lovely tea bags Caroline had included) were Easy Thai Green Curry Paste and Mexican Chilli Bean Deli Filling. Two things which I can use to make super quick tasty meals, as I get in from the hospital and/or work.Last but no means least, Caroline included 4 different flavoured tea bags. How did she know I was a tea enthusiast! I've got Twinings Rose Garden, Good Earth Organic White Tea, Dragonfly Organic Cape Malay Rooibos Chai and Ahmad Tea Rooibos and Cinnamon.Overall it was a fantastic swap box and I look forward to trying and eating and drinking everything in it! Thank you Caroline!Tomorrow I'll post what I sent to my swap box buddy. Have a good day!
Monday, 18 February 2013
As promised my taco recipe and yet another Mexican night! I love Mexican food, I must visit the Country, although I have heard that the food is nothing to what we class as Mexican here! A bit like Chinese I suppose.This was ready in half an hour so don't be put off with the ingredients and length of the instructions! It was extremely tasty and one recipe I will repeat over and over again now I've written down what I actually did! Before writing this blog I could never remember what I cooked up all I remembered was "that tasted GOOOOOOOD". This blog is a good record of what I get up to in the kitchen when my creative juices are flowing, so I can go back and recreate the tastiest of all my recipes.Ingredients2 celery stalks, diced1 onion, diced1 garlic clove, minced1 courgette, diced½ red pepper, diced10 standard size mushrooms, diced1 tsp paprika1 tsp chilli flakes1 tsp cumin1 tsp smoked paprika½ tsp chilli powder200g passata200g refried beansSoya 'mince'*1 tsp mixed herbs1 tsp paprika1 tsp ground black pepper½ tsp cuminBoiling water
* I forgot to weigh the soya mince but I think it was round about 1 cup. Follow the instructions on the packet of soya mince and add the required waterMethodSaute the onion until translucent then add the garlic and saute for a couple more minutes. Add the celery and red pepper and saute for another couple of minutes before adding the courgette and mushrooms. When the mushrooms have released their liquid add the spices and stir to combine.Add the tomato passata and simmer over a low heat for 5 minutesAdd the refried beans and stir through so they are evenly distributed.Add the mixed herbs, black pepper, paprika and cumin to the soya mince and stir to combine.Add the boiling water and leave to sit for 5 minutes. Mix thoroughly and add to the vegetables.Simmer for another 5 minutes and serve with taco shells, lettuce, tomato and cucumber.I also add some vegan mayonnaise which you can see in the second photo.
Well, as you are aware I haven't been publishing any posts for 2 weeks, that's because a very close family member (S) has been in hospital on the critical care ward and I have been spending most of my time at the hospital and trying at the same time to go into work for a couple of hours. Which meant once I was home all I was good for is a quick bite to eat and bed! Thankfully S is getting better and we are not needed as much at the hospital. I'm also on annual leave this week so I'm planning to cook up a storm in the kitchen too. I'm ashamed to say it but for the first week I lived off ready salted crisps and dry roasted peanuts! Hospital canteens really don't cater for vegans! But the second week I got better organised and prepared my lunch whilst cooking tea. Thank goodness for falafel!Next recipe to follow - Taco's!One night after a long day at hospital and then work I really craved something hot and spicy and the Tacos just fitted the bill.
Monday, 4 February 2013
Tonight we were tired and hungry and if not on a budget would have picked up the phone and ordered a take-away. We are lucky that there is a good Cantonese Restaurant not far away and they do deliveries. We were craving a Chinese so using store cupboard ingredients we rustled up just that. For me Tofu and Green Peppers in Black Bean Sauce and for hubby, Chicken and Green Peppers in Black Bean Sauce. We resorted to boil in the bag rice, a jar of Black Bean Sauce from Lidl and added onions, green peppers and either tofu or chicken. We have two woks in our house one each, they're engraved with a "V" or "M" so we don't get them mixed up. So we cooked (or should I say heated up) the meal together. It was ready within 15 minutes and it was very tasty!
Sunday, 3 February 2013
I was in the mood for cooking up a storm, the slow cooker was on for hubby's tea (this piece of equipment is an absolute god send for cooking his food. I just throw the ingredients in and turn it on)! I fancied something that was full of vegetables with a creamy sauce and this is what I concocted, it was very tasty, filling and filled the craving.Ingredients1 large carrot1 large onion½ head of cauliflower½ head of broccoli150g green beans1 tsp dried thyme2 tsp English mustard1 tbsp flour4 tbsp nutritional yeast (or more if you want a more 'cheesy taste')500ml soy milkSalt and pepperFilo pastry x 4 sheetsMethodTurn on your oven to 180°C. Dice the onion and carrot and cut the cauliflower and broccoli into small florets. Saute the onion in a little olive oil for 3 minutes and add the rest of the vegetables. Continue to saute until the vegetables start to go soft. Add the thyme and mustard and stir to combine thoroughly. Next add the flour and stir to combine, cook for a couple of minutes. Slowly add the milk whilst stirring until all the milk has been added. Next add the nutritional yeast and stir through the mixture. Slowly bring to a simmer and the mixture will start to thicken. Add salt and pepper to taste. Try a little and add more mustard, nutritional yeast or salt and pepper to your desired taste. Spoon into a baking dish and lay the filo over the top creating waves in the pastry. Bake for 20-25 minutes in the oven. Whilst the pie is in the oven boil some potatoes ready to mash to serve with the pie.
Saturday, 2 February 2013
If you're a reader of my blog you will remember I enrolled on a 10 week course on aromatherapy, and I pleased to announce that I passed with flying colours. I thoroughly enjoyed the course and I am seriously considering doing a full time course (over a couple of evenings a week) so I can become a fully qualified aromatherapist. I am confident with the oils that I have purchased and I am able to blend the oils to help promote a more balanced lifestyle, reduce stress and reduce the chance of everyday illnesses. However, without the relevant qualification I cannot continue my journey and become a practitioner. I'm not sure if that's where I want to be yet but it can't hurt opening more doors for the future can it? I need to start saving! Courses these days are not cheap are they?
I use what I have learnt almost every day and I always have an oil burner lit to either help me relax or increase my concentration. I've also made cleaning products, hand creams, body moisturisers, liquid soap, bubble bath, room spray's and my own pot pourri. I made a few creations for Christmas presents and I've received some good feedback which is always encouraging. The most popular was the sleep easy pillow spray I did, which has helped a few people I know.
If you're interested in learning more, check your nearest college to see what courses they offer or check within your community for bite sized courses. There are lots of books out there too, the books my 10 week course recommended are brilliant and you can buy them on Amazon at a reasonable price. The two I purchased are:
Encyclopedia of Essential Oils: The complete guide to the use of aromatic oils in aromatherapy, herbalism, health and well-being.
Aromatherapy: The Essential Blending Guide
Let me know if you decide to learn more and we can swap stories. Have fun!
FRIDAY, 1 FEBRUARY 2013Cowboy Stew PastaJust a quick post tonight as I'm off out with friends, something is better than nothing right? You'll remember the three bean chilli I made (and I made a lot) which hubby renamed cowboy stew. Well, even after the chilli and the cowboy stew topped jacket potato, I still had some left. It wasn't a vast amount so I heated it up and added a small carton of passata and some sweetcorn and mixed it through some pasta. It was great heated up for lunch today!
About Me
Hello my name is Jasmine. I'm passionate about food (growing and eating it!), health and nutrition. I'd been a vegetarian for 27 years and at the very start of 2013 I transferred to a vegan lifestyle. This blog is a record of my progress to becoming a more healthy, happy and less stressful individual. Wish me luck! | {
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Marion Rockefeller Weber
Marion Rockefeller Weber (born 1938) is the second eldest daughter of Laurance Spelman Rockefeller (1910–2004) and Mary French and a fourth generation member of the Rockefeller family. Her paternal great-grandfather is Standard Oil's founder John D. Rockefeller and maternal great-grandfather is Frederick Billings, a president of Northern Pacific Railway.
Biography
Weber is a philanthropist through her Flow Fund and is the founder and director of the Arts and Healing Network, which gives the prestigious "Most Outstanding Healing Artist for the Year" award annually. Weber is quoted as saying the "Arts and Healing Network honors and supports the emergence of healing artists and recognizes them as essential catalysts for positive change." She currently resides in the San Francisco Bay Area of California.
See also
Rockefeller family
Laurance Rockefeller
References
External links
Arts and Healing Network
Category:Rockefeller family
Category:American philanthropists
Category:1938 births
Category:Living people | {
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Q:
wicket authentication / login
I am following this tutorial http://wicket.wordpress.com/2010/01/08/template-for-building-authenticated-webapplication/ in order to learn how to make login and authentication using wicket.
My question/problem is that my login area is on the header and therefor one can login on every page.
If my application class should inherit AuthenticatedWebApplication, then I must override getSignInPageClass method. What page class should I provide?
Is there any other best tutorial to add authentication using wicket?
A:
The sign in page is displayed when the user attempts to access a Page or other component which requires authorization to create. If your application allows login on every page, then none of your pages require authorization, and the sign in page will never be displayed. I suggest you set it to the home page.
As all your pages are visible, you can't use the @AuthorizeInstantiation annotation on your page classes. Instead, you must control visibility of components within the page using the RENDER action instead. For example,
MetaDataRoleAuthorizationStrategy.authorize(mycomponent, RENDER, "SYSADMIN");
The only example I can find is at wicketstuff.org.
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Search
On Film: Los Angeles' LGBTQ History
At a glance, these three Los Angeles buildings look nondescript—completely unremarkable. One is a bar in a blocky white building on Sunset Boulevard in Silver Lake. Another is a U-shaped Spanish Colonial Revival building in a leafy, four-acre park that spans Vista Street, between Santa Monica Boulevard and Fountain Avenue in West Hollywood. Then there’s a three-story brick building on North Spring Street in Chinatown.
But each of these buildings holds a remarkable history. And their stories are told in a new short film series by the Los Angeles Conservancy, LGBTQ Historic Places in L.A. Funded in part by a grant from the Richard and Julia Moe Family Fund of the National Trust and released in partnership with local television station KCET, the three-part series debuted earlier this year.
“This is a way to shine the spotlight on places that are largely unknown, or in some cases forgotten,” says Adrian Scott Fine, director of advocacy at the Los Angeles Conservancy.
Using first-person interviews, photos, and archival material, the films tell the history and significance of these three different sites.
One film explores the history of The Black Cat in Silver
Lake, a working-class gay bar that opened in a 1939 Art Deco building in the
1960s.
Just after midnight on January 1, 1967, eight undercover police officers
raided the bar, beating patrons and dragging them into the street. In response,
local activists organized a demonstration. Hundreds of people gathered outside
The Black Cat on February 11, 1967, in what was one of the earliest known demonstrations
in support of LGBTQ civil rights.
Another film features Plummer Park in West Hollywood, which opened in 1938.
From 1987 to 1996, the Los Angeles chapter of advocacy group AIDS Coalition to Unleash Power, or ACT UP, held its meetings in the park’s Great Hall/Long Hall at the height of the HIV/AIDS epidemic. The group campaigned for greater visibility and more effective treatment for the disease, and played a huge role in getting the federal government to respond to the crisis through new research and healthcare programs.
Built in 1914 for the Standard Oil Company, the Beaux Arts building was The Woman’s Building, a public space for female artists, from 1975 until 1991. Artist Judy Chicago, art historian Arlene Raven, and graphic designer Sheila Levrant de Bretteville founded the Feminist Studio Workshop, the first independent art school for women, which was eventually headquartered there. For nearly two decades, The Woman’s Building was an experimental space for lesbian and feminist culture, with organized programs, activities and artist groups.
Choosing which three sites to feature was like “choosing among your children,” Fine says.
The Los Angeles Conservancy recently completed a fundraising campaign to expand the series and tell the story of at least one other site, if not more.
“Some of these places are starting to become threatened, or they’re closing down, or they’re under development pressure,” Fine says. This film series is a way to memorialize the significance of these places and, Fine hopes, broaden awareness of the LGBTQ story in greater Los Angeles.
Lauren Walser served as the Los Angeles-based field editor of Preservation magazine. She enjoys writing and thinking about art, architecture, and public space, and hopes to one day restore her very own Arts and Crafts-style bungalow. | {
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Q:
Change Oracle Database from Archive log mode to Non-archive log mode
I have an Oracle databse, it is Oracle 11g Standard Edition, Currently it is working in archive log mode. And I need it to be change to non-archive log mode. Because everyday the logs fill the Hard Disks of the server.
Please let me know the steps to do this..
Thanks in advance
Mahesh
A:
To set the database in NOARCHIVELOG MODE, You need to shutdown the db & start it in in mount state. Follow the below steps.
1. shutdown immediate;
2. startup mount;
3. alter database noarchivelog;
4. alter database open;
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Kensington Soldier's Monument
The Kensington Soldiers' Monument is a historic war memorial located at 371 Percival Road, on the grounds of the Kensington Congregational Church in Berlin, Connecticut. Erected in 1863, it is one of the oldest memorials to the American Civil War in the United States, and the first to be erected in Connecticut. It is a modest brownstone obelisk, with an accompanying cannon. It was listed on the National Register of Historic Places in 2013.
Description and history
The Kensington Soldiers' Monument is located in front of the Kensington Congregational Church, at the junction of Percival Avenue and Sheldon Street in Berlin's Kensington neighborhood. The memorial is a brownstone obelisk in height, mounted in a two-part base in height. Each face of the obelisk is engraved with inscriptions, that on the southeast naming the four Kensington men killed in 1863, and that on the southwest naming eight more killed in 1864 and 1865. Two plaques have been attached to the monument, identifying it as the first monument in the nation dedicated to Civil War dead.
Impetus for the erection of the monument originated with the Rev. Elias B. Hilliard of the Kensington Congregational Church in 1862, upon learning of six Kensington dead in Civil War battles. The monument was designed by Nelson Augustus Moore, a prominent Connecticut sculptor, and was cut in a Berlin stone yard from brownstone quarried in Portland. It was formally dedicated on July 28, 1863, with a speech by United States Senator Lafayette Foster. It is distinct from many later Civil War memorials, which tend to include figures of soldiers. A period cannon was placed in front of the monument during semi-centennial commemoration of the monument in 1913.
See also
National Register of Historic Places listings in Hartford County, Connecticut
References
Category:Monuments and memorials on the National Register of Historic Places in Connecticut
Category:National Register of Historic Places in Hartford County, Connecticut
Category:Buildings and structures completed in 1863
Category:Berlin, Connecticut | {
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Pages
05 May, 2013
On the Clock
Less than a minute later, we were in the Task Force Tank. It was kind of freeing to be able to say that a significant portion of our job, Diego and I, was driving a modified golf cart for the better part of a day. The family wasn't too happy, but I don't really give a damn what they have to say about-
"Jesus Christ!" Diego shouted. "Look out!"
I yanked the wheel, cutting the Tank back across the street, tires squealing. We rocked to one side before straightening back out, shooting down the street at a breakneck 20 miles an hour. I hoped none of our neighbors heard that. The last thing I need is for them to come out at 430 in the morning to discover that we've been drinking.
"Hah, sorry, dude."
"Just keep your eyes on the road. That harpy of a woman, Mrs. Fournier, doesn't need more of a reason to hate us." Diego stood up and looked around at the darkened houses for the sudden appearance of wakeful light in the windows. I chuckled to myself.
Appeased, he sat back down and took a gulp off the whiskey, and looked off, almost wistfully.
"How late do you think Sal'll be today?" I barked out a laugh.
"Hah! That's what's on your mind? You looked almost like you were having a thought for a second there."
"Well, if we ever decide to be honest to his folks...." He let the end of the sentence hang in the air.
"If we were ever honest with his parents, I think they'd string you and me up before he got into any trouble, so let's not go down that path, eh?" He seemed satisfied by my answer, so he just sat back in his seat, and took another drink, starting chatter about his usual early-morning topic: which, of two, celebrities would win in a fight.
Several minutes later, we pulled up to our maintenance shack beside the guard gate. There looked to be a man in the shack next to it, asleep at his post, and leaning back in his chair and feet up on the desk. I parked next to it, got out, and rapped on the glass window.
"Ahh, children. Good to see you. How late will the boy be today, hmm?" The three of us lit cigarettes as we thought about it. Cliff, or Clifford to those whom he doesn't care for, was probably the only person, next to Tilly, who didn't look at us like he just stepped in shit. He was a middle-aged black man, graying at the temples, and treated Diego and I as his children, having none of his own, despite having sometimes overwhelmingly powerful paternal instincts.
"Why are you in a towel, son? Is life really so short as to not allow you the opportunity to put on pants?" Diego and I just laughed.
"Hey, heads up, guys. Someone's coming. I wonder if Sal finally got his license." I pointed at the headlights approaching.
"Damn. Not even half done my smoke," grumbled Cliff as the SUV lights stopped before the gate. It was Sal's mom's car. I really hoped he got his license, as I didn't want to have to deal with her right now.
Cliff opened the gate, and Sal, driven by his mom, unfortunately, pulled into a parking spot next to our golf cart. As she got out, unusual by itself, and walked around the SUV, I could tell by the look on her face that she and I realized the same thing at the same time: I still wasn't wearing pants. Swearing under my breath, I took a step forward and greeted her, pretending I didn't notice.
"Good morning, ma'am. To what do we owe the pleasure of your company?" Sal rolled his eyes as he got out. Ahh, teenagers. How I don't miss being one.
"What sort of operation is this? Just what, aside from yourself, are you exposing my son to?" Uh-oh. This was going to turn ugly. I just knew it.
"To the best of my knowledge," I began, "Diego and I run the best lawn-care company this neighborhood has seen in at least a decade. Drive through once the sun is up, you'll see that we're second to none."
"Be that as it may, Mr. Dillinger, I think you should go put some pants on before we continue." Sal was enjoying watching me get scolded by his mom, trying not to laugh, while Diego stood at my side, trying to look sympathetic, and Cliff pretended he wasn't watching.
"Ma'am, our house is on the other end of the community, and we have a lot of ground to cover, if you'll excuse the pun. No one is awake, and the three of us are wholly dedicated to our work. Our craft, even. Blood, sweat, and tears go into creating such beauty." I took a step past Sal's mom and swept my arm over the sleeping houses before spinning back to face her.
"Also, I spilled my coffee on my pants less than a minute before you drove up." She turned to look at Diego, who pretty much looked like he just got out of a pool with that towel, for agreement.
"Is this true?" She raised an eyebrow at him.
"Uh, yes, ma'am," he responded, leaving it at that.
"Excuse me, miss?" came Cliff's voice from the doorway to the shack, joining us for the first time since she arrived. "I can prove it to you." With that, he produced a damp pair of pants from behind him, and I breathed a sigh of relief.
"Oh. Good." She felt the pants for herself. "Anyway, I was wondering when my Sal would be getting that raise you and I...discussed." She took a step towards me, and I took a step back, only slightly intimidated.
"As soon as I get approval from both the community and the state. Having a juvenile parolee on staff is concerning to the residents, and I have to be pliable, trying to get the best for everyone involved. Sal becomes a model employee, the company indispensable for helping troubled youth, and the community for giving a second chance to those whom society deems irreversibly contaminated." I flashed her my best grin, and she seemed to like that response.
"Well, then. Just see to it that you're not doing anything suspicious." She came up close to me and whispered. "And keep up the good work. The hard work and structure seems to be doing him some good."
By means of ending the conversation, she shook my hand, and just before turning around to shake Diego's, Sal yanked off his towel, and jumped back next to Cliff. She turned just in time to see the towel drop, and fainted.
Diego punched Sal, who was laughing his ass off, in the face, Cliff began scolding the both of them. After catching Sal's mother, I just buried my face in my palm, sighing. Some guys just can't ever catch a break. | {
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Garden Inspired Health and Well-Being
The U.S. Department of Agriculture (USDA) has established an organic certification program that requires all organic foods to meet strict government standards. These standards regulate how such foods are grown, handled and processed.
Any farmer or food manufacturer who labels and sells a product as organic must be USDA certified as meeting these standards. Only producers who sell less than $5,000 a year in organic foods are exempt from this certification; however, they must follow the same government standards to label their foods as organic.
If a food bears a USDA Organic label, it means it’s produced and processed according to the USDA standards and that at least 95 percent of the food’s ingredients are organically produced. The seal is voluntary, but many organic producers use it.
Products that are completely organic — such as fruits, vegetables, eggs or other single-ingredient foods — are labeled 100 percent organic and can carry a small USDA seal. Foods that have more than one ingredient, such as breakfast cereal, can use the USDA organic seal or the following wording on their package labels, depending on the number of organic ingredients:
100 percent organic.
Products that are completely organic or made of all organic ingredients.
Organic.
Products that are at least 95 percent organic.
Made with organic ingredients.
These are products that contain at least 70 percent organic ingredients. The organic seal can’t be used on these packages.
Foods containing less than 70 percent organic ingredients can’t use the organic seal or the word “organic” on their product label. They can include the organic items in their ingredient list, however.
You may see other terms on food labels, such as “all-natural,” “free-range” or “hormone-free.” These descriptions may be important to you, but don’t confuse them with the term “organic.” Only those foods that are grown and processed according to USDA organic standards can be labeled organic. | {
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Ukraine's Euromaidan protests are protected by multi-level barricades built from sacks filled with snow. Photo from zyalt.livejournal.com, used with permission
The task of changing what hundreds of thousands of citizens in Ukraine find to be a corrupt, authoritarian regime into a country where a simple, comfortable life is possible for everyone is one that has daunted Ukrainians for many years, but especially so during the years of current President Viktor Yanukovych. Those that oppose the government face persecution – any excuse for a jail sentence. Among the first and most public examples is the imprisonment of his political rival and former Ukrainian Prime Minister Yulia Tymoshenko.
But there is power in numbers. In just over two months, the ongoing anti-government Euromaidan protests pushing back against Yanukovych and other corrupt leaders have evolved into a full-fledged, self-financed organization – a self-organized government of its own. Ilya Varlamov, a popular Russian blogger, who traveled to Kyiv in January to report on Euromaidan for his blog, describes how the movement is run in what he calls a Virtual tour of Maidan:
It has its own army, storehouses with weapons (glass bottles, sticks, stones) and food, it has its own internal press, stores, and, of course, Maidan protects its own boundaries very well. All the approaches are reliably protected from assault by high barricades.
While standing up to the regime as an individual seldom makes a difference, Ukrainians now know that standing up as a group does. kraplya.com, a project that has grown out of the Euromaidan movement, takes a look at that very aspect of the protests (kraplya means “drop” in Ukrainian).The project's official website makes it clear: “Alone, we are just drops; together, we are an ocean.”
The people who gather on the streets to protest each day are the drops from all over Ukraine that have made this ocean, now visible to the world, possible. Some have been living in the streets by choice for more than two months. Some come to join them after work or other daily errands. Artist Oleksandr Komyakhov has drawn portraits of some of them.
Sister of mercy
Drawing of woman carrying bags full of medicine to Maidan. Drawing by Oleksandr Komyakhov, used with permission.
In her hands she carries bags full of medicine. The woman represents the many people who have brought the movement much-needed medical supplies. The Berkut special riot police often break ribs, bones and leave other injuries, while activists living in the frozen streets, and some of them for months now, at times need treatment.
The Euromaidan SOS Facebook page publishes hourly updates on the needs of Euromaidan protesters. The medicine brought to the protests is sorted by hundreds of volunteers every day. The Maidaners organized their own hospital and equipped it well enough to function and serve at a regional level, crowdfunding even defibrillators and other surgical equipment. They have a real need for such equipment as activists are being kidnapped from official hospitals by police forces, so protesters have decided it’s best not to show up there.
Wealthy terrorist
Not long ago, now former Prime Minister Mykola Azarov made a statement referring to the protesters at Euromaidan as “terrorists”.
Man bringing tires and fuel to the frontline. Drawing by Oleksandr Komyakhov, used with permission
In a story told by Andriy Priymachenko, the man on the right is is the sarcastically dubbed “wealthy terrorist”. He brings tires in his expensive car to the boys at the “frontline” between the protesters and the Berkut militia:
January 22. Around 23:00.
A white off-road Lexus is parking in the middle of the European square. The driver, a 50 year-old man, goes to the back of the car and searches for boys going to the frontline in the crowd.
- Guys, give me a hand!
A group of boys in masks immediately run up to him. All have helmets on their heads. The Lexuses [sic] owner takes his expensive leather gloves off, opens the trunk, and unloads tires. The boys ask no extra questions, take the tires and start carrying them in the direction of the frontline. Finally the driver takes a dark-green canister with fuel out of the trunk.
- This goes also there. Well, you’ll figure it out.
Berkut snipers have killed several protesters so far. A smoke curtain created by burning tires, put up by Euromaidan protesters, seems to have put an end to that. Thousands of tires, brought by thousands of cars, driven by thousands of people.
Other items that Maidan is constantly in need of come in the same way: clothes, food, firewood, computers, blankets, sleeping bags, helmets, gas masks, protective gear, even books for the library that has now been organised for the protester's needs.
Recently, police cut off access for large trucks carrying firewood to Maidan, but the little drops that are the protesters bring them to the main protest site on the subway.
Auntie Valya
One of Euromaidan's participants, Auntie Valya. Drawing by Oleksandr Komyakhov, used with permission
Speaking of such “terrorists”, they seem to come in all ages – and police forces don't seem to discriminate. Twitter user bruce springnote tweeted the apparent mishandling of this elderly Euromaidan protester:
This is my neighbor auntie Valya. Yesterday she was shot with a rubber bullet in her leg, but she came again. And today, when the berkuters were “killing a 86-year-old grandfather”, filming their “amusement” and heehawing, she fell to her knees and asked them to stop or at least to kill her instead of him. They did that, but, thanks to God, did not kill her. Beat her ribs with sticks and heehawed again and were very interested “So it’s not enough for you, bitch!??” “
The Gammy
One of Euromaidan's participants, the Gammy. Drawing by Oleksandr Komyakhov, used with permission
Maidan's drops come in all sizes, varieties, and physical abilities.
Some protesters with disabilities have abandoned their crutches and taken sticks in their hands, while people in wheelchairs are busy clearing snow. People with other disabilities, such as blind people serving sandwiches, have also been of help to the movement.
The Ant
One of Euromaidan's participants, “The Ant”. Drawing by Oleksandr Komyakhov, used with permission
Snow is a valuable resource. It is shoveled into sacks, carried by many hands over to the barricades, where the sacks are stacked like enormous bricks, then poured over with water, making a frozen wall that is almost impossible to pass.
Moscow deputy bureau chief for The Wall Street Journal and Maidan correspondent James Marsontweeted his observation:
Just saw a lady in high-heeled boots and fur coat shoveling snow for #euromaidan defenses. Really are all sorts here
Water cements the stacks and makes a solid wall up to 4-5 meters in height. Thus, Maidan is circled by a defensive wall like a medieval city and well protected. The wall prevent attacks from the Berkut forces who are constantly expected to come armed with water cannons, tear gas, clubs, and shields.
Artist Oleksandr Komyakhov is regularly updating his collection of portraits of drops that make up Euromaidan. His full gallery of Euromaidan participants can be viewed on his Facebook page. | {
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Joe Boozell has been a college basketball writer for NCAA.com since 2015. His work has also appeared in Bleacher Report, FOXSports.com and NBA.com. Joe’s claim to fame since joining NCAA.com: he’s predicted the correct national championship game twice… and picked the wrong winner both times. Growing up, Joe squared off against both Anthony Davis and Frank Kaminsky in the Chicagoland basketball scene. You can imagine how that went.
The views on this page do not necessarily reflect the views of the NCAA or its member institutions.
Oklahoma State won the national title on its home course last season, defeating Alabama in the finals at Karsten Creek. Led by U.S. Amateur champion Viktor Hovland and the Cowboys have won six tournaments this season, taking the Big 12 title in their previous start. | {
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Elope in Mykonos, Greece. The Cycladic dream!
Have you by any chance decided to elope in Greece and chosen Mykonos for your romantic intimate wedding? Excellent choice! Mykonos is by far the most popular and cosmopolitan Greek island. Every time I visit it, I feel allured by its unique mixture of traditional color and insular Cycladic architecture. Everything about it –the famous windmills, the narrow cobblestone streets, the freshly whitewashed houses with the blue shutters, and of course the awesome sandy beaches– are a wedding photographer’s dream!
Jonathan and Keleen decided to elope in Greece and experience an amazing once-in-a-lifetime adventure! After cruising in Europe for several days, they ended up in Mykonos, where they decided to exchange vows and prove their mutual love. Keleen was so ecstatic over the Mykonian windmills that she asked me if we could do an elopement photoshoot there… and so we did! The result was a series of excellent wedding photos of one of the sweetest couples I have ever met! I feel that I owe them a big thank you, not only for letting me be a part of their happy wedding day but also for sharing their unique energy with me.
Elopement couples
You know what elopement or adventure couples are? They are couples who live their life to the fullest travelling together and sharing adventures; no destination is too far away, no trip is impossible. To them, the world is full of wonderful places waiting for them to discover and explore them. This is exactly what Jonathan and Keleen do. They just love trips! Many times a year they set sail for new adventures by car, plane or train. No matter what the distances are and what obstacles or difficulties they may come across, the only thing that matters to them is living every moment together!
Photoshoot at St John hotel
Now, let us continue our story: As soon those two adventurers arrived at the Greek island of Mykonos they headed for St. John Hotel; it was time for the pre-wedding preparations and also the opportunity for some unique photos.
The secret of wedding photography lies in detail; you do not know when a special moment will arise. With your hands on the camera, you have to be ready to capture the moment. Fortunately Jonathan and Keleen offered me much more than I expected!
I took some excellent photos of Jonathan during his preparation. As to Keleen, during the bridal makeup and hair styling she posed so naturally that I was able to take some stunning photo portraits. Then it was time for the “first look” photos inside St. John Hotel. The setting was perfect: great terraces against a dazzling white background, with a view over the coast of Agios Sostis and of course the Cycladic windmills that Keleen was so fond of. The success of their photoshoot can be attributed to a mixture of various elements blended perfectly together: the love, happiness and joy emanating from this beautiful couple, the harmony between them, their relaxed stance and sweetness of disposition and the pure magic of an atmosphere created by the breathtaking scenery and the fascinating culture of Mykonos. To me, doing wedding photography –which I absolutely adore– while breathing the fresh breeze of the Aegean Sea is a lifetime dream!
A Greek elopement in Mykonos
If you want to elope in Greece, you have to be ready for an adventure. That’s the message that the photos of this happy couple convey. Jonathan & Keleen’s elopement was like the cheerful game of two kids who set sail for a distant Greek island and lost themselves through the narrow paved streets and among the sparkling white chapels against a backdrop of clear blue seas and skies.
It was now time for their elopement photoshoot, so we moved to one of the most picturesque places in Greece: the iconic little church of Panagia Paraportiani at the Chora of Mykonos, undeniably one of the best elopement choices for couples both from Greece and from abroad…
So the day rolled along, with some excellent shots at the white chapel of Panagia Paraportiani. The lovely couple seemed to be playing hide and seek among the whitewashed walls and the cobblestone alleys of Mykonos, reflecting the childhood innocence still alive inside them and their playful and cheerful mood. Jonathan and Keleen’s elopement in Greece was not just a love story; it was the amusing sweet game of two lovers and friends!
The wedding ceremony was held inside the hotel, at the church of St. John, a charming Mykonian white chapel. The air pulsed with joy and the couple seemed so devoted to each other that I am sure nothing in the world could ever break this bond!
Jonathan and Keleen, thank you from the bottom of my heart for your trust and for the wonderful time in Mykonos. I sincerely wish you all the happiness in the world and all the blessings in life! | {
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BOOK REVIEW: “Wired For Story” by: Lisa Cron
Two things that fascinate me are storytelling and how the brain works. Normally these are separate areas of study but in the book, “Wired for Story” the author Lisa Cron explores them both simultaneously. On a neurological level storytelling provides stimulus that allow our subconscious mind to create tools to help guide us through our lives. Below are a few excerpts from the book. If you are a playwright, novel writer or screenwriter this is a must read.
The biggest thing that this book does a good job of, is reminding us of the easily forgotten truth that it’s our job as the writer to keep the audience asking what’s going to happen next. In the first chapter, “How to hook the reader” the author says, “From the very first sentence, the reader must want to know what happens next.” This is such a simple truth but one that I know I can forget especially when I’m trying to remember all of the other story telling elements. This idea is the foundation of good storytelling and is a truth that all writers need to be reminded of.
Here are the rest of the ideas I really enjoyed from this book:
“Is there conflict and what’s happening? Will the conflict have a direct impact on the hotel you miss quest, even though your reader might not know what that quest is?
“Is there a sense that all is not as it seems? This is especially important if the protagonist isn’t introduced in the first few pages, in which case it pays to ask: Is there a growing sense of focused foreboding that’ll keep the reader hooked until the protagonist appears in the not-too-distant future?”
“It’s the synthesis of three elements that work in unison to create a story: the protagonist’s issue, the theme, and the plot.”
“…They had mistaken the story for what happens in it. But as we’ve learned, the real story is how what happens affects the protagonist, and what she does as a result.”
“That’s why in every scene you write, the protagonist must react in a way the reader can see and understand in the moment. This reaction must be specific, personal, and have an effect on whether the protagonist achieves her goal. What it can’t be is dispassionate objective commentary.”
“That’s what readers come for. Their unspoken hardwired question is, If something like this happened to me, what would it feel like? How should I best react?”
“Your job is not to judge your characters, no matter how despicable or wonderful they may be. Your job is to lay out what happens, as clearly and dispassionately as possible, show how it affects the protagonist, and then get the hell out of the way. The irony is, the less you tell us how to feel, the more likely will feel exactly what you want us to.”
“It’s no wonder that truth is stranger than fiction. Fiction has to make sense.”
“In fact, Steven Pinker defines intelligent life as “using knowledge of how things work to attain goals in the face of obstacles.” Almost sounds like the definition of story, doesn’t it?”
“… without a goal, everything is meaningless.”
“Books say: she did this because. Life says: she did this. Books are worth things are explained to you; Life is where things aren’t.” – Julian Barnes
Quote from Citizen Kane: “Nothing is ever better than finding out what makes people tick.”
“No one ever does anything for no reason, whether or not they’re aware of the reason. Nothing happens in a vacuum, or “just because”–especially in a story. The whole point of the story is to explore this ”why”…”
“Why, then, do writers so often leap in without knowing what, exactly, the protagonist’s problem actually is? Often it’s because they’re hoping it’ll become clear if they just start writing. But if you don’t know what’s broke, how can you write a story about fixing it?”
“That’s why, when writing your protagonists’s bio, the goal is to pinpoint two things: the event in his past that knocked his worldview out of alignment, triggering the internal issue that keeps him from achieving his goal; and the inception of his desire for the goal itself.”
“Have you made your characters reveal their deepest, darkest secrets to you?”
“…the only real constant is change, and change is driven by conflict.”
“Talk about conflict! And that brings us right back to story. Story’s job is to tackle exactly how we handle that conflict, which boils down to this: the battle between fear and desire.”
“This is crucial, since the protagonist is only as strong as the antagonist forces her to be.”
“If we don’t know there’s intrigue afoot, then there is no intrigue afoot.”
“Show me!”
“…there’s nothing readers love more than to be fooled, as long as, once the truth is revealed, everything still makes complete sense, both in the moment it happens and in hindsight after the “real truth” is revealed.”
“Have you made sure that the basis of future conflict is sprouting, beginning on page 1? Can we glimpse avenues that will lead to conflict? Can we anticipate the problems that the protagonist might not yet be aware of?”
“The good news is when it comes to keeping your story on track, it boils down to the mantra if, then, therefore. If I put my hand in the fire (action), then I’ll get burned (reaction). Therefore, I’d better not put my hand in the fire (decision).”
“The first law of thermodynamics: you can’t get something from nothing. Or as the equally brainy Albert Einstein reportedly quipped,”Nothing happens until something moves.”
“Does your story follow a cause-and-effect trajectory beginning on page 1, so that each scene is triggered by the one that proceeded it? It’s like setting up a line of dominoes, you tap the first one, and they all fall in perfect order as each scene puts the “decision” made in the prior scene to the test.”
“A story’s job is to put the protagonist through tests that, even in her wildest dreams, she doesn’t think she can pass.”
“We are social creatures, the need to belong is as basic to our survival as our need for food and oxygen.”
“No man is more unhappy than the one who is never in adversity; the greatest affliction of life is never to never be afflicted.”
“Information is currency. It has to be earned. No one gives it away for free, and everything has a price. Your protagonist needs a compelling reason to admit anything. It either gains him something or keep something bad from happening. It’s never neutral.”
“Surprise ’em with what they expect.”
“It must be that those who aim at great deeds should also suffer greatly.”
Carl Jung said, “One does not become enlightened by imagining figures of light, but by making the darkness conscious.”
“Does your protagonist earn everything she gets, and pay for everything she loses?”
“Does everything that you’re protagonist does to make this situation better actually make it worse?”
“Is the force opposition personified, present, and active?”
“Is there a clear series of events, a pattern, that begins with the set up and culminates in the payoff?”
“Do all your subplots affect the protagonist, either externally or internally, as he struggles with the story question?”
“Have you given your reader enough information to understand what’s happening, so that nothing a character does or says leaves are wondering whether she missed something?”
“When you leave into a subplot or flashback, can the readers sense why it was necessary at that very moment?”
This brings us to a very helpful set of questions to ask yourself as you begin writing or rewriting each scene:
–What is actually going on in the story’s “real world”– That is, objectively?
–What does it each character believe is going on?
–Where are there contradictions?
–Given what each character believes is true how would they act in the scene?
–Does what each character does in the scene makes sense, given what he or she believes is true?
“Finally, there is one more person whose shifting beliefs you want to chart: the reader.”
Feedback questions
– What do you think is going to happen next?
–Who do you think the important characters are?
– What do you think the characters want?
–what, if anything, leads out as a setup?
– What information did you think was really in porn?
– What information were you dying to know?
–what did you find confusing? (this is as close to a real critique as we’ll get.)
“Writers need impartial feedback, and one of a lot of places to get it is a writers’ group. The members of an effective writing group need to be astute and able to not only point out what isn’t working but also tell you why. The rub, of course, is that they also have to be right. The places where something isn’t working are not hard to spot. What’s hard is explaining exactly why it isn’t working. This often leads to misguided advice, which results in the writer either making the problem worse or simply substituting one thing that isn’t working for another.”
Everything that I have just cited are my personal notes. I’m documenting these more for myself than anyone but I believe that this book is a great read for anyone who is putting together a story. Good luck with your writing. | {
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Red snow (Watermelon snow)
Have you ever seen red colored snow ? Red snow or watermelon snow usually can be seen in spring or early summer when snow is thawing. Red snow is a common phenomenum on snow fields and glaciers in many parts of the world. Red snow is caused by blooming of snow algae. Microscopy of red snow shows red colored cells of snow algae. | {
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It's been a tough week of training for the Manchester United players in the hot Los Angeles heat.
Jose Mourinho's squad have been working hard to get back to fitness ahead of the start of the new season with intense double training session at their base at UCLA.
And while it's been a hard few days as the players prepare for their first of eight pre season tour games, including a Manchester derby and a Super Cup tie with Real Madrid, the players have been in high spirits.
The mood in the United camp is good with plenty of pictures of the players laughing and joking on the pitch and youngster Scott McTominay told MUTV that new recruits Victor Lindelof and Romelu Lukaku have already settled in. | {
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An exploration of women offenders' health literacy.
In the past decade the sentencing of women in Canada to correctional detention has increased. Compared to the general population, women in conflict with the law tend to have higher rates of mortality and morbidity. This exploratory research investigated health promotion and health-literacy issues for women offenders. Semistructured interviews of 12 women serving probation orders were analyzed. Data analysis highlighted three overarching themes: (a) health information access, (b) networks of support, and (c) tailoring the health system. These findings have relevancy for health promotion practice with women offenders, and implications for correctional services community reintegration programs and community health sectors. | {
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Abbott v Abbott
Abbott v Abbott [2007] UKPC 53 was advice from the Privy Council on a case from the Court of Appeal of Antigua and Barbuda, that is relevant for English land law and concerns the nature of constructive trusts.
Facts
Mr and Mrs Abbott were in Antigua and Barbuda and were married. There the shares would still be determined by property law. Mr Abbott was the registered owner. Mr Abbott did not dispute that Mrs Abbott had a share, but disputed the amount.
Judgment
Baroness Hale, delivering the opinion of the Board, said the following.
See also
English land law
English property law
Notes
References
External links
Category:English land case law
Category:2007 in Antigua and Barbuda
Category:2007 in case law
Category:Judicial Committee of the Privy Council cases on appeal from Antigua and Barbuda | {
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Tire fire
Tire fires are events that involve the combustion of large quantities of tires, typically in locations where they are stored, dumped, or processed. They exist in two forms: as fast-burning events, leading to almost immediate loss of control, and as slow-burning pyrolysis which can continue for over a decade. They are noted for being difficult to extinguish. Such fires produce much smoke, which carries toxic chemicals from the breakdown of synthetic rubber compounds while burning.
Tire fires are normally the result of arson or improper manipulation with open fire. Tires are not prone to self-ignition, as a tire must be heated to at least for a period of several minutes prior to ignition.
Extinguishing tire fires is difficult. The fire releases a dark, thick smoke that contains cyanide, carbon monoxide, sulfur dioxide, and products of butadiene and styrene. Burning tires are heated, and, as they have a low thermal conductivity, they are difficult to cool down. Moreover, they frequently burn inside even if they are extinguished from outside, and easily reignite when hot. One possible remedy is to cover the fire with sand, reducing the supply of oxygen and the exhaust of smoke. After extinguishing and cooling down (which may last several days), toxic chemicals can be neutralized.
In Northern Europe, new and used tires are stored in large warehouses also known as tire hotels. Fire is a growing concern, and as tire fires are difficult to extinguish, regular sprinkler systems are not sufficient. Inert gas extinguishing systems like INERGEN in combination with an effective detection system would be the preferred choice for protecting these warehouses. Tests for establishing the minimum design concentration (MDC) are currently being performed in Denmark.
Notable tire fires
Some notable tire fires include:
1983 – Seven million tires burned for nine months in Winchester, Virginia, polluting nearby areas with lead and arsenic. The location was cleaned up as a Superfund project from 1983 to 2002.
1984 – A pile estimated at four million tires, known locally as Mount Firestone, ignited in Everett, Washington, and burned for months as the fire department was unable to extinguish it.
1989 – In Heyope (near Knighton, Powys, Wales) a fire involving approximately 10 million tires burned for at least 15 years.
1990 – In Hagersville, Ontario, a fire started in a pile of 12 to 14 million tires; it burned for 17 days and forced 4,000 people to evacuate.
1994 – In East Chicago, Indiana, a fire consumed 70,000 tons of tires and shredded rubber. It started on July 16, 1994 and burned until August 22, 1994.
1995 – The Hornburg tire fire in Sinclairville, New York burned over a million tires in a blaze lasting more than a week.
1996 – An arson in March at an illegal tire yard underneath a section of I-95 in Philadelphia caused $6 million in damage and completely closed a section of the highway for weeks and partial closures for six months.
1998 – A grass fire ignited the 7 million tires at the unlicensed S.F. Royster Tire Disposal Facility in Tracy, California. It was extinguished, after 26 months, with water and foam in December 2000.
1999 – On August 21, arsonists ignited the former Kirby Tire Recycling facility, containing an estimated 25 million tires located on near Sycamore, Ohio. The fire burned for 30 hours, involved over 250 firefighters, the Ohio National Guard and the U.S. Environmental Protection Agency (EPA) and caused significant environmental damage. The fire was controlled and finally extinguished in part by covering it with dirt. In the intervening years the EPA has performed a massive clean up effort on the site.
1999 – Lightning struck a tire dump in Westley, California, which burned for 30 days. Pyrolitic oil flowed into a nearby stream and also ignited.
2002 – The EnTire Tire Recycling facility in Nebraska City, Nebraska burned for over eleven days. An explosion occurred during the firefighting effort, injuring thirteen firefighters. Multiple evacuations of up to a 30-block area were ordered during the event. Over 40 agencies assisted during the event at an estimated cost of $1.4 million.
2005 – A fire started at Watertown Tire Recyclers in Watertown, Wisconsin on July 19 and burned for six days. 108 fire departments and more than 25 agencies assisted in handling the disaster.
2008 – a malfunction in the chopper/shredder line of the Golden by-products tire recycling plant in Ballico, California ignited rubber debris around the conveyor system which then ignited two multi-ton piles of shredded/chopped rubber. It only burned for about 12 hours but took over 1 million gallons of water extinguish. The piles were allowed to form a crust which in turn smothered the fires in them. The plant was later cited for exceeding permitted capacity.
2012 – On January 27, 2012, a massive tire fire sparked at a tire recycling plant in Lockport, New York, causing dangerous amounts of soot and smoke to burn over the city for over 22 hours, causing serious damage to many homes.
2012 – In Jahra, Kuwait, a five million tire fire erupted on April 16, 2012. The fire was thought to be started deliberately by scrap metal hawkers looking to recover scrap metal.
2012 – In Iowa City, Iowa, at approximately 6:45 p.m. on May 26, 2012, a fire started in the ground tire bedding material at the Iowa City Landfill, involving at least 7.5 acres of landfill. It was finally extinguished on June 12, 2012, after a "stir, burn and cover" operation.
2012 – Tire fire protests erupted all over Lebanon. Protesters used burning tires to cut off main roads in Lebanon.
2013 – Tire fire ignited in Nassau, Bahamas. The poorly managed municipal dump has had multiple fires and finally resulted in a tire fire on August 13.
2014 – Tire fire ignited in Savannah, Georgia on February 8, 2014.
2015 – On August 18, in northwest Oklahoma, a tire fire in a large pile of tires next to the premises of A&T Tire and Wheel set the exterior of the business ablaze, but crews prevented flames from getting inside.
2015 – On August 18, a fire in Oregon disrupted the Warm Springs Tribal Reservation. Erroneously referred to by locals and news media as a "tire fire", the blaze caused by the sparks formed from a recreational vehicle driving on a bare rim engulfed more than 60,000 acres of land at the reservation.
2016 – On May 13, in Seseña, Spain, a fire started in a tire dump containing around 5 million tires.
2016 – On August 10, a tire fire sparked at Liberty Tire Recycling in Lockport, New York. Over 8 million pounds of crumb rubber ignited, destroying four buildings and evacuating over 400 families from nearby homes.
2017 – On January 17, a tire fire started at Federal Corporation Zhongli Factory in Taoyuan, Taiwan. More than half the factory (50,000 square meters) was on fire and over 140 families were evacuated from nearby homes. The area was heavily contaminated with carbon black.
2017 – Sunday March 5 at 10:58 p.m., firefighters responded to a fire at the EnTire Recycling facility in Phelps City, Missouri. Heavy smoke caused intermittent closure of Highway 136 and officials to advise nearby residents to avoid breathing the smoke, which could be seen over 10 miles away. This fire continued to smolder through August 2017.
See also
Tire recycling
Necklacing
References
External links
U.S. Environmental Protection Agency: Tire Fires
UK Health and Safety Executive - Spontaneous Tire Ignition
Fire
Category:Types of fire | {
"pile_set_name": "Wikipedia (en)"
} |
Instagram today announced new security and authenticity measures, the biggest of which is a handy application for users to request verification within the app.
Verified accounts are already a thing on Instagram, obviously. Like every other social media service, they’re identifiable by the blue check mark:
The difference is that now, anyone can ask for verification, as opposed to just hoping their influence will catch the company’s eye.
It’s surprisingly easy. Just go to your settings, and look for the new tab titled “Request Verification.” Then you have but to enter your handle, name, and a photo of your ID (though a business document such as a tax filing will suffice), and you’re off to the races. A spokesperson also confirmed the form is available to everyone — heck, I have the form, and my “reach,” if you can even call it that, is about that of the average town crier.
Granted, the ease of asking isn’t analogous to ease of verification. As the application informs you, it’s not a guarantee you’ll get the blue check mark — those are still reserved for accounts who need to prove they’re “the authentic presence of a notable public figure, celebrity, global brand or entity.” But if you do reach a large audience and the company hasn’t verified your identity already, it’s a much easier and legitimate way of getting to that mark than burning some sage and hoping for the best.
The other major tools Instagram announced were support for third-party authenticators, which will be rolling out in the coming weeks, and new “About” pages, which give a run down of basic account details, including how long it’s been active and what country it’s located in.
Mike Krieger, Instagram’s co-founder, says these tools are part of a larger effort to eradicate untrustworthy accounts:
As the CTO of Instagram, keeping people with bad intentions off our platform is incredibly important to me. That means trying to make sure the people you follow and the accounts you interact with are who they say they are, and stopping bad actors before they cause harm.
Verification is still a thorny topic. The question of who “deserves” that badge caused a stir on Twitter earlier this year when users rebelled against certain users being verified. While Twitter insisted the badge wasn’t a mark of prestige, it was at such a loss as to how to clarify this it temporarily suspended all verification requests.
Now that the application for verification is more straightforward, I suspect rejections will have much the same effect: “If X is verified, why not me?” But it’s still good to at least have the option of asking.
New Tools to Help Keep Instagram Safe on Instagram
Read next: Intel's new mobile processors brings faster Wi-Fi and mild performance boosts | {
"pile_set_name": "OpenWebText2"
} |
Endobronchial tuberculosis presenting as tumorous mass.
We report a case of an 18-year-old boy presenting with features of right middle lobe collapse. On bronchoscopy, a tumorous type of endobronchial tuberculosis was found to be obstructing the lumen of the right middle lobe bronchus. On treatment with anti-tuberculous drugs the growth resolved significantly within three months. The patient, however, developed mild stenosis of the airway. | {
"pile_set_name": "PubMed Abstracts"
} |
Q:
Create waffle chart in ggplot2
I'm trying to create a graph like this:
in ggplot2.
The idea is to visualize the distribution of True/False values, i.e. in the upper bar 3 out of 80 and in the lower bar 2 out of 280.
How would one do this in ggplot2?
A:
You can use the waffle package.
library(waffle)
parts <- c('TRUE' = 3, 'FALSE' = 77)
p <- waffle(parts, rows = 8, colors = c("black", "grey70"))
p
class(p)
#[1] "gg" "ggplot"
This is how you could combine two charts like in the graph above
iron(
waffle(
c('TRUE' = 3, 'FALSE' = 77),
colors = c("black", "grey70"),
size = 0.5,
pad = 20,
legend_pos = "none"
),
waffle(
c('TRUE' = 2, 'FALSE' = 278),
colors = c("black", "grey70"),
size = 0.5,
legend_pos = "bottom"
)
)
| {
"pile_set_name": "StackExchange"
} |
Revson Cordeiro dos Santos
Revson Cordeiro dos Santos (born 20 December 1987 in Cascavel), simply known as Revson, is a Brazilian footballer who plays as a midfielder. He currently plays for Operário Ferroviário.
References
External links
Revson at ZeroZero
Category:1987 births
Category:Living people
Category:Brazilian footballers
Category:Association football midfielders
Category:Grêmio Foot-Ball Porto Alegrense players
Category:Sociedade Esportiva e Recreativa Caxias do Sul players
Category:Associação Atlética Iguaçu players
Category:Pato Branco Esporte Clube players
Category:Avaí FC players
Category:Associação Desportiva São Caetano players
Category:Esporte Clube Internacional de Lages players
Category:C.D. Nacional players
Category:PFC CSKA Sofia players
Category:Primeira Liga players
Category:First Professional Football League (Bulgaria) players
Category:Expatriate footballers in Portugal
Category:Expatriate footballers in Bulgaria | {
"pile_set_name": "Wikipedia (en)"
} |
ird derivative of -280*b**3*n + 2*b**3 - b**2*n + 2*b**2 - 97*n wrt b?
-1680*n + 12
Differentiate -q*w**4 + 32*q*w**2 - 2752*q + 5*w**2 with respect to w.
-4*q*w**3 + 64*q*w + 10*w
What is the first derivative of -5*k**4 + 88*k*n**2 - 50*n**2 - n wrt k?
-20*k**3 + 88*n**2
Differentiate -2954*j**3 - 1714 with respect to j.
-8862*j**2
Find the third derivative of -239*k**3 + 134*k**2.
-1434
What is the second derivative of f**3*k**2 - f**3 - 16*f**2*k + 2*f**2*y**2 + 53*f*k**2*y**2 - 2*k**3*y + 2*k*y wrt k?
2*f**3 + 106*f*y**2 - 12*k*y
Find the second derivative of -1972*c**2 + 16*c + 142.
-3944
What is the third derivative of 17929*m**4 + 2773*m**2?
430296*m
What is the second derivative of 60*b**3*r**5 - b**3*r + 52*b*r + 2*r**5 + 2 wrt r?
1200*b**3*r**3 + 40*r**3
Find the third derivative of 3*w**2*z**3 - 46*w**2*z - 2*w - 6*z**5 - z**2 wrt z.
18*w**2 - 360*z**2
What is the second derivative of -4241*x**3 - 226*x - 9?
-25446*x
What is the first derivative of 11707*p**2 + 1358?
23414*p
Find the third derivative of 36*v**4 - 3*v**3 - 114*v**2 - 40 wrt v.
864*v - 18
What is the derivative of -1489*z**3 - 2026?
-4467*z**2
What is the third derivative of 14*z**6 + 16*z**4 + z**2 + 20*z wrt z?
1680*z**3 + 384*z
What is the third derivative of 8*z**4 - 204*z**3 + 2281*z**2 - 4*z wrt z?
192*z - 1224
Find the second derivative of -7*j**3 - 12*j**2 + 175*j.
-42*j - 24
Find the second derivative of -2*i**5*o - 4*i**4 - 2*i**2*o - 461*i*o wrt i.
-40*i**3*o - 48*i**2 - 4*o
Find the second derivative of -8*d**4 + 496*d wrt d.
-96*d**2
What is the third derivative of 16*o**6 - 96*o**5 + 242*o**2 + 8*o - 2?
1920*o**3 - 5760*o**2
What is the first derivative of 27*l*o*v*x - 14*l*v*x + l*x + l + 2*o*v*x + 1102*o*x wrt v?
27*l*o*x - 14*l*x + 2*o*x
Find the first derivative of -v**4*z - 2*v**2*z - 19*v + 23*z - 6 wrt v.
-4*v**3*z - 4*v*z - 19
What is the third derivative of -1355*p**3 + 7160*p**2 wrt p?
-8130
Find the third derivative of 20762*q**3 + 8*q**2 + q + 181 wrt q.
124572
Find the first derivative of 405*b**4 + 3*b**3 + 5878.
1620*b**3 + 9*b**2
What is the second derivative of -86*c**2 - 294*c?
-172
Find the second derivative of -19*d**3 + 6*d**2 - 26*d wrt d.
-114*d + 12
Find the third derivative of 3*c**2*f**3 - c**2*f**2*t**2 + 2*c**2*t - 400*c*f**3*t**3 - 18*c*f*t**3 - c*f wrt f.
18*c**2 - 2400*c*t**3
Find the third derivative of 3*d**6*g + 22*d**3*g**2 + d**2*g - 22*g**2 wrt d.
360*d**3*g + 132*g**2
What is the third derivative of 4833*o**3 - 13901*o**2?
28998
What is the second derivative of 1054*g**3*l**2 + 3*g**3 - 3*g*l**2 + 335*l wrt l?
2108*g**3 - 6*g
Differentiate 267*m*o**3 + 2*m*o + 2435*o**3 wrt m.
267*o**3 + 2*o
Find the first derivative of 90*j*s**2 + 117*j wrt s.
180*j*s
Find the first derivative of -17789*b + 13419.
-17789
Find the second derivative of -19870*d**4 - 76*d - 57.
-238440*d**2
Find the third derivative of -1201*h**5 + 2*h**4 - 2*h**3 + 212*h**2 - 9*h.
-72060*h**2 + 48*h - 12
What is the second derivative of -331*d**2 + 2*d + 3?
-662
Find the third derivative of -15*h**5*t**2 + h**2*t**2 - t**2 - 19*t wrt h.
-900*h**2*t**2
Differentiate -107*d**4 - 2*d**3 + 2*d + 8337.
-428*d**3 - 6*d**2 + 2
What is the third derivative of 1110*i**6 + 1170*i**2 wrt i?
133200*i**3
Find the second derivative of 2*p**5 + 117*p**3 + 473*p wrt p.
40*p**3 + 702*p
What is the derivative of -467*a**4*o**3 + a**4 - 2*o**3 + 62 wrt a?
-1868*a**3*o**3 + 4*a**3
Find the second derivative of -259*b**3*v**5 - 8*b**3*v**2 + 2*b**3*v - 2*b**3 + 413*b**2*v wrt v.
-5180*b**3*v**3 - 16*b**3
What is the first derivative of 51*c**2 - 6*c + 1169?
102*c - 6
Find the third derivative of 30*w**3*y**3 - 4*w**3*y - 4*w**2*y**3 + 12*w**2 - 2*y**3 wrt w.
180*y**3 - 24*y
Find the third derivative of -1085*d**4 + 210*d**2 - 17.
-26040*d
Differentiate -3*f**3 + 6*f*y**2 - 13*f - y**2 - 28 with respect to f.
-9*f**2 + 6*y**2 - 13
Find the first derivative of 386*p - 297 wrt p.
386
What is the second derivative of -18*c**2*u**3 - 69*c**2*u + 8*c*u**3 - c*u - 17*u**3 wrt c?
-36*u**3 - 138*u
What is the first derivative of 332*b*g*x**2 + b*g - 7*b*x + 43*x**2 wrt g?
332*b*x**2 + b
What is the first derivative of 19*i**2 + 19*i - 28563 wrt i?
38*i + 19
What is the third derivative of -203*o**6 - 180*o**2 wrt o?
-24360*o**3
Differentiate a*i*p**3 + 70*a*i - 5*a*p**3 + 2*i*p**3 - 3*i*p - 371*i with respect to a.
i*p**3 + 70*i - 5*p**3
What is the derivative of 1970*t**3 - 555?
5910*t**2
Find the first derivative of 7*a**3*j*m**3 + a**3*m**2 - 27*a*j*m**3 - 2*a - 5*m**3 wrt j.
7*a**3*m**3 - 27*a*m**3
Differentiate 2*d**2*o**2 + 10*d**2*o*s + 127*d*o**3*s - 46*d*o**3 - 2*d*o + 3*o**2 with respect to s.
10*d**2*o + 127*d*o**3
Find the third derivative of v**4 + 1351*v**3 + 2*v**2 + 33*v - 2 wrt v.
24*v + 8106
Find the second derivative of -210*b*p**3 + b*p**2 + 416*b*p wrt p.
-1260*b*p + 2*b
Find the second derivative of 61*v**5 + 20*v**2 + 1058*v wrt v.
1220*v**3 + 40
What is the third derivative of 1689*s**3 - 14*s**2 - 2*s + 45 wrt s?
10134
What is the first derivative of 19*k**2 + 44*k - 841 wrt k?
38*k + 44
What is the derivative of -3284*s**3 + 6605 wrt s?
-9852*s**2
Differentiate -396*b*d**2 + 849*d**2 wrt b.
-396*d**2
Find the third derivative of -2*i*k*q**3 + 3*i*q**3 + 3*i*q - 2*i - 9*k*q**3 - 3*k*q**2 - 15*k wrt q.
-12*i*k + 18*i - 54*k
What is the second derivative of 96*g**3 - g**2 + 18*g - 5 wrt g?
576*g - 2
Find the first derivative of n**3 - 4891*n**2 + 4863.
3*n**2 - 9782*n
What is the first derivative of -2*i*q**2*s - 32*i*q*s + 3*i*s + 3*i - 3*s wrt q?
-4*i*q*s - 32*i*s
What is the first derivative of -4180*y**3 + 857 wrt y?
-12540*y**2
Differentiate -a**3*k + 4*a**3*y**2 - 135*a**2*k*y - 55*a*k - 5*a*y**2 with respect to y.
8*a**3*y - 135*a**2*k - 10*a*y
Find the second derivative of 1022*l**5 + 4*l - 96.
20440*l**3
Find the first derivative of -16*h**4*t*v - 4*h*t*v - 2*h*v**2 + 2*t*v**2 + 2*t + 12*v**2 wrt h.
-64*h**3*t*v - 4*t*v - 2*v**2
Find the third derivative of 96*c*l**3*o**3 - 3*c*l**3*o - 2*c*l**2*o**2 + 2*c*l*o**3 + 2*c*o**3 + 2*l**3 - 164*l**2*o + 2*l*o**3 wrt l.
576*c*o**3 - 18*c*o + 12
Find the first derivative of -14696*b + 7013 wrt b.
-14696
What is the derivative of -a*w**2 + 129*a*w - 331*w**2 - 3*w wrt a?
-w**2 + 129*w
What is the third derivative of 2*h**4*u**2 + 2*h**4 + h**3*u + 2*h**2 + 36*h*u**2 + 2*u wrt h?
48*h*u**2 + 48*h + 6*u
What is the first derivative of 571*c*d**2 + 1378*c wrt d?
1142*c*d
What is the third derivative of 714*h**5 - 2632*h**2?
42840*h**2
Find the first derivative of 457*q**4 + 264 wrt q.
1828*q**3
What is the first derivative of 7631*g**2 + 3594 wrt g?
15262*g
Find the second derivative of 1791*s**3 + 2*s + 1852 wrt s.
10746*s
What is the derivative of 609*l**4 + 296?
2436*l**3
What is the second derivative of -6689*u**3 + 9073*u?
-40134*u
What is the first derivative of 82*q**2*s - 3*q**2 - 9*q + 2*s - 353 wrt q?
164*q*s - 6*q - 9
What is the third derivative of -2*d*r**3*u + 383*d*r**2*u**2 - 6*d*r*u**2 - 34*r**3*u**2 - r**2*u**2 + 1 wrt r?
-12*d*u - 204*u**2
Find the second derivative of 720*p**2 + 490*p wrt p.
1440
What is the derivative of 3*p**2*s + 8622*p**2 + 4*p*s**2 + 2*s**3 + 5*s wrt s?
3*p**2 + 8*p*s + 6*s**2 + 5
What is the second derivative of -14*h**2*i**3 + 21*h**2*i + 4*h*i**3 - 3*i**4 + 9 wrt i?
-84*h**2*i + 24*h*i - 36*i**2
What is the first derivative of 432*k**4 + 2*k**3*v - 1959*v wrt k?
1728*k**3 + 6*k**2*v
What is the second derivative of 3*q**3*r**2*z + q**3*z + q**2*r**2*z - 5*q*r**2*z - q*r*z + 30*q*r wrt r?
6*q**3*z + 2*q**2*z - 10*q*z
What is the second derivative of 5*s**5 - s**4 + 183*s**2 + 78*s - 16 wrt s?
100*s**3 - 12*s**2 + 366
What is the second derivative of v**3 + 251*v**2 + 6393*v wrt v?
6*v + 502
What is the second derivative of 476*c*o**4 + c*o - c + o**2 + 22*o wrt o?
5712*c*o**2 + 2
What is the second derivative of -565*p**2 + 1645*p?
-1130
Find the third derivative of -6*a**3*s**3 - 5*a**3*s**2*t - 2*a**3*s + 5*a**2*s**3*t - 2*a*s**3*t - 57*a*s*t wrt a.
-36*s**3 - 30*s**2*t - 12*s
Find the third derivative of a**6 - 28*a**3 - 42*a**2 wrt a.
120*a**3 - 168
What is the third derivative of 4*b*l**3*r**2 + 3*b*l**3*r + b*l**2*r**2 + b*l*r**2 - 6*b*r**2 - 2*l**3*r**2 + | {
"pile_set_name": "DM Mathematics"
} |
Christiane of Saxe-Merseburg
Christiane of Saxe-Merseburg (1 June 1659 – 13 March 1679), was a German noblewoman member of the House of Wettin and by marriage Duchess of Saxe-Gotha-Altenburg.
Born in Merseburg, she was a child of Christian I, Duke of Saxe-Merseburg and his wife Christiana of Schleswig-Holstein-Sonderburg-Glücksburg.
Life
In Merseburg on 13 February 1677 Christiane married Duke Christian of Saxe-Gotha-Altenburg. Both belonged to the House of Wettin: she was a member of the Albertine line while her husband belonged to the Ernestine branch. The couple settled in Eisenberg at the Christianburg Castle.
Two years later, on 4 March 1679, she gave birth to a daughter, named Christiane after her and later wife of Philip Ernst, Duke of Schleswig-Holstein-Glücksburg; however, nine days later (13 March) she died of childbirth complications aged 19, probably from puerperal fever. She was buried in Merseburg Cathedral. In her honour, her husband build the Castle church of St. Trinity (German: Schlosskirche St. Trinitatis) in the Christianburg Castle.
Notes
References
Publications about Christiane of Saxe-Merseburg in: VD 17 [retrieved 28 September 2014].
|-
Category:1659 births
Category:1679 deaths
Christiane | {
"pile_set_name": "Wikipedia (en)"
} |
An aggressive fish that gets even more aggressive as it ages, and it will attack fish larger than itself. It is best kept with similar sized aggressive fish or just with other damsels. Only one Bowtie Damsel should be kept in each tank. | {
"pile_set_name": "Pile-CC"
} |
FOR BETTER, FOR WORSE, FOREVER!
Great Marriages does not advocate for staying in abusive relationships.
If you are in an abusive relationship please contact Safe Harbor at (920) 452-8611.
Some of the best advice I ever heard for a relationship was to compliment your significant other during a fight. This has a two fold effect: first - you will stop saying angry things and fueling the fire of the fight, second - you will remember what you love about that person and begin to soften your heart to what is making you upset. In this moment, you are choosing love. You may not feel like you love the person at that moment, but you can remember the things you love about them. Love is a choice.
When a couple gets married they promise for better or for worse, they promise to love each other forever. Eventually, the stress of day to day life combined with getting comfortable in your relationship will lessen the feeling of love. It is at this point that we must decide to choose love. Don't forget what made you fall in love with that person, don't forget your plans and dreams, don't forget the promise you made of forever.
When you are fighting because your spouse forgot to take out the trash again or they said some unkind words, remember your promise of forever. If it feels like forever is over, remember why you fell in love and focus on those feelings. Choose love, every single day.
If you need help getting through a difficult time, call Great Marriages at (920)783.6142.
Ways to choose love every day:
Let go of the little things. (More of life is "little things" than you may think.) | {
"pile_set_name": "Pile-CC"
} |
A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition.
Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by determining the molecular mechanism of ActD inhibition followed by structure-based virtual screening. The molecular interaction of inhibition was determined by circular dichroism and tryptophan fluorescence quenching. The structure-based search and virtual screening were performed using the Molecular Operating Environment (MOE) program and SYBYL 7.5, respectively. Two inhibitors were identified with an IC(50) for pantothenate synthetase that was at least ten times better than that of ActD. | {
"pile_set_name": "PubMed Abstracts"
} |
INTRODUCTION {#s5}
============
One of the most frequent questions of patients with rheumatoid arthritis (RA) during counselling sessions is, 'does my disease influence my ability to take care of my children?' Women with RA are concerned about their parenting capacities after giving birth, with perceived inability to fulfil parenting roles. Previous studies identified feelings of guilt, anger and depression in mothers with RA.^[@R1]^ Although these problems were identified more than 20 years ago, recent studies still find an unmet need for information and focused care in mothers with a chronic rheumatic disease.^[@R2]^
Counselling patients with a wish to conceive is important to ensure safe pregnancy outcomes for mother and child.^[@R4]^ Parenting ability should be one of the topics discussed during these counselling sessions. Early identification of patients that will develop parenting problems gives these patients time to take additional precautions.
The Parenting Disability Index (PDI) was developed to measure parenting function and disability in women with a chronic rheumatic disease.^[@R5]^ It was developed and validated in a cohort with RA patients from the USA. Although this study included few mothers with young children (age 0--5 years), more than half of these patients reported difficulty regarding the physical activity domains of parenting. This suggests that a majority of women with RA experience difficulties in parenting.
The goals of this study are to describe the affected domains of the PDI for young children (0--5 years of age) over a 6 months postpartum period in a large sample of mothers with RA and to identify patients early in pregnancy who are at risk for developing parenting disabilities postpartum. The information provided in our study will help physicians and healthcare professionals to improve counselling on parenting abilities and to identify those patients who need extra care. Both will help women with RA better prepare for potential parenting challenges after delivery.
METHODS {#s6}
=======
Patients {#s6-s1}
--------
Patients were derived from the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) cohort (2002--2010).^[@R6]^ The PARA cohort is a large, prospective cohort study on RA and pregnancy from the Netherlands. Patients included in this study fulfilled the 1987 American College of Rheumatology for RA criteria.^[@R7]^ The PARA study was approved by the Erasmus MC ethics review board and was executed in compliance with the Helsinki Declaration. All patients gave a written informed consent.
Data collection {#s6-s2}
---------------
In the PARA study, visits were performed (preferably) before pregnancy, each trimester and three times postpartum (6, 12 and 26 weeks). At all visits during pregnancy and all visits postpartum, participants filled in questionnaires, including the PDI^[@R5]^ and Health Assessment Questionnaire (HAQ). The HAQ measures the difficulty in performing activities of daily living in eight categories.^[@R8]^ Data on patient and disease characteristics were collected at baseline. From August 2004 onwards, all participants of the PARA study were asked to fill in PDI questionnaires postpartum.
Parenting Disability Index {#s6-s3}
--------------------------
The PDI is an extensive, validated questionnaire with 25 domains to quantify parenting disability in mothers with arthritis.^[@R5]^ This questionnaire for women with children between 0 and 5 (including five additional questions) was translated into Dutch by two translators. It was translated back into English by two native English-speaking translators. Consensus on the translated version was reached after two versions. All questions could be retained as in the English version. The translated Dutch questionnaire for children between 0 and 5 years is available in [online supplementary A](#SP1){ref-type="supplementary-material"}. The PDI uses a five-point response scale: 0=no difficulty, 1=some difficulty, 2=a lot of difficulty, 3=unable to perform, 4=does not apply. The PDI has an additional category in which participants could state whether the task was performed less because of reasons related to arthritis. For all domains, except 'safety' and 'getting down to and up from the floor' domains, this additional question was asked. In the modified Parenting Disability score (mPDI), the domain score was increased to a 2 if a subject responded that she did an activity less due to arthritis. We calculated the mPDI score as described in literature.^[@R5]^
10.1136/rmdopen-2020-001276.supp1
Statistics {#s6-s4}
----------
Descriptive statistics are presented as numbers (n) and percentages (%). Values are given as mean±SD, number (percentage) or median±IQR. Records with available data in the first trimester of pregnancy and at least one time-point postpartum were included in the current analysis (complete case analysis).
Domains in which mothers with RA experienced parenting difficulty were described using descriptive statistics. We stratified patients to different parenting disability states: low parenting disability (0--4 domains affected), medium parenting disability (5--12 domains affected) and high parenting disability (13--25 domains affected). Affected domains of parenting were visualised for the entire group of patients and for the different parenting disability states by using histograms.
Agreement in parenting disability states at the different visits postpartum was determined by kappa statistics. Categories for kappa values were in line with previous literature.^[@R9]^ Correlations between the calculated mPDI scores at 6, 12 and 26 weeks postpartum were determined using Pearson's correlation coefficients. Correlation coefficients were interpreted as described in literature.^[@R10]^
To identify patients who are at risk for developing parenting disability, univariate logistic regression models were built for the analyses of patient characteristics associated with low parenting disability (low vs medium and high combined) and high parenting disability (high vs low and medium combined). Stepwise forward selection of covariates with a p value less than 0.2 in the univariate analysis was performed to create a multivariate model. P values ≤0.05 in the final multivariate model were considered statistically significant. The following patient characteristics, obtained in the first trimester of pregnancy, were considered as covariates: age (years), disease duration (years), already having children (yes/no), socioeconomic status (years of education), erosive disease (yes/no), disease activity (Disease Activity Score (DAS) with three variables: 28 swollen and tender joint count and C reactive protein (CRP) (DAS28CRP)) and the HAQ score. For clinical purposes, we stratified disease activity to low or high (low disease activity DAS28CRP\<3.2) and the HAQ score to low or high based on the median. All analyses were performed using STATA 15.
RESULTS {#s7}
=======
A detailed description of the 148 patients within the PARA cohort who were eligible for the current study is given in [table 1](#T1){ref-type="table"}. A total of 149 children were born in the current study, the mean maternal age was 33.2 years and the median gestational age of the newborn was 39 weeks. Of the 148 patients, 50.7% already had children, 71.6% were rheumatoid factor positive and 62.2% were anti-citrullinated protein antibody positive; the mean duration of RA was 6.4 years. The average number of years of schooling was 15.5 (2.9 SD), indicating that participants finished at least a vocational education and training or started and/or finished a higher education.
######
Clinical and demographic features from patients within the PARA cohort (n=148) with rheumatoid arthritis
--------------------------------------------- -------------
Mean age, years (SD) 33.2 (3.5)
Median gestational age, weeks (IQR) 39 (38--40)
Mean disease duration, years (SD) 6.4 (5.8)
Rheumatoid factor positive, n (%) 106 (71.6)
ACPA positive, n (%) 92 (62.2)
Nulliparity, n (%) 73 (49.3)
Erosions, n (%) 89 (60.1)
Smoking, n (%) 13 (8.8)
Education, years (SD) 15.5 (2.9)
Medication use postpartum (any use, n (%)):
Prednisone 61 (41.2)
Methotrexate 54 (36.5)
Sulfasalazine 49 (33.1)
Biological agents\* 20 (13.5)
Hydroxychloroquine 18 (12.2)
Azathioprine 2 (1.4)
Leflunomide 1 (0.7)
--------------------------------------------- -------------
\*adalimumab n=8, etanercept n=13.
ACPA, anti-citrullinated protein antibody; PARA, Pregnancy-induced Amelioration of Rheumatoid Arthritis.
The total number of available patients for analysis are as follows: at 6 weeks postpartum, n=116; 12 weeks postpartum, n=123; and 26 weeks postpartum, n=115.
Parenting postpartum {#s7-s1}
--------------------
Complete responses on all questions of the PDI, at 6, 12 and 26 weeks postpartum are shown in [online supplementary tables 1--3](#SP1){ref-type="supplementary-material"}, respectively. The domains in which respondents had the most difficulty were picking up or carrying your child, doing household chores or shopping, taking your child out in the car, getting up and down to the floor to play your with child, taking care of your child's hygiene, feeding your child and using a car seat. The domains in which mothers with RA had the least difficulties were taking care of your child when he or she is sick, maintaining discipline with your child, having other children in your home and having the energy to be available to listen and talk with your child.
######
Patient characteristics (obtained at first trimester of pregnancy) associated with parenting difficulty at 12 weeks postpartum (n=123): multivariate logistic regression model for low parenting disability
Low parenting disability (0--4 domains of the Parenting Disability Index affected)
------------------------------------------------------------ ------------------------------------------------------------------------------------ --------- -------------------- ---------
Age, years 1.00 (0.90--1.12) 0.96
DAS28CRP \<3.2 in the first trimester of pregnancy 4.77 (2.09--10.86) \<0.001 4.79 (1.77--12.91) 0.002
Low HAQ score (≤0.625) in the first trimester of pregnancy 10.80 (3.82--30.52) \<0.001 9.17 (3.04--27.69) \<0.001
Disease duration, years 0.89 (0.81--0.97) 0.009 0.87 (0.79--0.95) 0.003
Already having children ≥1 0.58 (0.26--1.26) 0.16
Socioeconomic status (years of education) 0.97 (0.85--1.12) 0.71
Presence of erosive disease 0.43 (0.20--0.95) 0.037
DAS28CRP, Disease Activity Score 28-joint count C reactive protein; HAQ, Health Assessment Questionnaire.
######
Patient characteristics (obtained at first trimester of pregnancy) associated with parenting difficulty at 12 weeks postpartum (n=123): multivariate logistic regression model for high parenting disability
High parenting disability (13--25 domains of the Parenting Disability Index affected)
------------------------------------------------------------ --------------------------------------------------------------------------------------- --------- -------------------- ---------
Age, years 1.05 (0.95--1.17) 0.99
DAS28CRP ≥3.2 in the 1st trimester of pregnancy 1.50 (1.08--2.09) 0.015 1.68 (0.71--3.96) 0.23
High HAQ score (\>0.625) in the 1st trimester of pregnancy 4.86 (2.21--10.66) \<0.001 4.54 (1.99--10.34) \<0.001
Disease duration, years 1.05 (0.99--1.12) 0.11
Already having children ≥1 1.44 (0.69--2.99) 0.33
Social economic status (years of education) 0.90 (0.79--1.03) 0.12
Presence of erosive disease 2.13 (0.98--4.59) 0.055 2.32 (1.00--5.35) 0.049
DAS28CRP, Disease Activity Score 28-joint count C reactive protein; HAQ, Health Assessment Questionnaire.
In this study, 78.5% of the patients reported any parenting problems at 6 weeks postpartum, 86.2% reported any problems at 12 weeks postpartum and 86.1% at 26 weeks postpartum. Twelve weeks postpartum was the visit with the highest percentage of any parenting difficulty reported. At this visit, low, medium and high parenting disability were observed in 37 (30.1%), 38 (30.9%) and 48 (39.0%) of the patients, respectively. [Figure 1](#F1){ref-type="fig"} shows the percentage of patients reporting any parenting difficulty per domain at 12 weeks postpartum; this is displayed for the entire group and displayed after stratification for parenting disability state. The most commonly reported domains in the low parenting disability group were getting up and down to the floor to play with your child (24.3%) and getting up with your child (18.9%). In the medium parenting disability group, the domainspicking up or carrying your child (86.8%) and doing household chores or shopping (73.7%)were most frequently reported. In the high parenting disability group, the domains picking up or carrying your child (100%), doing household chores or shopping (100%), getting up and down to the floor to play with your child (97.7%) and taking care of your child's hygiene (91.7%) were most frequently reported.
{#F1}
The calculated mPDI scores did not change over time: 6 weeks postpartum mean mPDI 0.66 (0.57 SD) at 6 weeks postpartum, mean mPDI 0.67 (0.56 SD) at 12 weeks postpartum and mean 0.64 (0.56 SD) at 6 months postpartum. Correlations between these mPDI scores were high at all time-points postpartum: 0.72\< rho \<0.86. Agreement in parenting disability states at the different time-points postpartum was moderate: 0.43\< kappa \<0.60.
Identification of patients at risk for parenting difficulties {#s7-s2}
-------------------------------------------------------------
The results of the univariate and multivariate logistic regression analyses for parenting disability at 12 weeks postpartum are shown in [tables 2](#T2){ref-type="table"} and [3](#T3){ref-type="table"}. The observed median HAQ score in the first trimester of pregnancy was 0.625. Multivariate logistic regression revealed that patients with a low HAQ score (≤0.625) in the first trimester of pregnancy (OR 9.17, 95% CI 3.04 to 27.69, p\<0.001) and low disease activity in the first trimester (DAS28CRP \<3.2) (OR 4.79, 95% CI 1.77 to 12.91, p=0.002) were likely to report low parenting disability. Patients with a longer disease duration (OR 0.87, 95% CI 0.79 to 0.95, p=0.003, per year increase in disease activity) were less likely to report low parenting disability postpartum. Reporting a high HAQ score in the first trimester of pregnancy greatly increased the odds of reporting high parenting disability postpartum (OR 4.54, 95% CI 1.99 to 10.34, p\<0.001). The presence of erosive disease was borderline significantly associated with reporting high parenting disability (OR 2.32, 95% CI 1.00 to 5.35, p=0.049).
To confirm the results of the multivariate logistic regression and for clinical use, we stratified patients to having a high or low HAQ in the first trimester, after that these two groups were stratified to having low or high disease activity in the first trimester. The results are shown in [table 4](#T4){ref-type="table"}. Only 2.7% of the patients reported low parenting disability postpartum when having a high HAQ and high disease activity in the first trimester, and 86.5% of the patients in the low parenting disability group had a low HAQ score in the first trimester. On the contrary, only 8.3% of the patients that had both a low HAQ score and low disease activity in the first trimester reported high parenting disability postpartum.
######
Stratification of patients for parenting disability states at 12 weeks postpartum by low or high HAQ score and low or high disease activity in first trimester of pregnancy (n, %)
Low parenting disability Medium parenting disability High parenting disability
------------------------------------------------- ---------------- -------------------------- ----------------------------- ---------------------------
High HAQ score in the first trimester (\>0.625) DAS28CRP ≥3.2 1 (2.7) 17 (44.7) 25 (52.1)
DAS28CRP \<3.2 4 (10.8) 4 (10.5) 9 (18.8)
Subtotal 5 (13.5) 28 (55.3) 34 (70.8)
Low HAQ score in the first trimester (≤0.625) DAS28CRP ≥3.2 12 (32.4) 9 (23.7) 10 (20.8)
DAS28CRP \<3.2 20 (54.1) 8 (21.1) 4 (8.3)
Subtotal 32 (86.5) 17 (44.7) 14 (29.2)
Total 37 38 48
DAS28CRP, Disease Activity Score 28-joint count C reactive protein; HAQ, Health Assessment Questionnaire.
DISCUSSION {#s8}
==========
Our study was the first to prospectively evaluate the PDI in a large group of mothers with RA. It provided detailed information for patients and healthcare professionals on parenting postpartum. We identified that in patients with RA postpartum, physical domains of parenting were most commonly affected: picking up and carrying, hygiene needs, feeding, getting up and down, household chores, shopping and getting out in the car. Domains with a social/psychosocial component caused less problems: maintaining discipline, taking care of the children when they are sick, listening and having other children over. We identified that patients with a low HAQ score in the first trimester of pregnancy and low disease activity in the first trimester were likely to report low parenting disability. Patients with a longer disease duration were less likely of reporting low parenting disability postpartum. Having a high HAQ score in the first trimester of pregnancy and the presence of erosive disease increased the risk for parenting disability postpartum.
Early identification of patients at risk for developing parenting problems postpartum will allow those patients extra time to take additional precautions. To assess the risk of developing parenting problems during counselling sessions, we advise physicians to take the following into account: disease activity, presence of erosive disease, disease duration and most importantly the HAQ score. In our analysis, we used the patient characteristics in the first trimester, because there were more patients included in our cohort at that time-point (n=116) than at the preconception visit (n=88). However, in some circumstances, counselling before pregnancy can be preferred. In our cohort, patients were seen before conception when contraindicated medication for use during pregnancy was stopped for at least 3 months. Pearson's coefficient between the HAQ in the first trimester and the HAQ before conception were good, rho=0.74. When we performed the multivariate logistic analysis with data obtained at the visit before conception, similar results were found (data not shown). A cut-off for the HAQ of 0.625 before conception or in the first trimester of pregnancy can be used to identify patients who are at risk for developing parenting problems, where a score of \>0.625 indicates an increased risk of developing parenting problems.
With the identification of the parenting domains that cause the most difficulties for patients and which patients are at risk for developing parenting disability, targeted interventions and education can be designed. For patients with a low risk of developing parenting disability, an information folder with tips on positioning and carrying the baby, the advice to roll the baby over instead of lifting when changing and the advice to have a baby changing table on the ground floor could be sufficient. Whereas in the group with a high probability of developing parenting difficulty, a training by a specialised nurse or occupational therapist on positioning of the baby, taking care of the child's hygiene, the use of equipment (car seat, nursing pillow, stroller, etc) and strategies on adjusting expectations might be appropriate. Further research should be conducted among patients with and without the above-described intervention, in order to determine whether additional training results in better parenting function.
Considering our findings, it is tempting to speculate that interventions, focused on improving HAQ scores, can improve parenting. HAQ scores are influenced by a variety of lifestyle and disease- and treatment-related factors of which disease activity and prior radiologic damage are often considered most important.^[@R11]^ Although radiologic damage cannot be changed, effective drug therapy and lower disease activity can improve HAQ scores.^[@R12]^ Future research should reveal whether this can be achieved in patients with a wish to conceive or who are pregnant.
Our study has several limitations. The PARA study was completed around a decade ago, the patients population might therefore not reflect the current patient population. Differences can be expected in medication use and disease activity. In the time period that the PARA study was conducted treating RA during pregnancy was uncommon. Previous literature with data from this cohort shows that a large percentage of patients were not treated during pregnancy or were treated with sulfasalazine or prednisone.^[@R6]^ However, the conclusion that HAQ identifies patients with future parenting disability is still valid.
Also, the PDI questionnaire was not tested in a reference group of mothers without a chronic rheumatic disease. Therefore, the results of this questionnaire cannot be compared to mothers in the general population. Also, we did not validate the results of the multivariate logistic regression analysis in a reference cohort.
A flaw in the PDI questionnaire is that it does not include questions on whether a patient received additional help with parenting. Additional help from, for example, a partner, (grand)parents or maternity assistant can make parenting tasks easier. We asked participants the number of days on which they received help from any third-party after delivery. This number of days did not differ between women who experienced high parenting disability postpartum versus women who did not (data not shown). Although this is only a proxy for the total amount of help received, it indicates that both groups received a similar amount of help in parenting tasks.
The current study was performed in a country where all patients are entitled to maternal leave and have easy access to healthcare. In other countries, a chronic disease might have a greater impact on parenting capability. Therefore, our results cannot be extrapolated. We do not suspect selection bias in the current study, because the number of missing values in our study is low and previous published literature from the PARA study showed that this study is a representative study population.
We observed no major differences in PDI score at different follow-up visits postpartum. This is probably explained by only slight changes in disease activity. The highest PDI score was observed at 12 weeks after delivery, which corresponds with the timing of a flare of disease activity postpartum found in literature.^[@R6]^
Our study reports slightly lower mPDI scores than the initial validation study by Katz *et al* and a more recent study by Zelkowitz *et al.*^[@R5]^ These differences can probably be explained by cultural differences between countries and a different study design.
In conclusion, physical domains of parenting are most commonly affected in mothers with RA. The domains picking up and carrying children, household chores, taking children out in the car, getting up and down to the floor to play and child's hygiene are affected in a large percentage of patients with RA. Therefore, during pregnancy counselling sessions, advice and instructions on these domains should be provided to all pregnant patients with RA, since postpartum parenting disability was influenced by disease activity. We advise that modifiable factors, such as effective drug therapy, should be discussed during counselling sessions to preserve the parenting tasks. Some patients might need more in-depth counselling, these patients can be identified in early pregnancy based upon high DAS28CRP and especially high HAQ scores.
###### Key messages
What is already known about this subject?
-----------------------------------------
- Women with RA are concerned about their parenting capacities after giving birth and experience an unmet need for information and focused care.
What does this study add?
-------------------------
- Almost 40% of mothers with RA reports high parenting disability postpartum.
- Physical domains are more often affected than social and psychosocial domains in mothers with RA.
- HAQ scores in the first trimester, disease activity in the first trimester, disease duration and the presence of erosive disease are predictive for developing parenting disability after delivery.
How might this impact on clinical practice?
-------------------------------------------
- When counselling patients with RA early in pregnancy, disease activity, disease duration, the presence of erosive disease and especially HAQ scores can help identifying patients at risk for developing parenting problems.
**Contributors:** All authors had a contribution to the conception and/or design of the manuscript and/or the acquisition/analysis/interpretation of the data. They revised the manuscript critically and gave final approval. HTWS and RJEMD take full responsibility for all aspects regarding the accuracy and integrity of the work.
**Funding:** This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26). RJEMD received an unrestricted grant from UCB Pharma.
**Competing interests:** RJEMD received an unrestricted grant from UCB Pharma.
**Patient consent for publication:** Not required.
**Provenance and peer review:** Not commissioned; externally peer reviewed.
**Data availability statement:** Data may be obtained from a third party and are not publicly available.
| {
"pile_set_name": "PubMed Central"
} |
[Genetic aspects of growth hormone deficiency].
Congenital growth hormone deficiency (GHD) is a rare cause of growth delay. It should be suspected when other causes of hypopituitarism (sellar tumor, postsurgical or radioinduced hypopituitarism, etc.) have been ruled out. GHD can be isolated (IGHD) or associated with at least one other pituitary hormone deficiency (CPHD) including thyrotroph, lactotroph, corticotroph, or gonadotroph deficiencies. CPHD is caused by mutations of genes coding for pituitary transcription factors involved in pituitary ontogenesis or in the hypothalamic-pituitary axis. Clinical presentation varies, depending on the type and severity of GHD, the age at diagnosis, the association with other pituitary hormone deficiencies, or extrapituitary malformations. Clinical, biological, and radiological work-up is very important to determine for which transcription factor the patient should be screened. There is a wide variety of phenotypes depending on the transcription factor involved: PROP1 (somatolactotroph, thyrotroph, gonadotroph, and sometimes corticotroph deficiencies ; pituitary hyper- or hypoplasia), POU1F1 (somatolactotroph and thyrotroph deficiencies, pituitary hypoplasia), HESX1 (variable pituitary deficiencies, septo-optic dysplasia), and less frequently LHX3 (somatolactotroph, thyrotroph, and gonadotroph deficiencies, deafness, and limited head and neck rotation), LHX4 (variable pituitary deficiencies, ectopic neurohypophysis, cerebral abnormalities), and OTX2 (variable pituitary deficiencies, ectopic neurohypophysis, ocular abnormalities). Mutations of PROP1 remain the first identified cause of CPHD, and as a consequence the first to be sought. POU1F1 mutations should be looked for in the postpubertal population presenting with GH/TSH deficiencies and no extrapituitary malformations. Once genetic diagnosis has been concluded, a strict follow-up is necessary because patients can develop new deficiencies (for example, late-onset corticotroph deficiency in patients with PROP1 mutations). Identification of gene defects allows early treatment of pituitary deficiency and prevention of their potentially lethal consequences. If untreated, the main symptoms include short stature, cognitive alterations, or delayed puberty. An appropriate replacement of hormone deficiencies is therefore required. Depending on the type of transmission (recessive transmission for PROP1 and LHX3, dominant for LHX4, autosomal dominant or recessive for POU1F1 and HESX1), genetic counseling might be proposed. Genotyping appears highly beneficial at an individual and familial level. | {
"pile_set_name": "PubMed Abstracts"
} |
Mount Tsukuba Ropeway
The is Japanese aerial lift line in Tsukuba, Ibaraki, operated by . The line, opened in 1965, climbs Mount Tsukuba. The company belongs to Keisei Group.
Basic data
Distance:
Vertical interval:
The ropeway tram passes 2 steel towers on the way to the final destination.
See also
List of aerial lifts in Japan
Mount Tsukuba Cable Car
External links
Tsukuba Kankō Railway official website
Category:Aerial tramways in Japan
Category:Articles containing video clips
Category:1965 establishments in Japan | {
"pile_set_name": "Wikipedia (en)"
} |
It could be by train, bus, plane, cycle, motorbike, taxi, rickshaw, jeep or even elephant.
______________________________ ____________
My first daytime experience of a proper Indian train (I had already done an overnight journey and went on the Blue Mountain Railway to Ooty) was from Mysore to Bangalore (about 3 hours).
A friend and I had Chair Class tickets, but moved to a half full second class carraige so we could see India (Chair Class, like air-con class has darkened windows).
It was the most amazing journey I have ever been on, no stunning scenery, no hills, I opened the outside door and sat with my feet on the footplate and watched India go by, there wasn’t a moment when I couldn’t see someone working in a field or washing clothes in a stream, some boys playing by the railway line and stopping to wave to you, stopping at small villages and watching people washing themselves and a cow by a well, children coming to the train just to touch you.
All the time on this train a local man was explaining everything I had found confusing about India, he could see my fascination with the countryside and kept telling me to keep looking around (and not at him) and he would explain everything I was seeing, I never wanted that journey to end.
Blue remembered hills
Bit of a long post here...but sometimes you really have to tell it like it was:
The most memorable part of our trip to India in 2001 has to be the journey from Chennai to Udhagamandalam. We left the comforting chaos of Chennai in the late evening on the Nilgiri Express – it was to be my first train journey in India. 2AC seemed a luxurious sanctuary from the long hot day and we had it for 9 hours. Our compartment was near the carriage door and the curtains to our compartment kept wafting open as people walked by and opened the door. We decided that stitching the curtains together with our sewing kit was vital for our privacy!
My husband, Richard, was on his second trip to India and, not unusually, slept soundly on the train. Not me! In my sleep deprived half-dreams I imagined what the scenery outside was like as we "expressed" by it, in the moonlight. As I watched Richard being shaken around his little bed in the half darkness, my delusional thoughts wondered at how this blue diesel behemoth that crawled out of Chennai, seemed to chuck itself around so much. Had we jumped the tracks and were we bumping across the desert in the wrong direction? Where would we end up in the morning? More worrying, would the stitches in the curtains hold? Minor things seem to become really important in India until you let go…
Our arrival at Mettupalayam the next morning, proved my theory of the escapee train were unfounded. A very different wall of sound met our ears as we stepped off the train, it was the beautiful chaos of rural India. A rooster announced the morning almost as frequently as the guy on the station said “Coffee coffee coffee coffee coffee coffee coffee.” The hot November sun started rising and the tracks stretched out in front of us. The little blue steam train pulled up at the station and apart from a cow on the line, we were ready for our trip on the Nilgiri Blue Mountain railway, up to Ooty, by raw steam power. The day stretched ahead of us, full of the promise of cool breezes amongst the tea plantations.
The train journey itself was filled with fantastic experiences. It could have been the sleep deprivation that added the mystical quality, but even the photographs we took managed to freeze a little of the magic of the ascent into those cool green forested Nilgiri hills. It was hazily warm with an intoxicatingly cool breeze as we snaked up the hills, through banana palms and neat terraced plantations. My senses were confused by the sight of eucalyptus forests that only mean home to me as I’d only ever seem them in Australia. Here was something a familiar, and yet so unknown - blue hazy hills.
Even though we had the safety of the train, it felt wild and surreal. If you looked carefully you could see that the bananas were covered in thick spider webs and I marvelled at the size of the spiders that must had woven them. Richard, as a steam train junkie was in his own perfect otherworld here. Once I saw the dragonflies, that was it for me – my favourite part of my trip had arrived on this second day of being in the country. My favourite denizens of the insect world were around in abundance, and it was a complete surprise. They zipped around like little red faeries in the dappled light.
Enough of hazy daydreams. There was pure reality to this journey too. You could tell when you were near a station because the track-sides were junked up with rubbish. Cups, packets, water bottles. Things are how they are, litter is a part of India, but you couldn’t look past it or ignore it or stop yourself from casting a judgement on those who chucked their rubbish out of the window, into this beautiful greenness. But, the only difference is that in places like the UK, we hide it. We put it in a bin, someone takes it away and buries it in the places that aren’t considered so beautiful. Like all things in India, you see things how they really are, not hidden by a glamour.
Every great adventure has river crossings, and the route had plenty of hairy ones. The tracks passed over extremely high bridges, with no sides and you could look down from the window straight into the chasms below. We stopped at a station where a sign told of a calamity in 1993 – a massive land-slide on the tracks that killed hundreds. You need to understand that I’m just summing it up - the actual sign gives the rainfall in exact millimetres and the precise cubic metres of earth and boulders that were cleared. It’s very real as you stand there in that place, doing your sums to work out the scale of it all.
Then we got back on the train and chuffed over bridges made from matchsticks, up to Ooty and its beautiful cool breezes and gardens. A man with a rifle joined our carriage. He rested his gun barrel on his knee. We checked out his uniform and tried to work out if he was the police. My husband struck up a conversation by saying “Hello Captain” and we found out that he was a train guard. We were glad we had tickets!
If by now you were in India, still clinging to your cotton-wool ideas of western safety, this was the time to let go and just give yourself up the spirit of being on the eastern edge.
Reality and dreams can be found on the tracks of the Blue Mountain Railway...
Funny that was my favourite ever journey in India too, although I also LOVED the narrow gauge train from Kalka to Shimla back in 1997, not to mention the trip from Coimbatore to Ernakulam in 2001 after our Ooty trip.
I am thinking of all of the treks that I have done in Ladakh, and each of them was totally memorable. The best was when I stayed in a Tibetan Nomad camp, at Tso Kar, for 10 days. I photographed everything that moved and most things that didn't, as well as keeping a detailed diary. But, my most enjoyable journey, is one that I have done many times. Calcutta, Howrah Station to Sudder Street, by river ferry and by rickshaw wallah. Maybe it's because I'm a Londoner.....
I liked the train ride from Kalka to Shimla too. I cried it was so beautiful, but my favourite journey was from Manali to Amritsar by bus. It was a long and bumpy ride but we had such a good time. There was 2 brothers who sat behind who kept teaching us how to sing hindu songs and in exchange we tried to teach them songs from Grease, then there was this crazy old guy to the left who kept teasing us with lies and laughing at us when we believed them. We met some lovely Israeli's lads who were so positive and interested in everything that it was contagious. We sat at the back of the bus and the bumps knocked us clean off our seats and the conductor guy kept laughing. It was the last time we would see the mountains and the sun was setting beautifully and I cried to be leaving the mountains because i was so lucky to ever have seen them. It sounds crap but it wasn't when i was there.
Mumbai to Goa doesn't have the most incredible scenery in India but it was my first taste of India outside a city and it totally blew me away. I'd also just met my friends Lisa and Paul in Mumbai and, having been travelling on my own for quite a while up to that point, was really glad to have such great company.
It was also the first time I heard " Chai, Ch-Chai Chai Chai-yaaaa !", a sound that I've grown to love.
The transition from the sun-scorched plains of Maharashtra to the lush greenery around the Chapora river was incredibly beautiful. Just to cap it all, a troupe (sp?) of HUGE monkeys casually wandered across the road as we got a taxi from Pernem to Arambol - the first time I'd ever seen so many monkeys in the wild.
Just brilliant.
A journey I'm looking forward to doing one day is the Manali - Leh bus ride. Anyone got any good stories about that? I've heard the scenery variously described as 'awesome', 'unbelievable' and 'the best thing on Earth' !
I was determined to leave Delhi ASAP but it being my first time in India I had not a clue how to get to Varanasi, after spending 6 hours of negotiating with many cups of chai and lectures about how wonderful other places where and that the salesman was going to be buried where he wanted me to go ,I got an All in Deal for Hotel and train ride , the train was going to leave in 40 minutes and we were still in the travel agency office :-( , I was rushed to the station Hollywood style , and finally made it in the train , it had my name posted on the side of the train!! , very strange !.
Boarded the train at 19:45 and got comfy Sleeper class AC, it left Delhi and with it the noise left my head , only the slow chucking of the diesel engine and the soft cry , chai ! Chai ! Chai ! that went on and on , the next morning I could not wait to have a peek outside as it stopped just before Allahabad, it was amazing like looking at a life painting , and being in it yourself , I really started to get the true feeling a feeling of having succeeded in leaving it all behind.
That old Rock n' Rolling Ferry Boat,,,,,,,
For my favourite trip I'm plumping for "That old Rock n' Rolling Ferry Boat,,,,,,,"
The one which sailed the high seas between Bombay & Goa uptill the mid eighties,,,,,,,
I'm remembering the seventies when we used to get down to the bombay docks early morning ready for the 11-30am sailing.
I did the trip loads of times,so these were'nt one off memories.
There were always 20, 30 or more westerners on board heading for goa, especially if you were there in december when goa for xmas & new year was espacially attractive.
Somehow the rear of the ship was were everyone aimed for, in fact it was usually taken over, there was only benches to sit on , but groups of people just seemed to get together,,,,,,,,,
As soon as the ferry left bombay chillums were lit up, guitars and what ever it needed for a jamming session appeared and that was how it carried on for the naxt 21 hrs all night down to panjim goa,,,,,,,,,
There was no LP guides or IM advice then, people just talked about their own experiences, & exchanged information about what to see & where to go.
Sadly That old ferry boat doesn't ply the seas anymore but for those who sailed on her the memories sail on,,,,,,,,,,,,,
1. Kalka-Shimla by train in 1995; an enjoyable journey for two reasons: one it was my first journey by rail to Shimla and two it was by Rail Car. The halt at lovely Barog station on the chilly, misty March morning is etched in memory.
2. Igatpuri to Deolali by train in 2000; a routine business trip to Igatpuri became a special one as I travelled in the loco of the Dadar-Nagpur Express between the two stations! My first and till date last journey in a loco; truly memorable !
The Kangra railway from Pathankot is a delight. A friend and I used this train on a sunny day last October as a scenic way of reaching McLeod Ganj. We needed both an auto-rickshaw and a taxi to travel the last 20 or so km up the mountain from the railway which follows the valley.
The jeep ride to Dharjeeling and onwards to Gangtok and Kalingpong is quite stunning ... and certainly a favourite of mine ... and I would definitely include the Kalka-Shimla toy-train ride in this list. I unfortunately could not do the Dharjeeling train trip but I believe that it is also up there with the best.
Being a hard core rail nut, the most recent rail trips always count as memorable. My rail trips: Palghat to Rameswaram, Madurai to Bodinayyakanur and Tirunelveli to Quilon and back were some memorable journeys I made last year.
But my most memorable journey was the road-drive from Bangalore to Udupi via Sakleshpur and Dharmasthala and return to Bangalore via Agumbe. Travelling through those densely wooded and wet regions felt like a trip through an enchanted forest. Especially the drive through Agumbe...the misty evening will be a memory forever. The rain swept Sringeri landscape, deep forests before Chickmagalur, coffee planations at Sakleshpur and the sparkling streams near Dharmasthala...all the while it rained now and then, rendering the whole journey literally dust free.
Originally Posted by beachSteve, This is the route you said above. The picture is taken from Chamundy Express crossing the Kavery river. The old abandoned bridge also on the photo.
Hey, I went over that bridge in an auto-rickshaw last November!!
I also enjoyed the trip Steve described. Like him, we sat in the doorway of a second class carraige and watched the world go by. Also did similar on the ride up through the Western Ghats from Mumbai to Guntakal. That was spectacular. | {
"pile_set_name": "Pile-CC"
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Reducing LDL cholesterol
Has anyone on the Wheat Belly diet had their LDL and HDL levels reck? Have you seen any improvements?I have been on the diet for 6months and feel great but have not done any labs. Also my asthma is no longer an issue and I am off all my asthma meds and doing great.I have NO food cravings and NO hunger.Love being wheat free. | {
"pile_set_name": "Pile-CC"
} |
John Mattke
John Mattke (born October 29, 1958) is a former professional tennis player from the United States.
Biography
Mattke was born in Minneapolis and came to Gustavus Adolphus College in 1977. While studying for a business degree he spent four years on the college's tennis team. He finished with a 132-31 record in singles and was the 1980 NAIA singles champion. In doubles he was 135-20, having formed a strong doubles partnership with Paul Holbach, which culminated in them winning the 1980 NCAA Division III doubles championship.
In 1983 he had his first year touring as a professional and made a Grand Prix quarter-final in the Washington Open doubles, with Chile's Juan Carlos Ayala.
His most noteworthy performance came at the Tokyo Outdoor Grand Prix tournament in 1984 where in the second round he upset the world's fifth ranked player Andrés Gómez, who was also the tournament's top seed.
At the 1984 Australian Open, Mattke made his only main draw appearance in singles and had a four-set win over Paul Kronk in the first round, before losing to New Zealander Bruce Derlin.
He won two Challenger titles during his career, both in doubles.
Still living in Minnesota, Mattke works as an executive at granite company Coldspring.
Challenger titles
Doubles: (2)
References
External links
Category:1958 births
Category:Living people
Category:American male tennis players
Category:Gustavus Adolphus College alumni
Category:Tennis people from Minnesota
Category:Sportspeople from Minneapolis | {
"pile_set_name": "Wikipedia (en)"
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Q:
In gradle how do I disable the findbugs or checkstyle plugins for individual projects
We have a multi-project build in Java where two of the 8 projects are system tests and we don't want to run FindBugs or Checkstyle against the System test code (which is located in 'src/main/java').
I enable findbugs / checkstyle at the top-level build.gradle file but want to "disable" the plugin from running in these two projects?
A:
I love gradle it turned out to be quite simple
//Disable findbugs and checkstyle as per legacy ant build.xml
findbugs {
sourceSets = []
}
checkstyle {
sourceSets = []
}
| {
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} |
Haunted House Card with the Galaxy Sky Technique
It’s time for one last scare of the year and this creepy card scene is the perfect way to do it. The Galaxy Sky Technique helps add the eerie darkness to this card. Head off to your craft rooms and create one last Halloween scare of your own using this easy to follow tutorial.
Working from the edge inwards, add some pink ink around the areas making sure to blend it into the yellow.
Add some purple ink blending it into the first two colors and covering any white areas that are showing.
Continue to layer the first three ink colors on adding more to darken the areas.
Add the blue ink working it into the center. Then, add the black ink making sure to darken the edges inward. Keep adding the black ink until the outside edges are really dark.
Dip your fingers in water and splash it onto the inked areas for a bleaching affect. Wait for a couple of seconds and then blot the paper dry with a paper towel.
For this next step, I like to use stencil brushes and dip them into the white paint. Then, run your finger over the bristles to splatter different sized spots of paint onto the piece and allow it to dry.
Whether you use the card to send a Halloween Hello or an invitation to your haunted party, this card will be the perfect fright for the night. The dark night sky will send a shudder up and down your spine with the Galaxy Sky Technique. So to all of you haunters out there have a, “Happy Halloween.”
About Peg
Peg Rounds lives in East Moline, Illinois with her husband and best friend, Kevin and their son Josh and 2 dogs. She was an elementary school teacher turned stay at home mom, and later a home school mom. Over the years, she designed cakes on the side and went to school to become a certified chocolatier. She always has loved to craft since she was young and it was something that she wanted to be doing, but set it aside due to her busy life. After 15 years of doing cakes she decided it was time to stop and focus more on her family. She began doing layouts, then cards and it went from there. Before she knew it, next to spending time with her family, she spent every free moment creating something and blogging about it. One thing led to another and here she is today! Check out Peg's blog, Peg's Crafting Corner to see what else she has been up to! | {
"pile_set_name": "Pile-CC"
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Call of Duty Black Ops Multiplayer Best Perks
One of the most crucial decisions a player can make in Call of Duty: Black Ops’ multiplayer mode is which perks to equip before jumping into battle. Each perk has its pros and cons, and deciding which to choose can depend on both playstyle and personal preference.
For the player interested in efficiency and maximizing his or her kill/death ratio, it makes sense to pick Black Ops perks that help the player stay alive as long as possible. Ghost, Sleight of Hand, and Hacker (and their pro versions) are three perks that can and will improve your overall performance in the game’s various multiplayer modes.
Ghost/Ghost Pro
Smart Black Ops players make extensive use of their mini map to locate incoming enemies and sniff out opponents who have concealed themselves near objectives. It stands to reason, then, that making yourself invisible on the mini map should give you a distinct advantage over unsuspecting opponents.
This is where Ghost comes in. Using this perk, you’ll be invisible to enemy spy planes. You know how sometimes enemies seem to know where you’ll be, even if they haven’t seen you? Ghost removes this advantage and gives you the upper hand.
As effective as Ghost is, Ghost Pro is even more so. Using the upgraded version of the perk, you’ll not only be invisible to spy planes, but enemy air support, sentry guns, and IR scopes as well. When using Ghost Pro you can stand right out in the open and take shots at enemy helicopters without fear of being targeted yourself (watch out for enemy players, though).
Another useful benefit of Ghost Pro is the fact that no red name appears over your head when enemy players target you. Now, you’ll be able to hide in dark corners and amongst foliage without fear of floating text giving away your position, which makes covering objectives and setting up ambushes much more effective.
The major advantage of this perk and its upgraded version is that they eliminate one of the most annoying sources of deaths, air support, and grant you the advantage of concealment. Both of which work together to keep you alive longer and keep your killstreaks going, thus increasing your overall effectiveness.
Page two has the rest of our perk recommendations, including a pair that can keep you from being killed while reloading and enable you to avoid enemy claymores without fail.
Sleight of Hand/Sleight of Hand Pro
Who among us hasn’t found themselves face to face with an enemy player in the middle of a reload? These situations almost always end the same way: you find yourself watching a kill cam replay while your opponent dances on your lifeless corpse.
Sleight of Hand levels the playing field a bit, increasing your reload speed approximately 100%. Now, you can reload most SMGs almost instantly and assault rifles only slightly slower. Utilizing this perk practically eliminates one of the most frequent (and most annoying) causes of death in Black Ops, dying while reloading.
Sleight of Hand Pro takes the huge advantage offered by Sleight of Hand and takes it a step further, also increasing the speed at which you aim down the sights when you press the LT or L2 button. Now you can acquire targets as quickly as possible and get those bullets headed toward your opponent before they even know what hit them. In Black Ops multiplayer, he who shoots first is usually the victor. Use Sleight of Hand Pro and make sure that person is you.
Hacker/Hacker Pro
If dying while reloading and getting killed by air support are the two most annoying and frequent ways to die in Black Ops, then getting killed by a claymore as you round a corner has got to be a close third. Fortunately, the Hacker perk not only allows you to see claymores, but also shows you the location of enemy jammers, C4 charges, SAM turrets, and more. Basically any type of enemy deployable shows up as a red outline that you can detect through walls.
No more sneaking up on a sniper only to be obliterated by his hidden explosive. Now, you can get the drop on well-hidden enemy shooters by locating their equipment. Where you find a claymore, an enemy is usually not far beyond.
Hacker Pro takes the advantage of hacker and transforms it into one of the most amusing perks in the game. With Hacker Pro, not only can you see enemy deployables, but you can sneak up and hack them, making them function for your team. Enemies have a sentry gun covering a valuable position? Sneak up behind it, hack it, and now your team has the objective covered. Same thing goes for motion sensors, SAM turrets, claymores, and more. Hacker Pro also makes you invisible to motion sensors, enabling you to hack them without fear of detection.
Using these three perks helps you eliminate the most frequent (and most annoying) methods of death from your opponents’ Call of Duty: Black Ops repertoire. Now that you don’t have to fear air support and enemy equipment, deaths while reloading, or showing up on your opponents’ mini map, you can concentrate on your primary objective: taking out as many enemies as humanly possible, racking up the killstreaks, and making them wish they’d chosen a perk setup as effective as yours. | {
"pile_set_name": "Pile-CC"
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Six to Midnight
Six to Midnight is the sixth studio album by Australian post-grunge band Grinspoon, released through Chk Chk Boom Records and Universal Music on 11 September 2009. "Dogs" was the first song made available to the public, being released for free over the internet before the album's release. "Comeback" is the album's first single.
The album debuted at number six on the Australian Albums Chart. The first official single, "Comeback", peaked at number 48 on the Australian Singles Chart.
Six to Midnight was produced by Rick Will (Johnny Cash, No Doubt, Nine Inch Nails), with the band returning to their home town of Byron Bay to record the album. Will also mixed the album.
The album has been the first Grinspoon release since 2002's New Detention to gain international release dates, starting off with Japan in early 2010 and the United Kingdom in February 2011.
The title of the album, according to guitarist Pat Davern, came after drummer, Kristian Hopes, saw a scene in Forgetting Sarah Marshall where Russell Brand is singing, "Inside Of You", and Jonah Hill sticks his hand down his pants, adjusts himself and says 'Dude, I just went from six to midnight.'
Track listing
"Dogs" – 3:07
"Run" – 3:07
"Comeback" – 3:07
"Takes One" – 3:22
"Premonitions" – 3:22
"Right Now" – 3:29
"Give You More" – 4:06
"Lockdown" – 3:27
"Tonight" – 3:40
"Passenger" – 3:43
"Innocence" – 3:21
"Surrender" – 3:31
"Summer" – 3:34
iTunes bonus track
"Progress" - 3:18
Getmusic preorder exclusive
"Tourist Season" - 3:37
UK bonus tracks
"Progress" - 3:18
"Tourist Season" - 3:37
"Strange Days" - 2:58
"Go Sign" - 2:48
"Champion (Rick Will Mix)" - 2:51
Japan edition
"Run"
"Comeback"
"Takes One"
"Strange Days"
"Summer"
"Premonitions"
"Right Now"
"Give You More"
"Dogs"
"Passenger"
"Surrender"
"Tonight"
"Innocence"
"Go Sign (bonus track)"
Charts
Weekly charts
Year-end charts
References
Category:2009 albums
Category:Grinspoon albums | {
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Summary
Computer engineer with a Master in Web technologies. Specialized in mobile application development, with broad experience using Agile methodologies and Certified Scrum Master.more...
I started my career as an Oracle trainee (2006-2007) developing internal applications for the sales department, where I was given with the "Oracle's best trainee of the year" award.
After finishing my training at Oracle, I decided to start up my own company with 2 friends, Wixel Solutions (2007-2008). We developed Open Doors, as well as other web applications for external customers. However, we didn't have the results we expected.
Therefore, 15 months later, I joined Mobivery (2009-2011) as the recruiter and manager of a new mobile development team in Madrid.
In April 2011, I moved to San Francisco (USA) and I worked as a mobile freelancer while studying, but after 9 months I decided to come back to Europe.
In January 2012 I moved to Amsterdam (Netherlands) where I have worked at Mobiquity as a Senior iOS developer and temporary performed as iOS lead.
In July 2016, I relocated back to Madrid.
Specialities
iOS Development
Starting on Jan 2009 in Mobivery, iOS Development is my main speciality. I have built and participated in more than 20 apps so far, some with complex data synchronization, security, geolocation and using libraries and technology such as CocoaTouch, CoreData, CoreAnimation, APNS, In-App Purchase, GCD, ARC …
Scrum
I love Agile! I am a Certified Scrum Master and I have enjoyed the opportunity to set up and work for 2 years as the Scrum Master of one of the top teams in Mobivery. I have also assisted to some SCRUM courses and conferences to improve and consolidate my knowledge about Scrum and Agile.
Even if my main role was iOS developer, both at Mobivery and Mobiquity, I have also participated in the development of a few native Android apps, which gives me a solid understanding of the framework and tools
Web Development
Previously to becoming a Mobile developer my main activity was Web development. I have used technlogies such as NodeJS (Javascript), Spring (Java), Symfony (PHP) and Rails (Ruby). I also have experience with client side technologies such as HTML5, XML, AngularJS (Javascript), AJAX and CSS
Honors & awards
AppStore featured apps
Some of my developed iPhone and iPad apps were ranked in the top10 and were featured by Apple in the Spanish AppStore.
Oracle's Best Trainee of the year
Beat other 50 trainees from Oracle Spain because of my initiative, hardworking and positive mind.
3rd position in CUPCAM 06
Representative of my university and third winner in the yearly speed programming contest in Madrid (30 contestants from 5 universities) | {
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Ein Elkorum
Ein Elkorum () is a Syrian village located in Al-Suqaylabiyah Nahiyah in Al-Suqaylabiyah District, Hama. According to the Syria Central Bureau of Statistics (CBS), Ein Elkorum had a population of 3929 in the 2004 census.
References
Category:Populated places in al-Suqaylabiyah District
Category:Populated places in al-Ghab Plain | {
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1. Field of the Invention
This invention relates to a continuously lockable adjusting device for use on pivotably mounted parts and vertically adjustable equipment, such as on slats and seats of vertically adjustable chairs.
2. Description of the Related Art
In the case of continuously lockable adjusting devices of the general type as of the present invention, it is known for a piston to be positioned, axially movably, via a piston rod, in a cylindrical housing filled with a fluid, with the piston subdividing the housing into two pressure chambers. A locking valve, present in the housing, allows the continuous locking of the adjusting device, such that, in the closed state, the locking valve prevents an exchange of the fluid between the two pressure chambers. To open the locking valve, a closing member of the locking valve is actuated by a transmission disc fastened to a trigger tappet. The trigger tappet, in turn, is positioned axially displaceably or pivotably in a guide bush with a bearing seat on which a transmission disc is supported, when the adjusting device is in a locked state. The bearing seat also prevents the trigger tappet and the transmission disc from coming loose from the housing. Because of certain tolerances of fit of the various components, due to machining of parts and their subsequent assembly, an inexact fit sometimes occurs between the trigger tappet with its transmission disc, and the closing member of the locking valve, resulting in the occurrence of some play or a gap between those parts, with the consequence that the transmission disc does not sit directly on the closing member. In the event of an actuation of the trigger tappet, the play first has to be overcome before the transmission disc impinges onto the closing member. This further reduces the extent of trigger-tappet travel, which, in any case, is only slight to begin with, which is available to actuate the closing member to open the locking valve. When the closing member is actuated as a result of a tilting movement of the transmission disc, the existence of any play between the closing member and the transmission disc has the effect that the locking valve does not open correctly and the adjusting device does not operate properly. | {
"pile_set_name": "USPTO Backgrounds"
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1. Technical Field
The present invention relates generally to reactors, and more particularly to fabricating substrates that may be used in reactors.
2. Description of Related Art
Many reactions involving fluids (e.g., gases, liquids, and the like) use reactors. Many reactions are temperature dependent, and so a reactor (or zone within a reactor) may be required to have certain chemical, mechanical, thermal, and other properties at a temperature of interest to the reaction. Some reactions are performed at high temperatures (e.g., above 100 C, above 400 C, above 800 C, above 1100 C, or even above 1500 C), and so may require reactors having appropriate properties at the temperature of interest. Some reactions entail a heterogeneous reaction (e.g., involving a fluid and a surface).
Abatement of exhaust streams (e.g., from engines, turbines, power plants, refineries, chemical reactions, solar panel manufacturing, electronics fabrication, and the like) may include heterogeneous reactions. In some cases, the period of time during which a fluid interacts with a surface may affect the efficacy of a reaction. Certain reactions may benefit from increased contact times between a fluid and a substrate. Certain reactions may benefit from reduced contact times between a fluid and a substrate.
Some reactions proceed at practical rates at high temperatures. In some cases, an exhaust stream may provide heat that may heat a reactor (e.g., as in a catalytic converter on an automobile). Controlling both contact time (e.g., between a fluid and a reactor) and a temperature at which the reaction occurs may be challenging with typical reactor designs, particularly when heat transfer and mass transfer are not independently controlled.
Effective reaction (e.g., mitigation of a pollutant) may require a reactor design that maintains a desired temperature or range of temperatures over a certain volume or region having a certain surface area, notwithstanding that the primary source of heat to the reactor may be the exhaust stream. Such requirements may be challenging, particularly when mass transfer and/or reaction kinetics are at odds with heat transfer kinetics (e.g., from an exhaust stream to a reactor, or from the reactor to the environment).
The use of exhaust heat to maintain a reactor temperature may result in impaired performance under some conditions. For example, a catalytic converter may inefficiently decompose pollutants prior to having been heated to an appropriate temperature (e.g., when the vehicle is cold). A diesel particulate filter may require “regeneration” (e.g., the creation of a temperature and oxygen partial pressure sufficient to oxidized accumulated soot). Regeneration often requires heating the filtered soot to an oxidation temperature, which often relies on heat from the exhaust stream and/or heat from other sources. Regeneration may require electrical heating of a reactor. Some combinations of engines and duty cycles may result in contaminants (e.g., soot) reaching unacceptable levels before a mitigation system begins efficient operation (e.g., a soot filter may “fill up” before regeneration occurs.
Regeneration may require injection of a fuel and associated combustion heating beyond the motive heat associated with the working engine (e.g., direct injection of fuel into an exhaust stream). In some cases, the provision of regeneration heat (e.g., via electrical heating, post-injection, downstream injection, and the like) may decrease the overall efficiency of a system.
Some streams of fluids may be subject to a plurality of reactions and/or reactors. For example, a diesel exhaust mitigation system may include a diesel oxidation reactor (e.g., to oxidize CO and/or hydrocarbons), a particulate filter, and a reactor to remove NOx (oxides of Nitrogen). In some cases, these reactors are disposed in series, and so an exhaust system may include several components, each having an inlet and outlet, with the outlet of one component connected to the inlet of another component. Such systems may be complex and/or difficult to integrate.
In some cases, each component may require a separate mass and/or heat injection apparatus. For example, excess diesel fuel may be injected into an exhaust stream to create combustion at a diesel oxidation reactor in order to raise an inlet temperature of a particulate filter. A NOx reactor may require injection of a reductant, (e.g., urea, ammonia, Hydrogen, and/or other fuel) in order to facilitate a reaction at a certain temperature. A diesel particulate filter may benefit from NOx injection (e.g., to oxidize soot).
In some cases, latent heat and/or chemical species exiting a first reactor may not be efficiently utilized in a second “downstream” reactor, notwithstanding that the heat and/or species might be useful in the downstream reactor. In some cases, the heat and/or species exiting a first reactor must be controlled in such a way that performance of a downstream reactor is not inhibited. Improved reactor designs might provide for such control.
Many refractory substrates (e.g., catalytic converter, diesel particulate filter, and the like) are fabricated using extrusion. Such substrates often have long channels, with the “long” direction of the channels associated with the extrusion direction. The long direction may also be aligned with the flow of fluid through the substrate. As a result, reaction kinetics, heat transfer kinetics, fluid flow properties, and the like may be constrained by the method of fabrication of the substrate (e.g., extrusion). For example, a certain minimum residence time (associated with a reaction) may require a substrate having a minimum length, which may dictate an extruded substrate whose length is impractical for a given application.
For a typical filter (e.g., a diesel particulate filter, or DPF), filtration may preferentially begin at regions having higher fluid flow rates. In some cases, the deposition of particles may preferentially occur at the downstream end of a filter substrate, and so a particulate filter may “fill up” from the downstream end toward the upstream end.
A DPF may be “regenerated” by oxidizing filtered particles (e.g., filtered soot). Often, the downstream end of a DPF substrate may be cooler than the upstream end, and so regeneration of soot may require that the coolest part of the substrate reach regeneration temperatures. In certain applications, it may be advantageous to provide for preferential soot filtration at portions of the substrate that heat up faster than other portions. | {
"pile_set_name": "USPTO Backgrounds"
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Twelve Inch Mixes
Twelve Inch Mixes may refer to:
The Twelve Inch Mixes, compilation album by Spandau Ballet
A series of EPs marketed by Columbia Records in the 1980s/90s
See also
12-inch single | {
"pile_set_name": "Wikipedia (en)"
} |
/*
* Copyright (c) 2010 Broadcom Corporation
*
* Permission to use, copy, modify, and/or distribute this software for any
* purpose with or without fee is hereby granted, provided that the above
* copyright notice and this permission notice appear in all copies.
*
* THE SOFTWARE IS PROVIDED "AS IS" AND THE AUTHOR DISCLAIMS ALL WARRANTIES
* WITH REGARD TO THIS SOFTWARE INCLUDING ALL IMPLIED WARRANTIES OF
* MERCHANTABILITY AND FITNESS. IN NO EVENT SHALL THE AUTHOR BE LIABLE FOR ANY
* SPECIAL, DIRECT, INDIRECT, OR CONSEQUENTIAL DAMAGES OR ANY DAMAGES
* WHATSOEVER RESULTING FROM LOSS OF USE, DATA OR PROFITS, WHETHER IN AN ACTION
* OF CONTRACT, NEGLIGENCE OR OTHER TORTIOUS ACTION, ARISING OUT OF OR IN
* CONNECTION WITH THE USE OR PERFORMANCE OF THIS SOFTWARE.
*/
#ifndef _BRCM_NICPCI_H_
#define _BRCM_NICPCI_H_
#include "types.h"
/* PCI configuration address space size */
#define PCI_SZPCR 256
/* Brcm PCI configuration registers */
/* backplane address space accessed by BAR0 */
#define PCI_BAR0_WIN 0x80
/* sprom property control */
#define PCI_SPROM_CONTROL 0x88
/* mask of PCI and other cores interrupts */
#define PCI_INT_MASK 0x94
/* backplane core interrupt mask bits offset */
#define PCI_SBIM_SHIFT 8
/* backplane address space accessed by second 4KB of BAR0 */
#define PCI_BAR0_WIN2 0xac
/* pci config space gpio input (>=rev3) */
#define PCI_GPIO_IN 0xb0
/* pci config space gpio output (>=rev3) */
#define PCI_GPIO_OUT 0xb4
/* pci config space gpio output enable (>=rev3) */
#define PCI_GPIO_OUTEN 0xb8
/* bar0 + 4K accesses external sprom */
#define PCI_BAR0_SPROM_OFFSET (4 * 1024)
/* bar0 + 6K accesses pci core registers */
#define PCI_BAR0_PCIREGS_OFFSET (6 * 1024)
/*
* pci core SB registers are at the end of the
* 8KB window, so their address is the "regular"
* address plus 4K
*/
#define PCI_BAR0_PCISBR_OFFSET (4 * 1024)
/* bar0 window size Match with corerev 13 */
#define PCI_BAR0_WINSZ (16 * 1024)
/* On pci corerev >= 13 and all pcie, the bar0 is now 16KB and it maps: */
/* bar0 + 8K accesses pci/pcie core registers */
#define PCI_16KB0_PCIREGS_OFFSET (8 * 1024)
/* bar0 + 12K accesses chipc core registers */
#define PCI_16KB0_CCREGS_OFFSET (12 * 1024)
struct sbpciregs;
struct sbpcieregs;
extern struct pcicore_info *pcicore_init(struct si_pub *sih,
struct bcma_device *core);
extern void pcicore_deinit(struct pcicore_info *pch);
extern void pcicore_attach(struct pcicore_info *pch, int state);
extern void pcicore_hwup(struct pcicore_info *pch);
extern void pcicore_up(struct pcicore_info *pch, int state);
extern void pcicore_sleep(struct pcicore_info *pch);
extern void pcicore_down(struct pcicore_info *pch, int state);
extern u8 pcicore_find_pci_capability(struct pci_dev *dev, u8 req_cap_id,
unsigned char *buf, u32 *buflen);
extern void pcicore_fixcfg(struct pcicore_info *pch);
extern void pcicore_pci_setup(struct pcicore_info *pch);
#endif /* _BRCM_NICPCI_H_ */
| {
"pile_set_name": "Github"
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Lloydminster Border Kings
The Lloydminster Border Kings are a Senior AAA ice hockey team based in Lloydminster, Saskatchewan, Canada. The team took a leave of absence beginning with the 2012–13 hockey season from the Chinook Hockey League and moved to the Sask West Hockey League. They moved again for the 2014–15 season to the Battle River Hockey League. After the BRHL folded for the 2015–16 season, the Border Kings attempted to join as many as 3 other leagues, being declined each time by the league officials. This leaves the team in limbo moving forward and taking a definite leave of absence for the 2015–16 season.
The Border Kings captured the Allan Cup – Canada's national senior championship – in 2001 and 2007. Their 2001 Allan Cup win was the first by a Saskatchewan team in 60 years, following the 1941 Regina Rangers.
2007 Allan Cup
The 2007 Allan Cup was held in Stony Plain, Alberta, from April 16–21. The Kings opened the tournament with a 4–1 loss to the Chinook League champion Bentley (Alberta) Generals. Border Kings captain Scott Hood opened the scoring, but the Generals tied it on a goal while two men short. The Kings were stymied the rest of the way.
The Kings next round robin game was against the Halifax Molson Canadians. Trailing 3–2 after two, the Kings rallied in the third for a 5–4 win. Their 1–1 record placed them second in their three team pool and set up a quarter-final match-up with the 0–2 Shawinigan Xtreme.
Shawinigan struck just 28 seconds into the game, but the Kings rallied again to lead 3–1 after 20 minutes. Lloydminster then held off the Xtreme for a 5–1 victory.
The semi-final pitted the Kings against the host Stony Plain Eagles. Once again, the Kings fell behind, trailing 3–2 after two. In the third, Aaron Foster, Dalyn Fallscheer, and Kevin Lavallee struck to vault the Kings into the lead. Stony Plain scored with 54 seconds left, but Lloydminster held on for a 5–4 victory. Whitby beat Bentley 3–2 in overtime in the other semi-final.
The championship game faced off at 7:30 PM on Saturday, April 21. Scott Hood scored short-handed to give Lloyd the lead, but Whitby tied it before the end of the first. Whitby went ahead early in the second, but then for the fourth straight game the Kings enjoyed a three-goal period, and led 4–2 after two. Whitby scored early in the third but could not pull even. The Border Kings lifted the Allan Cup after a 4–3 triumph.
Border Kings goaltender Cory McEachran was named Allan Cup MVP.
The Border Kings have hosted the Allan Cup tournament twice, in 2000 and 2005.
Season-by-season record
''Note: GP = Games played, W = Wins, L = Losses, T = Ties, OTL = Overtime losses, Pts = Points, GF = Goals for, GA = Goals against
See also
List of ice hockey teams in Alberta
List of ice hockey teams in Saskatchewan
Lloydminster Bobcats
References
Lloydminster Border Kings win Allan Cup, cbc.ca
http://www.allancup.ca
External links
Border Kings website
Category:Chinook Hockey League teams
Category:Ice hockey teams in Alberta
Category:Ice hockey teams in Saskatchewan
Category:Sport in Lloydminster
Category:Senior ice hockey teams | {
"pile_set_name": "Wikipedia (en)"
} |
Early primary immune response against erythrocytes: a case report.
Primary immune response against red blood cell (RBC) antigens often takes weeks or months to be detected. In previous reports, for children receiving multiple units of blood components, ranging from five to 81 units, the elapsed time between the first RBC transfusion and antibody detection ranged from 18 to 78 days. Cytomegalovirus (CMV) is sometimes associated with immunohaematologic findings and may modulate immune response. A 24-week-old male infant with interstitial pneumonia and hepatitis because of CMV developed an RBC auto antibody and two RBC alloantibodies: anti-Jka, detected in tube 11 days after a single RBC transfusion, and anti-K, detected only in papain gel test 18 days later. As anti-Jka is not a naturally occurring antibody, this is the most rapid primary immune response against an RBC antigen after a single RBC transfusion ever described, in the youngest child ever described. | {
"pile_set_name": "PubMed Abstracts"
} |
This invention relates to a method of handling a telephone call, and in particular to a method which allows long-distance telephone calls to be routed over the internet, to take advantage of the fact that this may be more cost effective for the telephone subscriber than relying on the normal telephone network.
WO96/20553 describes one possible communication system, in which the internet is used for an intermediate leg of a long-distance telephone call. Voice mail or facsimile messages can be sent to a subscriber, and will be stored at a dedicated node in the network, from which they may be retrieved by the subscriber. This document also describes an arrangement whereby one such subscriber may route a long-distance telephone call to another such subscriber, with the internet being used for an intermediate leg of the transmission, between the dedicated access nodes to which the two subscribers are connected.
However, this system requires that each subscriber should be registered with the network of dedicated access nodes, before the internet can be used to route a telephone call between them.
This invention relates to a method, and to a telephone exchange for use in such a method, which allows a telephone call to be routed over the internet, without requiring any specific registration by either of the subscribers. In preferred embodiments of the invention, when a calling subscriber indicates that he wishes a particular call to be routed over the internet, he is allocated an internet address for the duration of the call. His local telephone exchange determines which local exchange serves the called party, and establishes an internet connection thereto. The local exchange of the called party allocates an internet address to the called party for the duration of the call. This address is returned to the calling party""s exchange, thus allowing establishment of a connection over the internet for speech/data transfer between the calling and called parties.
Thus, the call can be routed over the internet without requiring either subscriber to have taken any special steps such as registering with a particular service provider, before the call is placed.
Moreover, the invention allows the call to be routed over the internet while using a desired telephone network protocol such as ISUP. This means that the use of the internet is transparent to the user, there is no feature of the call which appears different from a call which is routed over the normal telephone network. Moreover, the use of a telephone network protocol such as ISUP means that all services supported by ISUP, including IN services if available in the version of ISUP, are available even though the call is routed over the internet. | {
"pile_set_name": "USPTO Backgrounds"
} |
"You took one of me best whores for your private use." "Every day she's not under my roof costs me money." "(grunts)" "Wait, listen to me!" "(gagging)" "Good men will die for some hidden agenda, the Barlow woman's agenda." "Things will get better here." "I promise you they will." "We'll need some additional items." "New guns, 12-pounders." "You'll have it." "You want the guns from my ship to hand over to a pirate?" "That is correct." "Richard:" "Help me, Mr. Scott." "Please, help me save her." "Why don't I take over?" "Eleanor:" "The Andromache, it can't be." "Captain Bryson hasn't had time to unload." "He didn't." "She's riding low." "Those guns are still on board." " Eleanor:" "What are we going to do?" " Get them back." "(theme music playing)" "(wind blowing)" "Billy:" "Captain?" "We're steady at six knots, north by northeast." "You don't trust me, do you?" "With any luck, we'll sight the Andromache soon." "The battle will begin." "You and I will have our roles to play." "We have the chance for a few minutes' honesty first." "Honesty?" "Men died yesterday careening our ship faster than was safe." "Men are going to die today attacking that merchant ship out there, and they'll die not knowing it was all based on a lie." "A lie?" "We don't even know if the Urca's schedule is accurate." "We're completely relying on the cook." "How can you just pretend you have no doubts about any of this?" "Years of practice." "There's always doubt, Billy." "No sane man would deny that." "No good captain would acknowledge it." "Take our present route, for instance." "We tacked north by northeast, along Andromache's best point of sail." "If you're Bryson, that's the smart course." "Yeah..." "Well, he knows that I know that." "So wouldn't he have at least considered heading northwest to follow the coast, lose us in the dark?" "Or due east on the chance that we might sail right past him?" "There must be at least one chance in three that that horizon will remain bare and we'll never see the Andromache again." "That's the truth." "But what good would that knowledge do for any man on this crew trying to focus on doing his job?" "This crew needs certainty, and I need their support to achieve an end which is in all our best interests." "So we dance the dance." "Never was there a Caesar that couldn't sing the tune." "Who's Mrs. Barlow?" "Ah." "You've heard the stories, haven't you?" "She's a witch who pledged my soul to the devil, and anoints me with the blood of infants to keep me safe in battle." " Come on, I'm not stupid." " No, you're not." "So you can probably guess it isn't as much fun to tell stories about how your captain makes a home, with a nice Puritan woman who shares his love of books." "Is that the truth?" "Man:" "Sails!" "Man your posts!" "Man 2:" "Posts!" "Man 3:" "Have a look." "Man:" "It's the Andromache!" "(crew shouting)" "(bird trilling)" "(dogs barking)" "Well, this is a stupid fucking idea." "Given the straits we're in, I would suggest there is no such thing." "If we don't find a way to earn an income and soon, we will lose what little we have left of a crew." "Or worse yet, we will be eaten by what little we have left of a crew." "Wish me luck." "You gave him permission, dear." "We must stand by our word." "But I said he could put one finger in my bum, not three." "Then next time, charge him by the digit." "Mrs. Mapleton, a word, please." "What the fuck are you doing here?" "Mr. Noonan expressly forbade it, did he not?" "It turns out Mr. Noonan has had a change of heart." "A transfer?" "What is this?" "It means, madam, that the dispute over the whore with Mr. Noonan has been settled through an agreement to purchase this establishment from him... by us." " Noonan sold you the inn?" " Yes, ma'am." "And where is he now?" "From the tone in his voice, it sounded as if Mr. Noonan couldn't wait to be rid of this place and of its screeching pig of a bawd." "His words, not mine." "The last I saw him, he was seeking passage to Port Royal, and then to who knows where." "You're telling me that Mr. Noonan, who just a few hours ago had the intent of seeing your captain beaten to a pulp, that Mr. Noonan decided instead to sell you his life's work?" "Yes." "And you expect me to accept it based on a piece of paper and your word?" "And to keep my mouth shut about it when any half-wit can see that there's foul play at hand?" "Yes." "I want a raise." " What did you make before?" " Three percent of gross." "I'll give you 40." "Welcome aboard, sonny." "We are the proud new owners of a brothel." "Let's hope no one notices." "No one has seen or heard from Scott all morning." "He must have left with Bryson." "You're certain he said nothing to you about why he would do this?" "Nothing, ma'am." " Before I knew what was happening..." " Get my horse ready." "I'm going to see my father." "I want to know what the fuck's going on here." "(sighs)" "Hello." "What the fuck are you doing in my office?" "Flint stashed me here." "Presumably to stop what's in my head from spilling onto the deck of the Andromache." "Oh, that's Randall." "Why is Randall lying on my sofa?" "(chuckles)" "Well, he's not exactly going to be leading the charge after the day he had yesterday." "Why are you chained to him?" "So I don't try to run." "Thank you." "Sorry, have I done something to you?" "Excuse me?" "Well, you seem to harbor quite a bit of anger towards me, and considering we hardly even know each other," "I'm wondering if there's something I'm missing." "Flint and his crew offer you a life of freedom and prosperity for which you repay them by stealing the product of months of their labor and sacrifice." "But you're not finished." "Then you lure Max into your selfish scheme." "Hold on." "I specifically tried to talk her out of getting wrapped up in my selfish scheme." "I know all I need to know about the kind of man you are." "Ma'am, you should come outside right away." "Richard:" "For years, we've all profited in this place, trading on the stability of my family's name." "But unfortunately, our circumstances have changed." "A fortnight ago, His Majesty's Navy attempted to place me under arrest." "(crowd murmuring)" "I am, since that day, a fugitive marked for execution by the Crown." "(crowd groaning)" "Unbeknownst to me, my family in Boston learned of this and ordered Captain Bryson to liquidate our holdings here." " (crowd yelling)" " Man:" "What about our goods?" "I convinced him to leave behind the contents of our warehouse, but that is all." "To those of you owed credit or for whom we held goods on consignment," "I leave it to my daughter to see you made whole as best we can." "But once that is settled, our business with you must be considered complete." "(crowd groaning, yelling)" "I'm very sorry." "Godspeed to you all." "Man 2:" "I want my money back!" " (grunting) - (Water splashing)" "We aren't closing on her!" "I said to raise all the canvas!" " What's our speed?" " Sails are all raised!" "No, they're not." "Where are my t'gallants on the main and mizzen?" "De Groot:" "Captain, we're fully loaded." "If we raise the t'gallants, the mast won't hold." "Man:" "Stand by to stretch that starboard!" "Time." "Present speed: six knots." "We need at least another knot if we're to catch up by dark." " Raise the t'gallants." " Captain..." "Shift aft the back stays if you're worried about the masts." "Shift 'em to the stern if you have to." "Even if the back stays hold at such an angle, and I wager they won't, the load on the sails will exceed capacity and she'll dig in hard at the bow." "She'll hold." "Hard enough to shake loose the rigging entirely." "Captain, Mr. De Groot makes a good point." "The speed we'll pick up will come with dire risks for the ship." "But I think she can take it." "Mr. De Groot, quickly, please." " Raise the t'gallants!" " Man:" "Raise the t'gallants!" "Man 2:" "Out of the way!" "Brace up another five degrees!" " Five degrees!" " Five degrees!" "Bring her up into it." "(wind gusting)" "(grunting)" "More!" "Brace up a little more!" "More!" "That's well!" " That's well." " Man 2:" "Hold on!" "(yells, grunts)" "Now bring her up into it." "More, damn it. (grunts)" "Like this!" "(yelling)" "Aye, Captain!" "There." "Hold it there." "Hold her tight." "Speed!" "Again, please!" "Time!" "Seven and a half knots!" "(crew cheering)" "All right, ladies, get some rest." "In a few hours, things are gonna get awfully interesting." "Good morning, dear." ""Orders from Boston, unbeknownst to me."" "You sent Bryson away." "Yes." "You lied to my face, you shit." "And what choice did you leave me?" "You let Flint seduce you into his madness about the Spanish galleon all in furtherance of the fantasy that you can resist English rule, that your authority in this place is yours to do with as you please." "I am more to this place than you ever were." "You are a child." "I'm fully aware that Captain Flint left in pursuit of the Andromache last night." "But you should know" "Captain Bryson sailed the Velasco route for 10 years and was never boarded." "Not once." "Flint will be returning either empty-handed or not at all." "This treasure galleon business is over." "As for our future here," "I am working on a deal that'll make a safe place for us among the farmers in the interior." " (scoffs)" " When the pirates are gone, the landowners will drive commerce here." "They'll be indispensable to the lords and to Whitehall, and so we will make allies of them." "We will adapt and we will survive." "I won't ask you to walk out with me right now." "I know your pride would never permit it." "The Barlow cunt who was supposed to watch over you, that's Flint's problem." "But Scott... what the fuck did you have to threaten him with to get him to betray me?" "We talked like men and he saw reason." "Fuck you." "I been sayin' it." "You ain't been listening." "And now it's come to pass." "The day that gentleman and his daughter tell you that the money they took ain't never coming back." "(crowd yelling)" "Lilywhite:" "Yeah, that were just fucking theft!" "Right now, that little girl is sitting in there counting your money and laughing her scrawny ass off on how much she has lifted out of your pockets." "This is fucking nuts!" " We're not working!" " Good riddance, yeah!" "(gasps)" "I thought my men could help keep tempers from boiling over, for a while at least." "But for those owed money out there, it's only a matter of time before their tempers can no longer be held in check." "Now, if I may, I suggest an announcement of payments to settle debts." "The longer it takes them to hear it, the more fuel Lilywhite can throw on the fire." "I can't pay them all." "You're short?" "How short?" "Well, get out your books, then." "Certain crews may defer their debts if I ask them." "Any leads you have on future scores would soften the blow." "Troublemakers we need to pay off first..." "No." "I'm not winding things up here." "My business continues." "Captain Naft of the Intrepid." "Mr. Walker, her quartermaster." "Captain Lawrence of the Black Hind and Mr. Harrison." "And our friend Mr. Frasier." "Get them all here now." "Miss Guthrie?" "I'm not sure you recognize the gravity of this situation." "Have a drink." "Relax." "Everything's under control." "(crowd yelling)" "Hamund:" "She's fucking done!" "That Guthrie cunt is done." "Have you not heard?" "We've heard." "Well, then what the fuck are we doing in here?" "At the moment, I'm remembering what it feels like to have food in my belly." " Care to join us?" " Jesus, Jack." "We're free of her." "Free to hunt again." "So get off your ass and find us a ship." "To assume that we've seen the last of Eleanor Guthrie is, well, not to know her." "The fact that she appears to have Captain Hornigold and his men propping her up only adds to my conviction." "Right now, we'd do well to keep our mouths shut, be thankful we have some income from this place, for the moment, and bide our time." "Fuck that." "She's got no ships." "She's got no business." "That means she's out." "And I'm going over there to make sure she knows it." "Captain?" "I'll be upstairs." "Well, then, fuck you both." "Who's with me?" "Nothing can ever be simple." "(scoffs) I can make it simple." "Darling, this is a lovely stopgap, but if we are to ever hunt as a proper crew again, we will need, well, a crew." "Right now, those men are all we have." "It's unfortunate, perhaps, but no less a reality." "Why don't we take advantage of Mr. Hamund's momentary distraction and have Mrs. Mapleton tend to the whore on the beach?" "(drops fork)" "(scoffs)" " Man:" "Two six!" " Heave!" " Two six!" " Heave!" " Two six!" " Heave!" "Stand by!" "Stand by!" "(knock on door)" "Ahem." "Yes, Mr. Hayes?" "Hayes:" "The Walrus will be upon us in roughly four hours, present speed." "I assume preparations have been made." "Yes, sir." "And the shipment of china plate?" "I beg your pardon?" "We have 70 plates of Chinese porcelain in the hold, which I have undertaken to deliver to Boston unharmed." "May I suggest more straw in the chest?" "Yes, sir." "He's certain this is all we have?" "We emptied the girl before we careened her." "This is the best I could do before we set sail." "Same for food and water, I assume?" "Food, water, powder, all of it." "Right." "Take it all up top." "No reserves on this one." "Either we take Bryson's ship or we're..." "I believe the word you're looking for is "fucked."" " Yeah, thank you." " Yeah." "Dufresne?" "You can't be serious." "Andromache's manned like a warship." "60 men at least, and they're fighters." "So we'll need every body we can muster on this one, yours included." "Come on." "(birds screeching)" "(dogs barking)" "(goats bleating)" "Come on, everything's at sixes and sevens back at the house and I have to come and tend to this." "All right." "Come on, love." "Here we go." "Open your legs." " (water squirts) - (Winces)" "Oh, hush, unless you want to find yourself carrying one of those fools' brats." " (water squirts)" " Ow!" "Get out." "(whimpers)" "She wasn't using enough lotion." " (water squirting softly) - (Whimpering)" "You could've left." "(water squirting softly)" "When that cunt beat Hamund off of you, you could've left." "You didn't." "Thought you could sweet-talk them all, did ya?" "What do you care?" "Once, one of them came and put his balls on my shoulder whilst I was asleep." "Thought it was funny." "Last time he put them anywhere." "If you take it, they'll give it." "Why do you say these things?" "You were the one who threw me to them in the first place." "I only thought they'd kill you." "Lilywhite:" "Do you feel that soreness between your haunches?" "Yeah, well, that's what you get when you let some cunt who's never raised a sail, set foot on a deck tell you your business!" "(crowd shouting)" "Next thing you know, she'll have her boot on your throat and her hand in your fucking pocket." "I think he's talking about you." "Lilywhite:" "That's what you get when you're letting a wench tell you..." "If you're pretending to remain unconcerned for my peace of mind, please don't." "It amuses me that you think I would even give a shit" " about your peace of mind." " Silver:" "Of course." "Still, I don't think you're giving that problem out there its due attention." "(door opens)" "Naft and Walker just arrived." "That's everyone." "You've never seen a mob turn, have you?" "Funny thing." "The people most surprised when it happens, usually the ones that gave rise to it in the first place." "Can you join me, please, Captain?" "I want you to hear this, too." "Hamund:" "Is the cunt still here?" " Out on the street, friend." " Where is she?" "It's a rough world out there, isn't it?" "Someone opens their mouth, you can lose everything." "Tell me, lass... how's it feel?" "Out now." "Well, if we're not welcome in here," "I suppose we can go spend more time with our friend on the beach." "(pirate chuckles)" "Oh, wonderful lass she is." "So, um... resilient." "(pirates laugh)" "So appreciative of what she's given." "We'll send her your love." "(laughs)" " Come on, boys." " (Pirate laughs)" "(speaks African dialect)" "Billy:" "Gentlemen..." "I think we all know what we're up against today, so let's just get to it." "As we close the distance to the Andromache, the captain believes Bryson will attack port and set himself for a clean broadside volley." "He'll loose his guns, pay off downwind, and continue running." "Now, ordinarily, we would either match him and return fire or slip into his wake and make a run at his stern." "Unfortunately, we're too outgunned for the former, and Bryson is too skilled a captain for the latter." "He'll just keep shooting and delaying and shooting and delaying until nightfall, at which point he'll just slip away." "So..." "So, if we can't shoot at her and we can't get close to her, how the hell do we board her?" "(murmuring)" "We go straight at her." "Without the bow chasers, we'll be sitting ducks for her guns." "She'll rake us bow to stern." "Logan:" "Not to mention we'd be boarding bow to midship." "For all you virgins in the room, that's also known as fucking suicide." "Billy:" "Of course we'd need to board alongside her." "We just need Captain Bryson to cooperate and bring the Andromache about for us to do so." "And how the hell do we get him to do that?" "Mr. Beauclerc is going to convince him." "(blows)" "You're a natural, son." "When this is all over, I'll be lucky to still have a job." "(laughs)" " What..." " I keep accounts." "That's what I'm good at." "Do you see this number here?" "That's how much I've saved this crew this last year alone." "Can you say of any other man here that they've earned as much?" "Every man on this crew had a first time." "You're overdue." "But I've never even shot a pistol." "Well, that's all right." "Half the time they don't even fire." "I'm sorry." "Time has come for us to tell those who aim" " to make us slaves." " (Knock on door)" "Woman:" "Mr. Rackham asked me to tend to you." "Lilywhite:" "Yeah, well, that's what you get." "He said I wasn't to take no for an answer." "They're saying she may be finished." "She's finally got her due." "All I meant is that... that it should please you after what she did." "You hate her." "I hate her." "They all hate her." "Look what's good it's done us." "No captain on this island's ever known that kind of power." "Power that doesn't care how many votes you can tally, who loves you, who hates you, who fears you." "Power that just is." "Truth is, none of us have any right to hate her for it." "She's strong and we're weak." "That's the reality of things here." "And no one down there is strong enough to change anything." "Not you?" "You're not strong enough?" "I don't know." "But I think it's time I probably found out." "(creaking)" "What if he's wrong?" "There's a chance Bryson just keeps running, isn't there?" " That's it, steady." " Right?" "Bryson could still gain speed." "I mean, there has to be a chance this fight will never materialize." "Come on." "Come on, you bitch." "Come on." "There she goes!" "(crew shouting)" "Why isn't he attacking?" "Because he knows he'll never board us if he does." "I will say this for him." "He's no coward." "200 yards, you may fire at will." "(shouting)" "I don't think I can do this." "Yes, you can." "Listen." "Listen to me." "You will make it through this." "No one eats it their first time over the side." "I'm telling you, it's never happened." "Not on this crew." "Don't ask me why, it just is." "Men die all the time." "It can't be true." "No, not first-timers." "Name one." "You're gonna be all right." "Come on." "Damn it." "I hope you know what you're doing." "So do I." "Mr. Beauclerc?" "Range?" "Almost there!" "50 more yards, Captain!" "Fire!" " Let her go." " Fire!" " Incoming!" " (Men scream)" "Fire!" "(yelling)" "(groaning)" "(yelling)" "Get 'em back into the cookroom!" " Get 'em back!" " (Yelling)" "We can't take much more of this." "Aye." "Mr. Beauclerc!" " Two six!" " Heave!" " Two six!" " Heave!" "Hayes, another volley right away!" "Right cannon round!" "Mr. Burnett, prepare to bear away and bring us into the wind." "Man the braces!" "Fire!" "(man screams)" " (yells)" " Beauclerc, do it!" "Stay where you are!" "Bring us to starboard before we lose the wind!" " Mr. Harris, take the helm!" " Aye, sir!" "Fire." "Man:" "We've lost the wind, Captain." "Prepare to repel boarders!" "Bring us around to the port side!" "On the rails!" "(shouting)" " (guns firing) - (Gasping)" "Now!" "20 yards!" "At the ready." "Get across the gap, choose your targets!" "Pistols at zero range." "Don't waste a shot." "Nets in!" "(crew shouting)" "Nets up, nets up, nets up!" "Get it!" "10 yards!" "Go, go, go!" "Over!" "Get it over!" "Hold, get down!" "Hold, hold!" " (gunfire continues)" " Hold!" "(all grunt)" "(exhales)" "Go, go, go!" "(all shouting)" "(grunting)" "(yells)" "(panting)" "(muffled yelling)" "(gasps)" "(yelling)" "(buzzing)" "Dufresne?" "Jesus." "Come on." "(cheering)" "No fucking longer!" "Gentlemen, you all heard my father this morning, that the Guthrie trading operation here in Nassau is dead." "To that, I just have this to add... fuck him and fuck that." "Mr. Frasier, you hold a charter from the Massachusetts Bay Provincial Authority to ship rare items abroad, is that correct?" "That's correct, yes." "And, theoretically, that charter should pass muster at any customshouse in the colonies, yes?" "Well, I suppose so, but..." "Gentlemen, by my count, the Black Hind and the Intrepid have accumulated prizes totaling approximately" "1,600 pieces of eight since the new year." "That's gross." "That's both ships." "That barely exceeds your operating costs over the same time." "If you brought us here to insult us..." "It's not an insult, it's a fact." "You command the two least profitable ships on the island as a function of basic arithmetic." "But they are ships, and large ones at that." "At this table, we have a legitimate front." "We have ships and crews that can ferry heavy cargo." "We have relationships with the merchants and customs men that kept my father's trade moving." "Your father said he'll take no part in any further..." "They're my relationships now." "We're going to recreate my father's system here... without my father." "A consortium, with all of you sharing in the profits." " You're mad." " How so?" "My men aren't merchant sailors." "They're hunters." "Yes, but they're bad at it, Geoffrey." "What good is that doing anyone?" "I put this to them, they'll vote me out before I stop to take a breath." "I'm amazed they haven't voted you out already, given the shit prizes you've been chasing." "Your men will earn three times as much in half the time..." " (scoffs)" " Not facing a single sword or pistol in the process." "You're telling me that you can't sell that?" "I can sell that." "(sighs)" "And you're supporting this?" "I don't know." "Am I?" "None of this matters unless we can get people to agree to sell through us." "We need a respected captain to stand up and bless it." "And we need a strong captain to ensure that no one dares fuck with us." "You're both." "You know that I want nothing more than to make this place strong and stable." "I think you want the same things." "Bless this endeavor and we can have them." "I'll do that... the moment you lift the ban on Captain Vane." " Excuse me?" " Listen to that mob outside." "They're tired of your edicts, your rule by fear." "They believe you to be a tyrant in a petticoat." "Your action against Captain Vane is, to them, the most egregious case." "You want me to lift the ban on Charles Vane to appease a handful of malcontents on the street?" "Those malcontents will be a problem to anyone in this room who stands behind you today." "Provocation, even sabotage." "And then you'll ask my men to assume the responsibility of defending all of you from it." "Charles Vane is an animal, as are the men that remain with him." "Because they saw fit to punish a thieving whore." "I'm not about to say otherwise for the benefit of Captain Lilywhite or any of the other idiots out there listening to him." "I'm listening to him." "Your commitment to this place is admirable, but you're young and you're rash." "Show everyone your motive here is for the common good." "Show them that you can be trusted to keep petty animosity separate from business." "Rescind the ban on Captain Vane and show me that." "Do it and I'll back you as your father's successor here, the boss behind all trade." "Until then, I'm sorry." "I can't help you." "I won't do it." "You have until dark to come to your senses." "At that point, I will withdraw my men and the business of the street becomes your business alone." "Good afternoon, gentlemen." "Ah!" " Man:" "Oh, no!" "Get down!" " (Explosion)" "(men yell)" "Man:" "Take this." "Checked all the dead and injured." "None of them are Bryson." "He only left three men to defend the quarterdeck bunker." "How does that make sense?" "Gates:" "The vanguard are on their way to clear the cargo hold." "Maybe Bryson is hiding down there." "Something's not right." "Captain, the rudder's not responding." "Someone must've cut the mechanism below decks." "Call back the vanguard." " (gunfire) - (All yell)" " (labored breathing) - (Metal squeaking)" "Three men dead on their end, Captain." "Perhaps it's time we sent them our terms." "I do apologize for this." "Mr. Guthrie's orders were explicit." "No matter what, I was to make sure that you were on this ship." "This was not the deal." "(chuckles)" "Assist the Andromache to depart unmolested and you can remain with the girl and pick up the pieces and explain yourself." "Mr. Scott, you sided with his daughter against him." "You forgot your duty." "You must have known there would be consequences." "But we men of duty must often put our feelings aside... as you're about to witness." "(speaks West African Pidgin English)" "Do it." "(groans)" " And this one?" " (Speaks West African Pidgin English)" "(door opens)" "(crowd chanting)" "At the risk of overstepping my bounds," "I think you should agree to Captain Hornigold's terms." "Lift the ban." "What do you care about..." "They're beating her." "She chose it." "(scoffs) "She chose it"?" ""She chose it."" "I've been repeating those words to myself for well over a week now and I find them wanting." "Now he asks me to back off Charles, to proclaim to the world that what happened to Max is acceptable, to apologize to those animals for having ever said otherwise, and smile while they lord it over me." "To make a dangerous situation a lot less dangerous." "Then convince me." "Convince me that I should betray her a second time... because that's what it feels like I would be doing." "Max chose." "Why?" "I don't know." "Maybe it was spite, maybe it was strength, maybe it was who the fuck knows what." "To be perfectly honest, I don't care because the moment I start making choices based on her decisions," "I've given her a hell of a lot more power over my life than I am quite comfortable ceding to a perfect stranger." "Guilt is natural." "It also goes away if you let it." "Losing your life's work... that doesn't go away." " Lilywhite:" "No fucking longer!" " (Cheering)" "Captain?" "Charles?" "Do I understand correctly that you've requested a skiff?" "I suppose that's none of my business, but you do realize that we may be able to hunt again soon." "What I'm hearing is all second and thirdhand, but something is happening in that tavern." "Our problem isn't in there." "Never was." "What the hell are you talking about?" "Chaz?" "Where are you going?" "Where is he?" "Gates:" "He's in a reinforced hold directly beneath us here." "Forward end of the lower gundeck." "Doors as thick as the outer hull, as is the roof." "Impossible to breach from here." "He's also sitting right in front of a powder magazine, so if we try to blow our way through, this whole ship is going down fast." "Unless we can find a way in, there's no way to get the guns off the boat." "Anybody we send down there is just gonna get cut to shreds." "And we cannot sail." "And we cannot sail." "It doesn't make sense." "If Bryson wants to force us to withdraw, what's to stop me from burning the ship once we leave?" "We're missing something." " (wood creaking) - (Lamps creaking)" "There you are." "Been looking all over for you." "Thought I'd get a head start going through Bryson's papers." "Jameson." "Beg your pardon?" "You said no man ever died his first time over the side, but you forgot about Tom Jameson, boatswain's mate, about two years back." "That's right." "Also Christian Thoms, Will Robbins, Jean DuBois, that Portuguese guy with the lisp... what was his name?" " That is funny." " (Chuckles)" "Thank you... for doing that." "It helped." "(pats back)" "Miranda Barlow?" "Man:" "Away from the hatch!" "Everyone!" "(guns cock)" "Captain Flint." "(speaks African dialect)" "He says, "I'm secure in the hold below."" "(man speaking African dialect)" ""With 20 of my men." "I can wait, but you cannot."" "(speaking African dialect)" ""Before departing,"" "I sent a message to the captain of the Scarborough." "I told him where I was headed," ""and I told him where he would find you."" "Man:" "Sail to the east!" "Good God." "The Scarborough!" " (yells)" " Man 2:" "Look out!" "(gunshot)" "(grunts)" "(panting)" "(music playing)" | {
"pile_set_name": "OpenSubtitles"
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Diversity marks the makeup of new Congress
Democrats have taken the majority in the House and the new Congress is like none other. There are more women than ever before, with a new generation of Muslims, Latinos, Native Americans and African-Americans joining in. (Jan. 4) | {
"pile_set_name": "OpenWebText2"
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I saw a lot of people complaining about how the girl’s faces in overwatch are all the same, so I decided to do the test and see if people were right or they were just overreacting.
I did this face retrace to see clearly if the overwatch girls had the same faces syndrome compared to the guys and what I found out was pretty interesting.
The first thing that jumped into my eyes were the fact that the faces type on the girl side ARE PRETTY DIFFERENT! Some girls have pretty squared shaped face like Symmetra and Brigitte, other have really round faces like Mei, Widow or Sombra and others are in between with a round face, but a really squared jaw like Tracer or Pharah. I do have to admit that most of the girls noses are the same which is a shame, but beside that they face are different shapes.
After being a lil’ bit happier about the fact that even if the girls looks like they have the same face, but they really don’t, I got scared to compare on the guys side. I thought that maybe all the lil’ subtle differences might not be strong enough to go against the guys faces, but I was quite surprised.
I realized that most of the guy’s faces are squared shaped and nothing else. There’s always the cheek bones that migh make a difference from one character to another. The only exceptions being Junkrat (with his long face ), Hanzo ( with his more pointy chin ) and Mccree ( with his jaw and chin being standing out more than his forehead ).
So yeah! What we should ask blizzard on their faces designs is to make more guys with round faces! | {
"pile_set_name": "OpenWebText2"
} |
Warm Nights
Warm Nights is the fourth album by Robert Forster. It was released on LP and CD by Beggars Banquet in 1996 and was highlighted with a new version of the Go-Betweens' "Rock 'n' Roll Friend", which was a single B-side in 1988.
Forster later said, "It was about sweaty Brisbane nights, banana trees in the backyard, animals walking around at night, fruitbats flying in the air. I was looking at Brisbane with new eyes in this new suburb, and I was listening to this music that had more space, more rhythm. I wrote all the songs in about eight months, quicker than I had written since the late 70s."
Track listing
All songs written by Robert Forster, except where noted.
Side one
"I Can Do" – 3:00
"Warm Nights" – 4:25
"Cryin' Love" – 5:28
"Snake Skin Lady" – 3:35
"Loneliness" – 3:21
Side two
"Jug of Wine" – 6:03
"Fortress" – 4:57
"Rock 'n' Roll Friend" (Forster/Grant McLennan) – 5:13
"On a Street Corner" – 5:29
"I'll Jump" – 3:01
Personnel
Robert Forster – vocals, guitar
Edwyn Collins – guitar
Martin Drover – trumpet, flugelhorn
Clare Kenny – bass
Oliver Karus – cell
Neil Pentelow – saxophone
Dave Ruffy – drums
J. Neil Sidwell – trombone
References
Category:1996 albums
Category:Robert Forster (musician) albums
Category:Beggars Banquet Records albums | {
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... on the upper terrace with sea view (fabulous under the stars in the cool of the night!). Anti-stress massages available. Full board / all inclusive* From August the 1st. - September the 15th.: $120 a ...
... shutters. 2 rooms have a loft (more like a complete second floor, with full-height ceiling and "real" beds - not just mattresses on the floor). FOOD: Excellent mixed cuisine prepared by chef. FACILITIES: ...
A beautiful colonial house that has been maintained over time. Full of luxury. One room has an antique tub. A haven of good taste with a great terrace. All executive rooms have mini fridge and the rate ...
... using local produce, fresh vegetables always with a touch of cocoa present. The big attraction is the cocoa plantation, yoga, meditation, mantras accompanied by De-stressing massage, bird watching and ...
... massages, mud baths and hydrotherapy. Ideal for families and nature lowers. Included you find three anti-stress therapies, three meals a day, tours and use of all facilities. Real adventure and nature. ... | {
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Crude oil is currently the source of most commodity and specialty organic chemicals. Many of these chemicals are employed in the manufacture of polymers and other materials. Examples include ethylene, propylene, styrene, bisphenol A, terephthalic acid, adipic acid, caprolactam, hexamethylene diamine, adiponitrile, caprolactone, acrylic acid, acrylonitrile, 1,6-hexanediol, 1,3-propanediol, and others. Crude oil is first refined into hydrocarbon intermediates such as ethylene, propylene, benzene, and cyclohexane. These hydrocarbon intermediates are then typically selectively oxidized using various processes to produce the desired chemical. For example, crude oil is refined into cyclohexane which is then selectively oxidized to “KA oil” which is then further oxidized for the production of adipic acid, an important industrial monomer used for the production of nylon 6,6. Many known processes are employed industrially to produce these petrochemicals from precursors found in crude oil. For example, see Ullmann's Encyclopedia of Industrial Chemistry, Wiley 2009 (7th edition), which is incorporated herein by reference.
For many years there has been an interest in using biorenewable materials as a feedstock to replace or supplement crude oil. See, for example, Klass, Biomass for Renewable Energy, Fuels, and Chemicals, Academic Press, 1998, which is incorporated herein by reference. Moreover, there have been efforts to produce adipic acid from renewable resources using processes involving a combination of biocatalytic and chemocatalytic processes. See, for example, “Benzene-Free Synthesis of Adipic Acid”, Frost et al. Biotechnol. Prog. 2002, Vol. 18, pp. 201-211, and U.S. Pat. Nos. 4,400,468, and 5,487,987.
One of the major challenges for converting biorenewable resources such as carbohydrates (e.g. glucose derived from starch, cellulose or sucrose) to current commodity and specialty chemicals is the selective removal of oxygen atoms from the carbohydrate. Approaches are known for converting carbon-oxygen single bonds to carbon-hydrogen bonds. See, for example: U.S. Pat. No. 5,516,960; U.S. Patent App. Pub. US2007/0215484 and Japanese Patent No. 78,144,506. Each of these known approaches suffers from various limitations and we believe that, currently, none of such methods are used industrially for the manufacture of specialty or industrial chemicals.
Thus, there remains a need for new, industrially scalable methods for the selective and commercially-meaningful conversion of carbon-oxygen single bonds to carbon-hydrogen bonds, especially as applied in connection with the production of chemicals from polyhydroxyl-containing substrates (e.g., glucaric acid), and especially for the production of chemicals from polyhydroxyl-containing biorenewable materials (e.g., glucose derived from starch, cellulose or sucrose) to important chemical intermediates such as adipic acid. | {
"pile_set_name": "USPTO Backgrounds"
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? (a) -1/2 (b) 1 (c) 1/6 (d) 2/7 (e) 2
c
What is the second biggest value in -0.1, -1/3, 0.4, 0.09?
0.09
What is the second biggest value in 2/9, -2/53, 2/3?
2/9
Which is the second biggest value? (a) -2 (b) 3 (c) 2/11
c
Which is the third biggest value? (a) -2/37 (b) -1 (c) 2 (d) 3 (e) 5/7
e
What is the biggest value in 1/6, 0.1, 0, 2/15?
1/6
Which is the second biggest value? (a) 7 (b) 1 (c) 11
a
What is the third biggest value in 10, -0.3, 4/5, 1?
4/5
Which is the third smallest value? (a) 1/20 (b) -2 (c) -10
a
Which is the third biggest value? (a) 4 (b) 1 (c) -5 (d) -48/65
d
What is the third smallest value in 2, 0.47, 1/11, -3, -4?
1/11
Which is the fourth biggest value? (a) -0.8 (b) 4 (c) 0.2 (d) 7
a
What is the third biggest value in -433, -3, -4/5, 2/13?
-3
What is the third smallest value in -1.67, -1/3, -5, 0.4?
-1/3
Which is the smallest value? (a) 4 (b) -0.2 (c) 0 (d) 4/5 (e) 23
b
Which is the second biggest value? (a) -2 (b) 0.14 (c) -5 (d) 0.4 (e) -0.1
b
What is the second smallest value in -12.5, -2/9, 3?
-2/9
Which is the second smallest value? (a) 0.1 (b) -1/5 (c) 2 (d) -2/19
d
What is the biggest value in 0, -2, 0.4?
0.4
Which is the second smallest value? (a) -1 (b) 3/10 (c) -2
a
Which is the third biggest value? (a) -0.5 (b) -34 (c) -2/39 (d) 3 (e) 3/5
c
Which is the second biggest value? (a) 2 (b) -5 (c) 0.0441
c
Which is the fourth smallest value? (a) 2 (b) 5 (c) -0.1 (d) 0.2
b
Which is the third biggest value? (a) -4/5 (b) -0.18 (c) -0.4
a
What is the biggest value in 0, -0.3, -1/8, 6, -3/2?
6
Which is the biggest value? (a) -2 (b) 5 (c) -2.4 (d) 3
b
Which is the fourth biggest value? (a) -79 (b) -4/5 (c) 0.5 (d) 1
a
What is the smallest value in -5, 2/19, 18?
-5
What is the biggest value in 0.4, 5, -4, -127?
5
What is the third biggest value in -1, 1/10, 8?
-1
What is the second biggest value in 279/4, 2, -2?
2
What is the third biggest value in -2, -944, 4?
-944
Which is the third biggest value? (a) -0.4 (b) -51 (c) 3
b
Which is the third smallest value? (a) 0.8 (b) -8 (c) -1/2
a
Which is the biggest value? (a) -1/4 (b) -1 (c) 620
c
Which is the fourth biggest value? (a) -7/29 (b) -0.4 (c) 1 (d) -3
d
What is the second smallest value in 28/15, 2/3, -5?
2/3
What is the second biggest value in -6, -4, -1/4?
-4
What is the third smallest value in -2/13, -0.3, 270?
270
Which is the biggest value? (a) 5 (b) 8 (c) -2/11 (d) -19
b
Which is the fourth biggest value? (a) -3 (b) 0.028 (c) -4/5 (d) -1/4
a
Which is the biggest value? (a) -5 (b) 0.4 (c) -1/18
b
Which is the third smallest value? (a) -0.1 (b) 2 (c) -69
b
Which is the smallest value? (a) -123 (b) 1 (c) 4
a
Which is the biggest value? (a) 4/117 (b) 4 (c) 1
b
What is the fourth smallest value in 5, -10, -0.1, 3, -2?
3
Which is the third smallest value? (a) 4 (b) 3 (c) 5 (d) 0.06
a
What is the fourth smallest value in 7, -3, 6/5, -2/3, 21?
7
What is the second smallest value in 2/15, -3.7, 0.4?
2/15
What is the second biggest value in -0.19, 5, 1/5, 4?
4
Which is the second smallest value? (a) 0.2 (b) 1 (c) 0.1 (d) -0.2 (e) 0.07
e
Which is the smallest value? (a) 14 (b) -4 (c) 5
b
What is the third biggest value in 0.1, -0.22, 2/13, 0.16?
0.1
What is the third smallest value in 2/3, -329, -0.2, -1/3, 0.2?
-0.2
What is the biggest value in -2, -4, 114?
114
Which is the fourth smallest value? (a) 2 (b) 4 (c) 2/13 (d) -10.3
b
Which is the third biggest value? (a) 1 (b) -148 (c) 11
b
Which is the third smallest value? (a) 2/39 (b) -0.3 (c) 4 (d) -2/17
a
Which is the second biggest value? (a) -191 (b) -0.3 (c) -1 (d) 2 (e) 4
d
What is the fifth biggest value in 4, 0.11, 0.3, 0.04, 2?
0.04
Which is the second biggest value? (a) 2/3 (b) -0.2 (c) 3.81
a
Which is the biggest value? (a) -3 (b) 6 (c) 0.2 (d) -1.1
b
Which is the biggest value? (a) 5 (b) -0.5 (c) 0 (d) 27 (e) 8
d
What is the second biggest value in -0.2, 4, -68/9, 3?
3
Which is the third smallest value? (a) 1 (b) 3/5 (c) -4
a
What is the third biggest value in -1/22, 0, -5, -0.01?
-1/22
Which is the third smallest value? (a) 92 (b) 3 (c) 2
a
Which is the third biggest value? (a) 5.7 (b) 0.2 (c) -0.2
c
Which is the second smallest value? (a) -1 (b) 4/7 (c) 2 (d) 1/5 (e) -14
a
Which is the smallest value? (a) -2/7 (b) -4 (c) 2 (d) -0.8 (e) -1/4
b
Which is the fourth smallest value? (a) -1 (b) 12 (c) 0.3 (d) 2/7
b
What is the second biggest value in -1, -2, 4, 117?
4
What is the smallest value in 0.4, -38, 92?
-38
What is the fourth smallest value in 3, -1/4, 0, 0.06, 1?
1
What is the second smallest value in 0.2, 0.4, 1915?
0.4
What is the biggest value in -0.5, 1/8, -5, 15?
15
What is the second biggest value in 0.4, 0.62, -2/7, 1, 0.01?
0.62
What is the biggest value in -58/9, 3, 0.5?
3
What is the third biggest value in 0.3, -26, 2, 2/9?
2/9
Which is the second biggest value? (a) 3/7 (b) -0.3 (c) 16.2 (d) -0.2
a
Which is the fourth smallest value? (a) 15/2 (b) -2 (c) 2/19 (d) -5
a
Which is the second smallest value? (a) -1/3 (b) 5 (c) 2/9
c
What is the second smallest value in 2/15, -19, 3, -3?
-3
Which is the second biggest value? (a) 583 (b) 3/2 (c) 3
c
What is the biggest value in 0.0884, -1, -0.2?
0.0884
What is the second biggest value in 1772, 3, 4?
4
Which is the third biggest value? (a) 513/5 (b) 5 (c) 3/7
c
What is the fifth biggest value in -2/23, 3/7, 0.029, -3, -0.3?
-3
What is the fourth biggest value in 5, -0.19, -0.1, -3?
-3
Which is the second smallest value? (a) -1/3 (b) 106 (c) 2/7
c
Which is the second smallest value? (a) 0 (b) 5 (c) -0.1 (d) 2/3
a
What is the second smallest value in 32, -1/6, 1, 0, 0.01?
0
Which is the fourth smallest value? (a) -0.2 (b) 4 (c) -2/11 (d) 0.3
b
What is the third smallest value in -1/2, 2/7, 0.3?
0.3
Which is the third biggest value? (a) 3 (b) 2 (c) 22 (d) -3.6
b
Which is the second biggest value? (a) -4278 (b) -2 (c) -5 (d) -1
b
Which is the fifth biggest value? (a) -3/4 (b) -11 (c) 4 (d) 11 (e) -2
b
What is the second smallest value in 0.5, -249.1, -1/3?
-1/3
Which is the fourth biggest value? (a) -1/3 (b) 2/5 (c) -35 (d) -0.1
c
What is the fifth smallest value in 1, -0.3, 2, 3, 0?
3
Which is the fourth smallest value? (a) -1 (b) 1 (c) 6 (d) -2
c
What is the fifth biggest value in 0.08, -3, 0.1, 0.4, -0.01?
-3
What is the fourth smallest value in -0.11, -1, -0.4, -64, 4?
-0.11
Which is the fifth smallest value? (a) -4/7 (b) 5 (c) 18 (d) -0.2 (e) -3
c
Which is the second biggest value? (a) 6/5 (b) -1 (c) 25 (d) 1/6
a
What is the smallest value in 2/3, 1, -2, -21?
-21
What is the third smallest value in 2/27, 12, 1?
12
Which is the second biggest value? (a) 0.6 (b) 3/4 (c) 2/21 (d) 0.1
a
Which is the fourth smallest value? (a) -2 (b) -1/9 (c) 7 (d) -4
c
Which is the biggest value? (a) -5 (b) 0.1 (c) -4/3 (d) 0.4
d
What is the third smallest value in -1, 0.9, 4/5, 0?
4/5
What is the second smallest value in -18, -5, -8?
-8
What is the smallest value in -0.4, 124/7, -1/5, 0?
-0.4
What is the second biggest value in 0.08, 0.5, 2?
0.5
What is the smallest value in -0.2814, -0.3, -4, 4?
-4
Which is the third smallest value? (a) 129 (b) -1/3 (c) 1
a
Which is the biggest value? (a) -0.1 (b) 24/11 (c) 1 (d) 0.4
b
Which is the biggest value? (a) 1 (b) 2/15 (c) 27 (d) -3
c
Which is the smallest value? (a) -3 (b) -4 (c) 1 (d) 3/11
b
Which is the smallest value? (a) -5 (b) -2 (c) 0.4 (d) -3 (e) 0.02
a
Which is the second smallest value? (a) -2/7 (b) 2/15 (c) 56
b
Which is the second biggest value? (a) -9 (b) -4 (c) -2/3
b
What is the smallest value in 1/66, -0.1, 2/5, 0.03?
-0.1
What is the third biggest value in -5, -6/7, 4, -7?
-5
Which is the smallest value? (a) 3/449 (b) -4 (c) 1
b
Which is the third biggest value? (a) -10 (b) 2/29 (c) 0
a
Which is the second smallest value? (a) -38 (b) 2 (c) -0.4 (d) 1/5
c
Which is the biggest value? (a) -5 (b) 0.5 (c) 5 (d) 0.4 (e) -3/13
c
What is the fourth smallest value in -3, -5, 5, 235?
235
Which is the second biggest value? (a) -2 (b) 0.1 (c) -2/793
c
Wh | {
"pile_set_name": "DM Mathematics"
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A Santa Clara University professor suffered major head injuries after he rode his bicycle into an SUV in Los Gatos on Wednesday, police said.
Bahram Saghari, 52, was in critical condition at Valley Medical Center on Thursday, Los Gatos/Monte Sereno police said. Although he was wearing a helmet during the crash, Saghari’s head was severely fractured.
Saghari, a lecturer in the Leavey School of Business, was riding his bike to work at Santa Clara University in the northbound bike lane of Los Gatos Boulevard at 7:40 a.m. on Wednesday, police and relatives said.
Alongside the bike lane, a row of cars were stopped waiting for the light to turn green at the Highway 9 intersection. Just then, a Ford Explorer made a left turn through the stopped traffic using the “keep clear” space and was hit broadside by Saghari’s bike.
The Explorer’s driver, San Jose resident Juan Antonio Rodriguez-Gallegos, 42, was cited for being an unlicensed driver. The cause of the accident remains under investigation.
Police ask anyone with information to call Sgt. Steve Walpole at 408-354-6851.
Los Gatos Boulevard, a main thoroughfare just east of Highway 17, was also the site of a crash in February 2008 in which a van struck and killed a bicyclist. In October 2009, a van hit and badly injured a bicyclist on the same street.
Contact Mike Rosenberg at 408-920-5705. | {
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1. Technical Field
This invention relates to products resulting from fermentation of poultry manure and having practical utility as organic fertilizers and soil conditioners. Further, the invention relates to a process for producing such a fermentation product.
2. Prior Art
As a result of a recent expansion of the poultry industry, great concern has been directed toward a quantitative increase in manure or dung. This poultry manure exhales malodor and tends to cause environmental pollution. The offensive odor peculiar to the manure is known to be attributable to organic matter present in the feed wasted as indigested from hens and chicks.
Attempts have been made to deodorize poultry manure as disclosed for instance in Japanese Patent Publication No. 55-3006. This prior method involves treating a poultry manure material with synthetic wollantonite and concentrated sulfuric acid and drying the thus treated manure in a speedy manner. Though acceptable in the efficiency of deordorization, such method fails to fully decompose the feed remaining as indigestive in the manure. This means that the manure thus treated will be made inadequate or ineffective for purposes of fertilization.
In addition to the above problem in poultry farming, a similar problem has been aroused by the disposal of serums in the territories where natural rubber is produced. Such a serum is byproduced upon coagulation and removal of rubber components from a natural rubber latex. Contained in the byproduct are non-rubber components such as proteins, saccharides and the like. The serum is rather decomposable and unpleasantly odorous due to those non-rubber components and hence environmentally pollutional. | {
"pile_set_name": "USPTO Backgrounds"
} |
Introduction {#Sec1}
============
Key Summary Points {#FPar01}
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Interleukin-6 (IL-6) plays an important role in the development of rheumatoid arthritis (RA) disease state within the joint.Beyond the joint, IL-6 is also linked to extra-articular manifestations and common comorbidities in patients with RA.Interleukin-6 receptor (IL-6R) blockade treatment with the humanized monoclonal antibody (mAb) tocilizumab, and more recently with the human mAb sarilumab, has been shown in clinical studies to be an important advancement for treating RA-associated disease manifestations within and beyond the joint.The benefits of IL-6R blockade seem to extend to improvements in many of the extra-articular manifestations of the condition, such as pain, fatigue, and anemia, as well as potentially beneficial effects on certain comorbidities, such as improvements in glycemic control in patients with RA and comorbid diabetes, improvements in bone mineral density in patients with RA prone to osteoporosis, and improvements in mood disorders.
Rheumatoid arthritis (RA) is a chronic, debilitating autoimmune disorder affecting up to 1% of the population \[[@CR1]\]. While RA is characterized by inflammation of the synovial joint tissues, it has also been linked to a variety of extra-articular systemic manifestations including pain, fatigue, morning stiffness, anemia, weight loss, and common comorbidities such as osteoporosis, cardiovascular (CV) disease (CVD), diabetes, infection, malignancies, depression, sleep disturbances, and other mood/mental disorders. The pathogenesis of RA is driven by a complex network of proinflammatory cells and cytokines, which in the past two decades have become the target of biotechnologic drugs. The expanding number of available targeted drugs in the therapeutic armamentarium of RA has progressively increased the need for predictive factors useful to drive the prescription of the right therapy for the right patients according to a personalized approach \[[@CR2]\]. In this scenario, a better understanding of the pathways leading to disease development can be the key for population stratification according to the heterogeneous manifestations of RA in different patients \[[@CR3]--[@CR6]\].
Among the actors involved in the network of RA, interleukin-6 (IL-6) seems to be the most pleiotropic cytokine with the greatest number of downstream influences \[[@CR7], [@CR8]\] (major IL-6 influences are detailed in Fig. [1](#Fig1){ref-type="fig"}). This narrative review describes the role of IL-6 in the pathogenesis of RA, and in the associated extra-articular systemic manifestations and comorbidities often observed in clinical practice, as well as the beneficial effects of the IL-6 receptor (IL-6R) blockers sarilumab and tocilizumab from the perspectives of both the physician and the patient. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. The peer-reviewed primary articles used as a basis for this review were obtained from PubMed or from literature reviews.Fig. 1IL-6 as a pleiotropic cytokine. *CNS* central nervous system, *CRP* C-reactive protein, *HPA* hypothalamic--pituitary--adrenal, *IL-6* interleukin-6, *IL-8* interleukin-8, *RA* rheumatoid arthritis, *RANKL* Receptor Activator of Nuclear Factor-κB Ligand. Body image, Mikael Häggström <https://commons.wikimedia.org/w/index.php?curid=15298838>
IL-6 Inhibition: Which Options? {#Sec2}
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IL-6 inhibitors target either the IL-6 ligand itself or the IL-6R \[[@CR9], [@CR10]\]. In contrast to the disappointing study status for the IL-6 ligand inhibitors (sirukumab, the most advanced anti-IL-6 ligand, completed phase III trials but was rejected for approval by the US Food and Drug Administration due to safety concerns, olokizumab is in phase III, clazakizumab has not progressed from phase II, and development of gerilimzumab seems to have been halted), two agents targeting IL-6R have shown impressive results in clinical studies and are now available clinically. Tocilizumab is a humanized monoclonal antibody (mAb) targeting IL-6R, first approved for RA as an intravenous (IV) formulation in 2009 in Europe \[[@CR11]\] and in 2010 in the USA \[[@CR12]\], and then approved as a subcutaneous (SC) formulation. Sarilumab is a human mAb targeting IL-6R, which was more recently approved (2017) in the USA and the EU \[[@CR13], [@CR14]\] for SC administration. Tocilizumab and sarilumab target both membrane-bound IL-6R (mIL-6R) and soluble IL-6R (sIL-6R), and both are indicated in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy \[[@CR9], [@CR10]\].
The recommended starting doses for tocilizumab are different in Europe and the USA \[[@CR11], [@CR12]\]. In the USA, IV tocilizumab should be started at 4 mg/kg every 4 weeks (Q4W), followed by an increase to 8 mg/kg Q4W based on clinical response; SC tocilizumab should be started at 162 mg every 2 weeks (Q2W), followed by an increase in dosing frequency to weekly (QW) based on clinical response (except in patients ≥ 100 kg who should start on the more frequent administration schedule) \[[@CR12]\]. In Europe, IV tocilizumab should be started at 8 mg/kg body weight Q4W with a reduction of dose to 4 mg/kg for laboratory abnormalities, and SC tocilizumab should be started at 162 mg QW with a reduction to a less frequent Q2W dosing schedule for laboratory abnormalities \[[@CR11]\]. The recommended sarilumab dose is the same in Europe and the USA: 200 mg Q2W administered as an SC injection, with a reduction of dose to 150 mg Q2W recommended for the management of neutropenia, thrombocytopenia, and liver enzyme elevations \[[@CR13], [@CR14]\].
Why IL-6 Blockade for RA? {#Sec3}
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IL-6 is a soluble mediator originally cloned in 1986 \[[@CR15]\], and subsequently named IL-6 in 1989 \[[@CR16]\]. The effects of IL-6 are brought about by two mechanisms known as classical (or *cis*-) signaling and *trans*-signaling, as reviewed previously by many authors \[[@CR17]--[@CR20]\], and described below and in Fig. [2](#Fig2){ref-type="fig"}.Fig. 2The classical (or *cis*-) and *trans*-signaling pathways of IL-6. *gp130* glycoprotein 130, *IL-6* interleukin-6, *IL-6Rα* interleukin-6 receptor alpha, *JAK* Janus kinase, *MAPK* mitogen-activated protein kinase, *P* phosphate, *SOCS3* suppressor of cytokine signaling 3, *STAT3* signal transducer and activator of transcription 3, *Y* tyrosine
IL-6 activates cells via a signaling mechanism that requires two receptor components, an 80-kDa IL-6-binding alpha chain (IL-6Rα) and a 130-kDa signal-transducing beta chain, glycoprotein 130 (gp130) \[[@CR17]\]. First, IL-6 interacts with the IL-6Rα subunit and then this IL-6/IL-6Rα pair forms a complex with the gp130 subunit (IL-6 does not bind directly to the gp130 subunit). The high-affinity IL-6/IL-6Rα/gp130 complex associates with a second high-affinity complex, forming a hexameric complex consisting of two members of each protein (IL-6/IL-6Rα/gp130), which is required to induce signal transduction \[[@CR18]\].
IL-6Rα is expressed on only a few cell types, including hepatocytes, monocytes/macrophages, neutrophils, and some T cell subsets \[[@CR21]\]. In classical signaling, IL-6 first binds to its membrane-bound receptor mIL-6Rα, to form an IL-6/mIL-6Rα pair and initiate the signaling as described above in this narrow range of cells \[[@CR19], [@CR21]\]. In *trans*-signaling, IL-6 first forms a pair with the circulating sIL-6Rα and this pair then forms a complex with membrane-bound gp130, which is ubiquitously expressed on many cell types. The IL-6/sIL-6R/gp130 complex then dimerizes as described above to initiate signaling in a much wider range of cells \[[@CR19], [@CR21]\].
Activation of the receptor complex leads to signaling through Janus kinase, which binds to membrane-proximal regions of activated gp130, and phosphorylates specific tyrosine residues on gp130 and other target substrates, including the transcription factor signal transducer and activator of transcription 3 (STAT3) \[[@CR22]\]. Phosphorylated STAT3 then translocates to the nucleus, and binds to specific DNA response elements and initiates the transcription of specific genes \[[@CR22]\]. IL-6 also activates the Ras/mitogen-activated protein kinase and phosphoinositide 3-kinase/Akt pathways \[[@CR23], [@CR24]\].
Classical *cis*-signaling is thought to mediate normal homeostatic effects, while *trans*-signaling predominantly mediates systemic proinflammatory effects including monocyte recruitment, macrophage differentiation, and T cell recruitment and differentiation \[[@CR19], [@CR25]\]. Soluble gp130 can specifically inhibit IL-6 *trans*-signaling by binding to the IL-6/sIL-6R pair, thus preventing the pair from binding membrane-bound gp130. During inflammation, IL-6 levels are sufficiently high to overcome this protective mechanism and *trans*-signaling predominates \[[@CR19], [@CR25]\].
RA Pathogenesis: the Impact of IL-6 on Autoimmunity and Joint Inflammation {#Sec4}
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In RA, under the right set of risk factors, including genetic background and environmental factors, an immune response develops, autoantibodies are generated, and self-tolerance is lost \[[@CR26]--[@CR28]\]. The first steps in the development of RA have been considered akin to the normal adaptive immune response \[[@CR29]\]. The transition from normal immunity to the beginnings of the RA pathogenic process happens when autoimmunity occurs \[[@CR28], [@CR30], [@CR31]\]. Dysregulated citrullination resulting in the autoimmune production of antibodies for citrullinated proteins is key to disease development, and is stimulated by genetic predisposition and environmental factors, such as smoking or *Porphyromonas gingivalis* oral infections \[[@CR28]\].
The IL-6R is expressed on both osteoclasts and osteoblasts \[[@CR22]\], and IL-6 is known to be a central mediator of osteoclast activity \[[@CR32]\]. In models of early RA, in the absence of glucocorticoid treatment, IL-6 increases bone resorption, resulting in bone loss \[[@CR33], [@CR34]\]. IL-6 also increases osteoblast Receptor Activator of Nuclear Factor-κB (RANK) Ligand (RANKL) production, induces RANKL messenger ribonucleic acid (mRNA) expression, and increases bone resorption through the RANK/RANKL/osteoprotegerin (OPG) interaction \[[@CR35]\]. In addition, IL-6 acts indirectly on bone, mediating the bone resorption-inducing effects of tumor necrosis factor α (TNFα) and interleukin-1 (IL-1) \[[@CR36]\]. The resulting erosion of bone and cartilage, accompanied by the inflammation and thickening of the synovial membranes, causes irreversible damage to the joint as the pannus develops \[[@CR36]\].
From early in the disease process (preclinical RA), IL-6 binds to various cell types and causes migration of neutrophils into the joints, contributing to the subsequent transition from acute to chronic inflammation, alterations in B cell differentiation, T cell differentiation, and angiogenesis \[[@CR37]\]. Circulating levels of IL-6 are normally low, but are increased in response to infection or trauma \[[@CR37]\]. After IL-6 is synthesized in a local lesion in the initial stage of inflammation, it moves to the liver through the bloodstream and stimulates hepatocytes to produce acute-phase reactants such as C-reactive protein (CRP), a marker of systemic inflammation, fibrinogen, and serum amyloid A \[[@CR38]\]. The increased production of these then leads to heightened activation of the adaptive immune system, which allows continued chronic inflammation and associated joint destruction, and is a major contributor to the advancement of RA disease pathogenesis in the joint \[[@CR38]\].
Effect of Sarilumab and Tocilizumab on Clinical Endpoints in RA {#Sec5}
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Given the pivotal role of IL-6 in the destruction of the joint, there is a strong scientific rationale for the beneficial effects observed on key endpoints as listed (Table [1](#Tab1){ref-type="table"}) for the phase III studies of IV and SC tocilizumab, and SC sarilumab, and summarized in this section.Table 1Overview of phase III studies with tocilizumab IV and SC, and sarilumab SC, on individual clinical endpointsStudy populationTreatment armsACR responseCRPESRDAS28-CRPDAS28-ESRCDAIRadiographic outcomesSarilumab combination studies MOBILITY \[[@CR39]\]MTX-IR (*n* = 1197)S 150 mg SCS 200 mg SCPlacebo SC Q2W52 weeksCo-primary endpoint: ACR20 W24Secondary endpoint: ACR50, ACR70 W24, W52Secondary endpointNot reportedSecondary endpoints: proportion with DAS28-CRP ≤ 2.6 W24, W52; change from baseline in DAS28-CRP W24, W52Not reportedSecondary endpoints: change from baseline W24, W52; proportion with CDAI remission ≤ 2.8 W24, W52Co-primary endpoint: vdH-mTSS W52Secondary endpoints: erosion and JSN score change W24, W52 vdH-mTSS W24<https://clinicaltrials.gov/ct2/show/NCT01061736>Patients also received MTX TARGET \[[@CR40]\]TNF-IR (*n* = 546)S 150 mg SCS 200 mg SCPlacebo SC Q2W24 weeksCo-primary endpoint: ACR20 W24Secondary endpoints: ACR50, ACR70 W24Secondary endpoint: change from baseline W12, W24Not reportedSecondary endpoints: change from baseline W24; proportion with DAS28-CRP \< 2.6 W24Not reportedSecondary endpoint: change from baseline in CDAI W24Not reported<https://clinicaltrials.gov/ct2/show/NCT01709578>Patients also received csDMARDsSarilumab monotherapy studies MONARCH \[[@CR41]\]MTX-IR (*n* = 369)S 200 mg SCA 40 mg SCPlacebo SC Q2W24 weeksSecondary endpoints: ACR20, ACR50, ACR70 W24Secondary endpoint: change from baseline W24Secondary endpoint: change from baseline W24Secondary endpoints: proportion with DAS28-CRP ≤ 2.8 and ≤ 3.3 W24; change from baseline in DAS28-CRP W24Primary endpoint: change from baseline W24Secondary endpoint: proportion with DAS28-ESR \< 2.6 W24Secondary endpoint: change from baseline W24 proportion with CDAI remission ≤ 2.8 W24Not reported<https://clinicaltrials.gov/ct2/show/NCT02332590>SC tocilizumab combination studies SUMMACTA \[[@CR42]\]csDMARD-IR (*n* = 1262)T 162 mg SC QWT 8 mg/kg IV Q4W24 weeksPrimary endpoint: ACR20 W24Secondary endpoints: ACR50, ACR70 W24; ACR20, ACR50, ACR70 W97Not reportedNot reportedNot reportedSecondary endpoint: proportion with \< 2.6 W24, W97Additional endpoint of CDAI remission ≤ 2.8 W24Not reported<https://clinicaltrials.gov/ct2/show/NCT01194414> BREVACTA \[[@CR43]\]csDMARD-IR (*n* = 656)T 162 mg SCPlacebo SC Q2W24 weeksPrimary endpoint: ACR20 W24Secondary endpoints: ACR50, ACR70 W24Secondary endpoint: change from baseline W24Secondary endpoint: change from baseline W24Not reportedSecondary endpoint: change from baseline W24; proportion with \< 2.6 W24; proportion with ≤ 3.2 W24Not reportedSecondary endpoint: change from baseline in vdH-mTSS W24<https://clinicaltrials.gov/ct2/show/NCT01232569>IV tocilizumab combination studies LITHE \[[@CR44]\]MTX-IR (*n* = 1196)T 4 mg/kg IVT 8 mg/kg IVPlacebo IV Q4W52 weeksCo-primary endpoint: ACR20 W24Secondary endpoints: ACR20 W52; ACR50/70 W24, W52, W104Secondary endpoint: change from baseline W24, W52, W104Secondary endpoint: change from baseline W24, W52, W104Not reportedSecondary endpoints: change in DAS28-ESR W24, W52, W104; proportion with DAS28 ≤ 3.2 and DAS28 \< 2.6, W24, W52, W104Not reportedCo-primary endpoint: change from baseline in total G-mTSS W52, W104Secondary endpoints: change from baseline in erosion and JSN W24, W52, G-mTSS W24; proportion with no progression of the total erosion or JSN W24<https://clinicaltrials.gov/ct2/show/NCT00106535>Patients also receive MTX OPTION \[[@CR45]\]csDMARD-IR (*n* = 623)T 8 mg/kg IVT 4 mg/kg IVPlacebo IV Q4W24 weeksPrimary endpoint: ACR20 W24Secondary endpoints: ACR50, ACR70 W24Laboratory measure: change from baseline W24Laboratory measure: change from baseline W24Secondary endpoint: change from baseline W24; proportion with DAS28 \< 2.6 W24Not reportedNot reported<https://clinicaltrials.gov/ct2/show/NCT00106548>Patients also receive MTX TOWARD \[[@CR46]\]csDMARD-IR (*n* = 1220)T 8 mg/kg IVPlacebo IVQ4W24 weeksPrimary endpoint: ACR20 W24Secondary endpoints: ACR50, ACR70 W24Additional endpoint: change from baseline W24Additional endpoint: change from baseline W24Not reportedAdditional endpoint: DAS28-ESR W24Not reportedNot reported<https://clinicaltrials.gov/ct2/show/NCT00106574>Patients also receive csDMARDs RADIATE \[[@CR47]\]TNF-IR (*n* = 499)T 8 mg/kg IVT 4 mg/kg IVPlacebo IV Q4W24 weeksPrimary endpoint: ACR20 W24 Secondary endpoints: ACR50, ACR70 W24Not reportedNot reportedNot reportedNot reportedNot reportedNot reported<https://clinicaltrials.gov/ct2/show/NCT00106522>Patients also receive MTXIV tocilizumab monotherapy studies U-ACT-EARLY \[[@CR48]\]Newly diagnosed DMARD-naïve (*n* = 317)T 8 mg/kg IV + MTXQ4W104 weeksSecondary endpoints: ACR20, ACR50, ACR70 W12, W24, W52, W104Secondary endpoint: change from baseline at W12, W24, W52, W104Not reportedSecondary endpoint: DAS28-CRP W24, W52, W104Primary endpoint: proportion with \< 2.6 sustainedSecondary endpoint: DAS28-ESR W24, W52, W104Secondary endpoint: change from baseline W24, W52, W104Secondary endpoint: change from baseline in vdH-mTSS W52, W104<https://clinicaltrials.gov/ct2/show/NCT01034137>FUNCTION \[[@CR49]\]MTX-naïve patients with early progressive RA (*n* = 1162)T 8 mg/kg IVT 8 mg/kg IV + MTXT 4 mg/kg + MTXQ4W104 weeksSecondary endpoints: ACR20, ACR50, ACR70 W24 and W52Not reportedNot reportedNot reportedPrimary endpoint: proportion with \< 2.6 W24Secondary endpoint: proportion with \< 2.6 W52CDAI remission (\< 2.8)Secondary endpoints: change from baseline vdH-mTSS W52, change from baseline vdH erosion score W52, change from baseline JSN W52, proportion with no progression W52, W104<https://clinicaltrials.gov/ct2/show/NCT01007435> ACT-RAY \[[@CR50]\]MTX-IR (*n* = 556)T 8 mg/kgIV + MTXT 8 mg/kg IV104 weeksSecondary endpoints: ACR20, ACR50, ACR70, ACR90 W24, W52, W104 (and time to each)Secondary endpoint: change from baseline W24, W52Secondary endpoint: change from baseline W24, W52Not reportedPrimary endpoint: proportion with \< 2.6 W24Secondary endpoint: proportion with \< 3.2 W24 change from baseline W24, W52Not reportedSecondary endpoint: change from baseline G-mTSS W24, W52, W104<https://clinicaltrials.gov/ct2/show/NCT00810199> ADACTA \[[@CR51]\]MTX-INT (*n* = 326)T 8 mg/kg IV Q4WA 40 mg SC Q2W24 weeksSecondary endpoints: ACR20, ACR50, ACR70 W24Not reportedNot reportedNot reportedPrimary endpoint: change from baseline W24Secondary endpoint: proportion with ≤ 3.2 and \< 2.6 W24Not reportedNot reported<https://clinicaltrials.gov/ct2/show/NCT01119859>*A* adalimumab, *ACR20/50/70/90* American College of Rheumatology 20%/50%/70%/90% response, *CDAI* Clinical Disease Activity Index, *CRP* C-reactive protein, *csDMARD* conventional synthetic disease-modifying antirheumatic drug, *DAS28* 28-Joint Disease Activity Score, *DMARD* disease-modifying antirheumatic drug, *ESR* erythrocyte sedimentation rate, *G-mTSS* Genant-modified Total Sharp Score, *INT* intolerant, *IR* inadequate response, *IV* intravenous, *JSN* joint space narrowing, *mTSS* modified Total Sharp Score, *MTX* methotrexate, *n* number of patients, *Q2W* every 2 weeks, *Q4W* every 4 weeks, *QW* weekly, *RA* rheumatoid arthritis, *S* sarilumab, *SC* subcutaneous, *T* tocilizumab, *TNF* tumor necrosis factor, *vdH* van der Heijde,*vdH-mTSS* van der Heijde-modified Total Sharp Score, *W* week
Sarilumab or Tocilizumab in Combination with csDMARDs/Methotrexate (MTX) {#Sec6}
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### American College of Rheumatology (ACR) Responses {#Sec7}
While rheumatologists agree that ACR 20% response (ACR20) is not high, it was routinely used in the phase III trials of all licensed biologic drugs, including sarilumab and tocilizumab (Table [2](#Tab2){ref-type="table"}) \[[@CR52]\]. For sarilumab, ACR20 was a co-primary endpoint in both MOBILITY and TARGET. In MOBILITY, patients who had an inadequate response (IR) to MTX received SC sarilumab + MTX compared with placebo + MTX. In TARGET, patients who had IR (92.3%) to anti-TNFα biologic DMARDs (bDMARDs), or who were intolerant (INT) to anti-TNFα bDMARDs (7.7%), received sarilumab + csDMARDs \[[@CR39], [@CR40]\]. In both cases, sarilumab produced statistically significant improvements in the signs and manifestations of RA as defined by ACR20 at week 24, which was sustained throughout treatment \[[@CR39], [@CR40]\]. ACR20 was also the primary endpoint in SUMMACTA (which compared SC and IV tocilizumab) and BREVACTA (which compared SC tocilizumab with placebo) in csDMARD-IR populations \[[@CR43], [@CR53]\]. As measured by ACR20, SC tocilizumab 162 mg Q2W was superior to placebo \[[@CR43]\] and SC tocilizumab 162 mg QW demonstrated comparable efficacy to IV tocilizumab 8 mg/kg \[[@CR42]\]. Prior to this, IV tocilizumab had shown consistent improvements in ACR20 across clinical studies, including in combination with csDMARDs in MTX-IR and TNF-IR/INT patients, and as monotherapy (Table [2](#Tab2){ref-type="table"}) \[[@CR44]--[@CR47]\].Table 2Overview of the primary outcomes of the phase III studies with tocilizumab IV and SC, and sarilumab SCPrimary endpoint/sOutcomeSarilumab combination studies MOBILITY \[[@CR39]\] MTX-IR (*n* = 1197)Co-primary endpoints:ACR20 W24S 150 mg SC: 58% (*p* \< 0.0001 vs. placebo)S 200 mg SC: 66.4% (*p* \< 0.0001 vs. placebo)Placebo SC: 33.4%Q2WvdH-mTSS W52S 150 mg SC: 0.90 (*p* \< 0.0001 vs. placebo)S 200 mg SC: 0.25 (*p* \< 0.0001 vs. placebo)Placebo SC: 2.78Q2W TARGET \[[@CR40]\] TNF-IR (*n* = 546)Co-primary endpoints:ACR20 W24S 150 mg SC: 55.8% (*p* \< 0.0001 vs. placebo)S 200 mg SC: 60.9% (*p* \< 0.0001 vs. placebo)Placebo SC: 33.7%Q2WHAQ-DI change from baseline W12S 150 mg SC: -- 0.46 (*p* = 0.0007 vs. placebo)S 200 mg SC: -- 0.47 (*p* = 0.0004 vs. placebo)Placebo SC: -- 0.26Q2WSarilumab monotherapy studies MONARCH \[[@CR41]\] MTX-IR (*n* = 369)DAS28-ESR change from baseline W24S 200 mg SC: -- 3.28 (*p* \< 0.0001 vs. A)A 40 mg SC: -- 2.20Q2WSC tocilizumab combination studies SUMMACTA \[[@CR42]\] csDMARD-IR (*n* = 1262)ACR20 W24T 162 mg SC QW: 69.4%T 8 mg/kg IV Q4W: 73.4% BREVACTA \[[@CR43]\] csDMARD-IR (*n* = 656)ACR20 W24T 162 mg SC: 60.9% (*p* \< 0.0001 vs. placebo)Placebo SC: 31.5%Q2WIV tocilizumab combination studies LITHE \[[@CR44]\] MTX-IR (*n* = 1196)Co-primary endpoints:HAQ-DI AUC change from baselineT 4 mg/kg IV: -- 128.4 (*p* \< 0.0001 vs. placebo)T 8 mg/kg IV: -- 144.1 (*p* \< 0.0001 vs. placebo)Placebo IV: -- 58.1Q4WRadiographic outcome change from baseline in total G-mTSS W52, W104T 4 mg/kg IV: 0.34 (*p* \< 0.0001 vs. placebo)T 8 mg/kg IV: 0.29 (*p* \< 0.0001 vs. placebo)Placebo IV: 1.13Q4W OPTION \[[@CR45]\] csDMARD-IR (*n* = 623)ACR20 W24T 4 mg/kg IV: 48% (*p* \< 0.0001 vs. placebo)T 8 mg/kg IV: 59% (*p* \< 0.0001 vs. placebo)Placebo IV: 26%Q4W TOWARD \[[@CR46]\] csDMARD-IR (*n* = 1220)ACR20 W24T 8 mg/kg IV: 61% (*p* \< 0.0001 vs. placebo)Placebo IV: 25%Q4W RADIATE \[[@CR47]\] TNF-IR (*n* = 499)ACR20 W24T 4 mg/kg IV: 30.4% (*p* \< 0.001 vs. placebo)T 8 mg/kg IV: 50% (*p* \< 0.001 vs. placebo)Placebo IV: 10.1%Q4WIV tocilizumab monotherapy studies U-ACT-EARLY \[[@CR48]\] Newly diagnosed DMARD-naïve (*n* = 317)DAS28-ESR proportion with \< 2.6 sustainedT 8 mg/kg IV + MTX: 86% (*p* = 0.06 vs. MTX)T 8 mg/kg IV: 88% (*p* = 0.0356 vs. MTX)MTX: 77%Q4W FUNCTION \[[@CR54]\] MTX-naïve patients with early progressive RA (*n* = 1162)DAS28-ESR proportion with \< 2.6 W24T 4 mg/kg + MTX: 31.9% (*p* \< 0.0001 vs. MTX)T 8 mg/kg IV: 38.7% (*p* \< 0.0001 vs. MTX)T 8 mg/kg IV + MTX: 44.8% (*p* \< 0.0001 vs. MTX)MTX: 15.0%Q4WACT-RAY \[[@CR50]\] MTX-IR (*n* = 556)DAS28-ESR proportion with \< 2.6 W24T 8 mg/kg IV + MTX: 40.4% (*p* = 0.19 vs. T)T 8 mg/kg IV: 34.8%ADACTA \[[@CR51]\] MTX-INT (*n* = 326)DAS28-ESR change from baseline W24T 8 mg/kg IV Q4W: -- 3.3 (*p* \< 0.0001 vs. A)A 40 mg SC Q2W: -- 1.8*A* adalimumab, *ACR20* American College of Rheumatology 20% response, *AUC* area under the curve, *csDMARD* conventional synthetic disease-modifying antirheumatic drug, *DAS28* 28-Joint Disease Activity Score,*ESR* erythrocyte sedimentation rate, *G-mTSS* Genant-modified Total Sharp Score, *HAQ-DI* Health Assessment Questionnaire-Disability Index, *INT* intolerant, *IR* inadequate response, *IV* intravenous,*mTSS* modified Total Sharp Score, *MTX* methotrexate,*n* number of patients, *Q2W* every 2 weeks, *Q4W* every 4 weeks, *QW* weekly, *RA* rheumatoid arthritis, *S* sarilumab, *SC* subcutaneous, *T* tocilizumab, *TNF* tumor necrosis factor, *vdH* van der Heijde, *vdH-mTSS* van der Heijde-modified Total Sharp Score, *W* week
### CRP and Erythrocyte Sedimentation Rate (ESR), and 28-Joint Disease Activity Score (DAS28)-CRP and DAS28-ESR {#Sec8}
The acute-phase reactants, CRP and ESR, comprise one aspect of the composite ACR measure described above and, in both MOBILITY and TARGET, CRP was the acute-phase reactant evaluated, with baseline levels 20--31 mg/l across the different randomization groups \[[@CR39], [@CR40]\]. In MOBILITY, mean change from baseline in CRP at week 24 was − 17 mg/l with SC sarilumab 200 mg Q2W \[[@CR39]\] compared with 0.0 mg/l with placebo, and in TARGET, mean change from baseline in CRP at week 24 was − 23.3 mg/l with SC sarilumab 200 mg Q2W compared with − 3.6 with placebo \[[@CR40]\]. In sarilumab clinical studies, similar results with the DAS28 based on CRP (DAS28-CRP) have been observed. Changes from baseline in DAS28-CRP, and the proportions of patients achieving DAS28-CRP \< 2.6 or \< 3.2 at week 24, were secondary endpoints of MOBILITY and TARGET \[[@CR39], [@CR40]\]. In both MOBILITY and TARGET, significantly more patients treated with sarilumab achieved a DAS28-CRP score \< 2.6 at week 24 compared with patients receiving placebo (MOBILITY: 34% with sarilumab 200 mg Q2W compared with 10% with placebo \[[@CR39]\]; TARGET: 29% with sarilumab 200 mg Q2W compared with 8% with placebo \[[@CR40]\]).
Data from the SUMMACTA and BREVACTA trials have expanded what was known from studies evaluating IV tocilizumab administration. Data showed that mean reductions from baseline in CRP and ESR were comparable for the QW SC tocilizumab 162-mg dose and Q4W IV tocilizumab 8-mg/kg regimens, but less pronounced when SC tocilizumab was administered Q2W \[[@CR55]\]. Reductions in CRP and ESR were rapid (by week 2 or 4) and sustained through 24 and 97 weeks of treatment \[[@CR55]\].
In BREVACTA, the proportions of patients achieving DAS28 based on ESR (DAS28-ESR) \< 2.6 by week 24 were similar with SC tocilizumab 162 mg QW and IV tocilizumab 8 mg/kg (38% and 36%, respectively) \[[@CR43]\], and by week 24 in SUMMACTA, 32% of patients treated with SC tocilizumab 162 mg Q2W achieved DAS28-ESR \< 2.6 (compared with 4% of patients receiving placebo) \[[@CR53]\]. Across the previous clinical studies of IV tocilizumab, the proportion of patients achieving DAS28-ESR \< 2.6 was 28--34% in patients receiving tocilizumab compared with 1--12% of control patients at 24 weeks \[[@CR44]--[@CR46]\].
### Clinical Disease Activity Index (CDAI) {#Sec9}
Given the massive effect of IL-6 inhibition in decreasing CRP levels and the high impact of CRP in the calculation of DAS28-CRP, the CDAI is considered to be the most valuable index for the evaluation of the clinical response in patients treated with sarilumab or tocilizumab. Both MOBILITY and TARGET included CDAI as a secondary efficacy endpoint, evaluating the change from baseline in TARGET and the proportion of patients achieving remission (≤ 2.8) in MOBILITY \[[@CR39], [@CR40]\]. After 24 weeks of treatment with sarilumab 200 mg Q2W in MOBILITY \[[@CR39]\], 14% of patients achieved CDAI remission (compared with 5.0% on placebo), and in TARGET \[[@CR40]\], CDAI decreased by − 26.1 (compared with − 16.4 with placebo). A 2-year update from MOBILITY showed that the initial reduction in CDAI obtained with sarilumab was maintained \[[@CR56]\], and with 5 years of treatment, 40% of patients (observed cases) achieved CDAI remission \[[@CR57]\].
For SC tocilizumab, CDAI was evaluated in SUMMACTA but not BREVACTA and showed, after 24 weeks of treatment, that 14--15% of patients treated with either SC or IV tocilizumab achieved CDAI ≤ 2.8 \[[@CR53]\]. CDAI was not routinely evaluated in the IV tocilizumab clinical program, but the results of FUNCTION showed numerically higher remission rates with IV tocilizumab compared with placebo at week 24 \[[@CR49]\].
### Structural Damage {#Sec10}
Data on structural damage currently exist for SC sarilumab (from the MOBILITY study) and IV, but not SC, tocilizumab \[[@CR39]\]. In the MOBILITY study (using the van der Heijde-modified Total Sharp Score \[mTSS\]), sarilumab was shown to have a significant effect on reducing pathologic radiographic progression compared with placebo: after 52 weeks, mean change in mTSS was 0.25 with sarilumab 200 mg Q2W and 2.78 with placebo \[[@CR39]\]. In a 5-year follow-up of MOBILITY \[[@CR57]\], early treatment with sarilumab 200 mg Q2W was associated with reduced radiographic progression versus patients who received placebo for 52 weeks and then switched to sarilumab 200 mg Q2W (mean change from baseline in mTSS score of 1.46 vs. 3.68, respectively), and almost 50% of patients had no progression of radiographic damage (mTSS change from baseline ≤ 0). Post hoc analysis of the MOBILITY clinical studies showed that patients with high IL-6 levels had more joint damage at baseline compared with patients with normal IL-6 levels, and had greater response in mTSS to sarilumab than patients with normal IL-6 levels \[[@CR58]\].
Although radiographic progression has not been evaluated with SC tocilizumab, several studies have evaluated the effects of the IV formulation on structural damage. In the LITHE study \[[@CR44]\], 84% of patients had no progression of structural joint damage (defined as change in Genant-mTSS ≤ 0 from baseline to week 52), compared with 67% of patients receiving placebo after 1 year of treatment with tocilizumab + MTX; between weeks 52 and 104, 93% had no progression \[[@CR59]\]. In less-established disease, the FUNCTION study showed that tocilizumab treatment for 1 year resulted in up to 83% of patients exhibiting no radiographic progression (by change from baseline in van der Heijde-mTSS), compared with 73% with placebo, in patients with early RA of ≤ 2 years' duration who had not previously received MTX or bDMARDs \[[@CR49]\]. Similar results were seen in the Dutch U-ACT-EARLY study of patients with early RA of ≤ 1 year's duration who were DMARD-naïve; radiographic joint damage progression was low in all treatment arms, but significantly less with tocilizumab + MTX than with MTX alone \[[@CR48]\].
Monotherapy with Sarilumab or Tocilizumab {#Sec11}
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International guidelines recommend using bDMARDs in combination with csDMARDs, and as monotherapy when the combination with a csDMARD is not possible \[[@CR60]\]. MTX is the most commonly used csDMARD and results in an ACR20 at 1 year of 54--67% \[[@CR61]\]; however, many MTX-treated patients complain of headaches, fatigue, feeling "wiped out," and describe an "MTX fog." Other patients experience nausea, which can be lessened by evening administration or SC rather than oral administration \[[@CR62], [@CR63]\]. On MTX, patients should be closely monitored for bone marrow, liver, lung, and kidney toxicities: acute elevations of liver enzymes are frequent and acute MTX-induced lung disease may occur at any time during therapy \[[@CR62], [@CR63]\]. Diarrhea and ulcerative stomatitis require interruption of therapy to reduce the risk of hemorrhagic enteritis, and death from intestinal perforation and serious, potentially fatal opportunistic infections may occur \[[@CR62]--[@CR64]\]. Consequently, patients may discontinue MTX therapy because they cannot tolerate it \[[@CR62], [@CR63]\], while those who are able to continue MTX may not be fully adherent \[[@CR65], [@CR66]\]. Hence, a bDMARD monotherapy solution may be necessary. In such cases, an anti-IL-6R may be a better approach than an anti-TNFα therapy \[[@CR60]\].
### Sarilumab Monotherapy {#Sec12}
The efficacy of sarilumab 200 mg Q2W in monotherapy was assessed in the MONARCH study \[[@CR41]\] and compared with adalimumab 40 mg Q2W over a 24-week randomized treatment period. Sarilumab outperformed adalimumab across key endpoints: at week 24, DAS28-ESR was decreased − 3.28 compared with − 2.20 (27% vs. 7% of patients achieving DAS28-ESR ≤ 2.6), and more patients achieved ACR20 responses (71.7% vs. 58.4%) as well as ACR 50% and 70% (ACR50/70) responses. Additionally, by week 24, the rate of CDAI remission and low disease activity (LDA) was higher in the sarilumab group (7% and 42%, respectively) than in the adalimumab group (3% and 25%, respectively). Structural damage was not evaluated. Analysis of the open-label period of MONARCH, where patients were initially randomized to adalimumab for 24 weeks and then switched to sarilumab monotherapy, showed that (despite the improvements described above in the randomized portion of the study) adalimumab patients who switched to sarilumab achieved additional clinically meaningful improvements in disease activity primarily within 12 weeks of switching \[[@CR67]\].
### Tocilizumab Monotherapy {#Sec13}
Evidence regarding the efficacy of the anti-IL-6R class was first published a decade ago, with the AMBITION study comparing IV tocilizumab 8 mg/kg Q4W to MTX over 24 weeks \[[@CR68]\]. The study, conducted in patients with relatively early active RA for whom previous treatment with MTX or bDMARDs had not failed, showed better ACR20 response with tocilizumab (70% vs. 53%; *p* \< 0.001) and a higher rate of DAS28-ESR \< 2.6 (34% vs. 12%). Subsequently, ADACTA (a comparable study to MONARCH, comparing IV tocilizumab to SC adalimumab) was published and showed the benefits of anti-IL-6R over anti-TNFα monotherapy \[[@CR51]\]. Mean change from baseline in DAS28-ESR was − 3.3 with tocilizumab, compared with − 1.8 with adalimumab after 24 weeks of treatment; 40% of patients in the tocilizumab group achieved DAS28-ESR \< 2.6, compared with 11% of patients in the adalimumab group. ACR response rates were also significantly higher with tocilizumab compared with adalimumab. The FUNCTION and U-ACT-EARLY studies also had monotherapy arms. FUNCTION \[[@CR49]\] demonstrated that changes from baseline to week 52 in mTSS were smaller with IV tocilizumab 8 mg/kg (mean 0.26) than with MTX (1.14). U-ACT-EARLY \[[@CR48]\] demonstrated a trend toward better protection against structural progression with IV tocilizumab compared with MTX at week 52 (change from baseline in van der Heijde-mTSS of 0.79 vs. 0.96) that was significant after 2 years (1.45 vs. 1.53). While the effects of sarilumab and tocilizumab on the clinical efficacy endpoints leading to their approvals are well established, it is the emerging effects of IL-6 and IL-6R inhibition beyond the joint that are of increasing interest and are described below.
IL-6 Beyond the Joint: Extra-Articular Manifestations of Ra {#Sec14}
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RA and Anemia {#Sec15}
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"Anemia of chronic disease" and "anemia of inflammation" are terms that are used interchangeably, and refer to a condition that is common in RA, being observed in 33--66% of patients with RA \[[@CR69], [@CR70]\]. Clinically, patients with anemia of chronic disease are more likely to experience increased disease severity and duration than patients who have chronic disease without anemia; in patients with RA and associated anemia, disease is typically more severe, outcomes are poorer, and there is greater radiographic progression \[[@CR71]\]. As described by Weiss and Schett in their 2013 review \[[@CR72]\], in systemic inflammatory diseases such as RA, anemia is considered to be mainly an immune-driven disorder caused by alterations of iron homeostasis (largely mediated by hepcidin), impaired erythroid progenitor proliferation, reduced biologic activity of erythropoietin, and a decrease in erythrocyte half-life.
Hepcidin has been shown to inhibit the absorption of iron in the small intestine and the release of recycled iron from macrophages, effectively decreasing the delivery of iron to maturing erythrocytes in the bone marrow \[[@CR73]\]. IL-6 results in increased transcription of the human antimicrobial peptide gene that encodes hepcidin in liver cells \[[@CR74]\], and has also been shown to mediate anemia through decreasing saturation of transferrin, the primary transporter delivering iron to the bone marrow for erythropoiesis \[[@CR75]\].
### IL-6R Blockade and Anemia {#Sec16}
Recently, a post hoc analysis showed that treatment with sarilumab resulted in larger reductions in hepcidin compared with adalimumab (− 36% compared with − 28%, respectively, at week 2, but not measured thereafter) and significantly larger increases in hemoglobin levels compared with adalimumab (least squares mean change from baseline 0.528 vs. 0.119 g/dl at week 12 and 0.591 vs. 0.075 g/dl at week 24, respectively) \[[@CR76]\]. Consequently, there were fewer patients with anemia (hemoglobin \< 12 g/dl for females or \< 13 g/dl for males) with sarilumab compared with adalimumab (10.9% vs. 16.3%) after 24 weeks of treatment and compared with 25% of patients in both arms at baseline \[[@CR76]\]. Furthermore, a separate analysis exploring markers of chronic inflammation in patients with RA showed larger increases in hemoglobin in patients treated with sarilumab 200 mg and 150 mg compared with placebo at week 2 (68.5, 64, and 40.2% of patients with change \> 0 g/dl from baseline, respectively) that were sustained over 52 weeks (83.8, 76.6, and 44.12% of patients with change \> 0 g/dl from baseline, respectively, at week 52) \[[@CR77]\]. Similar effects of IL-6R blockade have been shown with tocilizumab in a post hoc analysis of a placebo-controlled study \[[@CR78]\] and in a small prospective study versus adalimumab \[[@CR70]\].
RA and Fatigue and Morning Stiffness {#Sec17}
------------------------------------
Fatigue may affect up to 80% of patients with RA and is severe in up to 40% of patients \[[@CR79], [@CR80]\]. Fatigue must not be mistaken for simple tiredness, since patients describe far-reaching effects permeating various aspects of life: not just physical activities, but emotions, relationships, and social activities \[[@CR81]\]. In a small, but interesting, study of patient perspectives, most patients did not discuss fatigue with their doctors, but when they did, they felt the symptom was largely dismissed \[[@CR81]\]. For many patients, their fatigue is "extreme" and "unresolving" \[[@CR81]\]. Assessing fatigue in RA clinical trials was initially recommended in 2007 by the OMERACT group \[[@CR82]\], but to this day, it is not routinely measured in interventional studies. It would be naïve to think that anemia and poor sleep, discussed elsewhere in this review, do not impact fatigue in patients with RA, but there is also increasing evidence implicating the involvement of IL-6 and the hypothalamic--pituitary--adrenal (HPA) axis, and dysfunction of the HPA axis (particularly regarding glucocorticoid and cortisol levels) in chronic fatigue \[[@CR83], [@CR84], [@CR85]\].
Morning stiffness is another common symptom of RA, with variable intensity, timing (not just associated with the morning), location, and duration \[[@CR86]\]. Most importantly, perhaps, stiffness is frequently described as impacting patients' daily activities, including getting dressed, driving, cooking, and the ability or desire to socialize \[[@CR86]\]. Despite its importance, morning stiffness is seldom assessed in clinical practice and usually only the duration of morning stiffness is measured in the research setting \[[@CR86]\]. Debates concerning whether the intensity, timing, and/or location of morning stiffness should also be assessed in clinical trials are ongoing \[[@CR86]\].
As major RA manifestations, such as joint pain and stiffness, are most pronounced in the morning, it is postulated that this may be due to circadian rhythms of cytokine and hormone levels \[[@CR87]\]. Significant circadian variation in levels of IL-6 has been identified: peaks in the morning, and low levels in the afternoon and evening \[[@CR88]\]. Indeed, associations between IL-6 and the duration of morning stiffness have been identified \[[@CR89]\].
### IL-6R Blockade, Fatigue, and Morning Stiffness {#Sec18}
The positive effect of IL-6R blockade on fatigue and morning stiffness in patients with RA is described in "The importance of IL-6R blockade from a patient's perspective" section below.
RA and Pain {#Sec19}
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In RA, pain is often reported as the patient's most important symptom, and often persists despite RA control \[[@CR90], [@CR91]\]. Since the pain in RA arises from multiple mechanisms, including inflammation, and peripheral and central pain processing, it also has a wide range of characteristics in terms of attributes, location, duration, and temporal occurrence \[[@CR92]\]. Pain is also strongly associated with the patient's quality of life, including functional capacity, emotional health, and sleep \[[@CR93], [@CR94]\].
Neurons, glial cells of the spinal cord, and dorsal root ganglia express gp130, permitting IL-6/sIL-6R *trans*-signaling to occur \[[@CR95]\]. Animal studies have shown that injections of IL-6 or IL-6/sIL-6R into normal knee joints cause increased responses of spinal neurons to mechanical stimulation \[[@CR96]\], and a long-lasting sensitization of nociceptive C-fibers to mechanical stimuli \[[@CR97]\]. Utilizing a rat model of antigen-induced arthritis, and soluble gp130 to bind and inactivate IL-6, Boettger et al. \[[@CR98]\] showed antinociceptive effects in the knee joint, which were greater when administered locally than systemically, and normalized weight-bearing, gait measures, and locomotion. These pain-relieving effects could be achieved after a single administration of gp130 and in the absence of effects on joint inflammation. The culmination of these studies indicates that IL-6 has direct actions on the nociceptive system, and pain-relieving effects that are additional to anti-inflammatory and immunomodulatory effects.
### IL-6R Blockade and Pain {#Sec20}
The positive effect of IL-6R blockade on pain in patients with RA is described in "The importance of IL-6R blockade from a patient's perspective" section below.
RA, Weight, and Body Composition {#Sec21}
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While being overweight or obese can increase the risk of developing RA, rheumatoid cachexia (low muscle mass with or without weight loss), sarcopenia (both low muscle mass and muscle function), or sarcopenic obesity can occur in patients with RA. A recent meta-analysis showed a prevalence of rheumatoid cachexia of 15--32%, according to different diagnostic criteria \[[@CR99]\]. Utilization of dual-energy X-ray absorptiometry to evaluate visceral adipose tissue has shown that chronic, high inflammatory activity is associated with both lower muscle and fat mass (including visceral adipose tissue), while moderate inflammatory activity is associated with greater visceral adipose tissue, which is associated with increased CV risk \[[@CR100]\].
Recent claims are that IL-6 supports healthy weight maintenance in a normal physiologic state \[[@CR101]\], and while the causes of rheumatoid cachexia are multifactorial, the excess of proinflammatory cytokines is considered to be a central feature \[[@CR102]\]. Anorexia and body-weight loss are common complications of inflammatory states, and IL-6, along with the proinflammatory cytokines TNFα and IL-1β, has previously been found to be implicated in anorexia of inflammation and infection \[[@CR103], [@CR104]\]. In animal studies, IL-6 − / − mice develop spontaneous mature-onset obesity, increased body weight, SC fat, and dysregulation of glucose metabolism \[[@CR105]\]. Furthermore, centrally administered IL-6 (into the parabrachial nuclei) reduces food intake and increases brown adipose tissue thermogenesis in lean and obese rats (by increasing thyroid and sympathetic outflow to the adipocytes), and interacts with leptin to reduce feeding \[[@CR106]\].
### IL-6R Blockade and Weight {#Sec22}
There is some evidence of weight gain with IL-6R blockade with tocilizumab \[[@CR12], [@CR107]\]. Tournadre et al. reported the first study of the impact of IL-6 inhibition on body composition in patients with RA \[[@CR108]\] and showed that a gain in weight after 1 year of treatment was likely to be related to a significant increase in muscle mass, as no change in fat mass was detected, and favorable fat redistribution toward peripheral and SC fat was observed. Serum levels of leptin were significantly decreased after 6 months of tocilizumab treatment compared with pretreatment levels, and the authors suggest a proinflammatory IL-6-mediated effect on leptin, as leptin is a key regulator of appetite, inducing the expression of anorexigenic factors and inhibiting the production of orexigenic peptides. Therefore, IL-6R blockade may have utility in underweight patients with RA.
In contrast to IL-6R blockers, TNFα inhibitors have been shown to be associated with poor RA remission rates in obese patients with RA \[[@CR109]\]. Gremese et al. \[[@CR109]\] showed that disease remission according to the proportion of patients with DAS28 \< 2.6 in long-standing receivers of TNFα inhibitors (adalimumab, etanercept, or infliximab) was 15% in obese patients (\> 30 kg/m^2^), compared with \> 30% in patients with a non-obese body mass index (BMI) (≤ 30 kg/m^2^). Increased adipose tissue in an obese state may cause increased expression of TNFα, leading to a more inflammatory and therapy-resistant state \[[@CR109]\]. Consequently, high BMI in patients with RA is a potential driver toward treatments with mechanisms of action other than anti-TNFα, such as IL-6R blockade \[[@CR109]\].
IL-6 Beyond the Joint: Common Comorbidities of RA {#Sec23}
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RA can be complicated by several disorders that are more common in patients with RA than in the healthy population \[[@CR110]\]. The majority of these comorbidities are deeply interconnected with RA through shared pathogenic pathways leading to chronic inflammation or to the increased presence of traditional risk factors, such as smoking \[[@CR111]\]. Indeed, a genetic association with a non-synonymous variant of the IL-6R may underpin the pathogenic processes that connect RA and conditions such as CVD and type 1 diabetes \[[@CR112]\] (T1D). This allele, Asp358A1a, is associated with decreased membrane-bound IL-6R and increased sIL-6R and is protective for RA, CVD, and T1D. It was demonstrated that reduced levels of IL-6R on the surface of immune cells resulted in functional impairment of classical IL-6R signaling and dampening of IL-6R-mediated inflammation. This observation supports a role for IL-6R signaling in RA beyond the inflammatory processes found in the joints, which may overlap with the pathogenic processes underpinning other diseases with an inflammatory component \[[@CR112]\].
The impact of comorbidities on the treatment of RA can be bidirectional. In one way, the increased prevalence of comorbidities can contribute to worsening the long-term prognosis and compromising the life expectancy in patients with RA \[[@CR110], [@CR113]\]. Additionally, a poorer clinical response has been observed in patients with RA carrying a great burden of comorbid disorders \[[@CR114]\]. The most common comorbidities observed in patients with RA are osteoporosis \[[@CR115]\], CVD \[[@CR116]\] and pulmonary disease \[[@CR117]\], infections \[[@CR118], [@CR119]\], depression \[[@CR120]\], type 2 diabetes (T2D) \[[@CR121]\], and malignancies \[[@CR122]\].
RA and Osteoporosis {#Sec24}
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Osteoporosis has long been recognized as one of the most common comorbidities associated with RA \[[@CR115], [@CR123], [@CR124]\]. It is prevalent in 10--50% of patients with RA depending on the population studied, and has been shown to be over twice as common in patients with RA than in age- and sex-matched controls \[[@CR115], [@CR123], [@CR124]\]. The consequences of this comorbidity are important. It is well known that the use of glucocorticoids, commonly used in RA, is associated with reduced bone mineral density (BMD) due to a reduction in bone formation (rather than an increase in bone turnover) \[[@CR125]\]; however, the risk of fracture in patients with RA is increased irrespective of glucocorticoid use \[[@CR126]--[@CR128]\].
The systemic effect of IL-6 on bone integrity (as described above) can be considered as a manifestation of RA outside the joints. Serum levels of IL-6R are increased in osteoporosis and variants of the IL-6R gene are associated with differential BMD, supporting the link between the cytokine and the pathologic process \[[@CR129]--[@CR131]\].
### IL-6R Blockade, Bone Turnover, and BMD {#Sec25}
The effects of tocilizumab and, more recently, sarilumab on markers of bone metabolism (specifically, markers of bone formation: osteocalcin, OPG, RANKL, and N-terminal propeptide of type I collagen \[P1NP\]; and of bone resorption: C-terminal telopeptide of type I collagen \[CTX-I\] and CTX-I generated by matrix metalloproteinases \[ICTP\]) have been reported from randomized controlled trials. Most recently, in a monotherapy study of sarilumab versus adalimumab, after 24 weeks of treatment, blockade of IL-6R with sarilumab treatment significantly increased concentrations of P1NP and resulted in a numeric increase in osteocalcin compared with adalimumab. In addition, reductions in total RANKL compared with adalimumab were observed as early as week 2 and persisted through week 24 \[[@CR132]\]. This was consistent with other studies that had shown that sarilumab produced an early (week 2) decrease in total RANKL levels and the soluble RANKL:OPG ratio through week 24 \[[@CR133], [@CR134]\]. In previous studies, tocilizumab was shown to provide overall improvement in net bone biomarker balance as measured by a 25% decrease in the CTX-I:osteocalcin ratio after 16 weeks of treatment \[[@CR135]\], to produce small (up to 15%) decreases in the bone degradation markers CTX-I and ICTP after 24 weeks of treatment \[[@CR136]\], and to increase osteocalcin \> 100% after 52 weeks of treatment \[[@CR137]\].
In animal models of collagen-induced arthritis, the reduction in the number of osteoclast precursors in bone marrow with IL-6R blockade contributes to the prevention of bone loss and protection against the reduction in bone strength \[[@CR138], [@CR139]\]. Clinical studies in patients with RA on the effects of IL-6R blockade on BMD have also been encouraging, although randomized trials are lacking. In several recent, but relatively small, open-label studies of patients treated with tocilizumab (*n* = 76--145), BMD was stable over the long term and, in patients who were anti-citrullinated protein antibody-positive and/or had osteopenia at baseline, BMD increased \[[@CR140]--[@CR142]\]. In addition, considering the glucocorticoid-sparing effects of anti-IL-6R bDMARDs \[[@CR143]\], there are various routes through which this class of agents can have beneficial effects on bone metabolism in patients with RA.
RA and CVD {#Sec26}
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CVD is the leading cause of mortality in patients with RA, and the risk of CVD is increased up to twofold in patients with RA compared with the general population \[[@CR116], [@CR144]--[@CR146]\]. Additionally, the use of glucocorticoids \> 7.5 mg/day or at a cumulative dose of 40 g is associated with a considerable increased risk of CV mortality \[[@CR147]\]. After adjusting for traditional CV risk factors, such as hypertension, smoking, and lipid abnormalities, RA itself (or rather the high systemic inflammatory burden associated with it) is an independent risk factor for CVD \[[@CR148], [@CR149]\]. Furthermore, a large CV study in \> 15,000 individuals showed a clear link between CRP and CV risk \[[@CR150]\], providing support for the central role of inflammation in the initiation and progression of atherothrombosis, and the prompting of CV events. Elevated ESR levels are also associated with increased CV risk \[[@CR151]\].
The chronic systemic inflammatory burden in patients with RA is thought to explain, in part, what is known as the "lipid paradox": the phenomenon where patients with RA are at an increased risk of CVD and associated mortality, despite lower levels of total cholesterol or low-density lipoprotein cholesterol (LDL-C), or the ratio of total:high-density lipoprotein cholesterol (HDL-C), which would traditionally be considered to indicate low risk \[[@CR151]\]. High levels of lipoprotein(a) (Lp(a)), which is atherogenic in nature, have also been reported in patients with RA \[[@CR152]\].
The mechanisms by which inflammation confounds the association of cholesterol and CVD remain somewhat unclear, but are likely due to a myriad of factors. Given that increased CRP and ESR levels are linked to increased CVD rates, and the hepatic synthesis of CRP is largely regulated by IL-6, the direct and indirect links between IL-6 and CVD are clear, particularly in patients with inflammatory conditions such as RA. Adipose tissue is one of the main sources of inflammatory mediators, including IL-6, and animal studies have suggested that adipose tissue-derived IL-6 may affect adipose tissue-specific gene expression, suppressing total adiponectin release from human adipocytes \[[@CR153]\], triglyceride release \[[@CR154]\], and lipoprotein lipase activity \[[@CR155]\]. It has also been shown in humans that coronary calcification mediated by IL-6 also contributes to the development of atherosclerosis \[[@CR156]\]. Therefore, it is unsurprising that, in a large meta-analysis, elevated IL-6 was associated with an increased risk of coronary heart disease after adjusting for several classic vascular risk factors and correcting for within-person variability \[[@CR157]\]. In another meta-analysis, the presence of an IL-6R variant (Asp358Ala), with effects consistent with IL-6R blockade, conferred a decreased risk of coronary heart disease \[[@CR158]\].
### IL-6R Blockade, Lipid Levels, CV Risk, and Events {#Sec27}
The IL-6R blockers are of interest with respect to CVD risk because of their observed effects on lipid profiles in phase III studies. Across phase III studies, both sarilumab and tocilizumab treatment was associated with increases in total cholesterol, LDL-C, and HDL-C (whereas the HDL:LDL ratio remained generally stable). Consequently, prescribing guidelines recommend that physicians assess lipid parameters 4--8 weeks following initiation of treatment with IL-6R, and at regular intervals thereafter.
A recent analysis of the phase III MONARCH study, which compared the effects of sarilumab with the anti-TNFα bDMARD adalimumab, showed significantly greater reductions in Lp(a) after 24 weeks of treatment with sarilumab compared with adalimumab, and normalization of Lp(a) occurred in a numerically greater percentage of patients treated with sarilumab \[[@CR132]\]. In a much smaller study, inhibition of IL-6 signaling with tocilizumab decreased Lp(a) serum levels, indicating a beneficial effect of IL-6R blockade on CV risk \[[@CR159]\]. Other small studies have shown that IL-6R blockade improves endothelial function and/or reduces arterial stiffness \[[@CR160], [@CR161]\].
Because of the effects of tocilizumab on lipid levels, and because it was the first anti-IL-6R bDMARD, regulatory authorities requested a phase IV trial comparing the CV safety of tocilizumab with an anti-TNFα bDMARD in patients with RA \[[@CR162]\]. The study, with a follow-up period of 3.2 years, showed that tocilizumab did not increase the rate of major CV events compared with etanercept (hazard ratio 1:1). This finding is consistent with the integrated safety analyses of the phase III studies of both anti-IL-6R bDMARDs. Fleischmann et al. \[[@CR163]\] recently published a report with 9000 years of patient exposure to sarilumab, which showed that the exposure-adjusted incidences of major CV events with sarilumab combination and monotherapy (0.5 and 0.2/100 patient-years \[PY\], respectively) were no greater than those reported in the general RA population. Similar reports have been shown previously with tocilizumab \[[@CR164]\].
RA, Diabetes, and the Metabolic Syndrome {#Sec28}
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The incidence of T2D is at least twice that in patients with RA compared with the general population, and there is an increased risk for CVD in patients with both conditions relative to patients with either RA or T2D alone \[[@CR121], [@CR165]\]. The coexistence of RA and T1D is less common than that of RA and T2D (Bao et al. \[[@CR166]\] reported that 2% of \> 150,000 patients with T1D in the USA have RA), but the risk of more than one autoimmune disease in the same patient is an established phenomenon.
Elevated circulating levels of IL-6 have been associated with dysfunctional glucose metabolism, and the induction of insulin resistance in the hepatocytes and adipocytes of obese patients with and without T2D \[[@CR167], [@CR168]\]. Furthermore, increased levels of IL-6 have been associated with increased risk for the development of T2D \[[@CR169], [@CR170]\]. Additionally, pharmacologic management of T2D and RA can be complicated by the potential effects of RA treatments on glucose levels. In particular, oral glucocorticoids (especially higher doses and longer treatment durations) increase the risk for T2D \[[@CR171]\].
While T2D is associated with insulin resistance, T1D is characterized by insulin deficiency caused by immune-mediated selective destruction of beta cells in the islets of Langerhans. T1D can therefore be considered an inflammatory disease of the pancreatic islets, in which beta cell apoptosis results through the interaction of activated T cells and proinflammatory cytokines in the immune infiltrate \[[@CR172]\]. In vitro and in vivo research in animals has implicated IL-6 in T1D, identifying that, in addition to a possible role in regulating pancreatic beta cell function (inhibiting glucose-stimulated insulin secretion from pancreatic islets), IL-6 produced by pancreatic beta cells may act as a co-stimulator for autoreactive B and T lymphocytes in T1D \[[@CR173], [@CR174]\].
### IL-6R Blockade, Insulin Sensitivity, and Glycosylated Hemoglobin {#Sec29}
In recent post hoc analyses, the decreases in hemoglobin A1c (HbA1c) were greater in sarilumab groups than placebo or adalimumab groups at week 24 (*n* = 20) among patients with RA, both without and with T2D, as identified by medical history or use of antidiabetic medication \[[@CR175]\]. Similar reductions in HbA1c were shown in a small open-label study of patients with active RA (*n* = 10 with T2D and HbA1c ≥ 6.4%) treated with IV tocilizumab 8 mg/kg Q4W for 24 weeks \[[@CR176]\], and in an observational study where tocilizumab decreased HbA1c levels in patients with RA to a greater extent than anti-TNFα bDMARDs \[[@CR177]\]. Tocilizumab has also been shown to improve insulin sensitivity as determined by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and the leptin:adiponectin ratio in non-diabetic patients with rheumatoid disease \[[@CR159]\].
To date, there are limited data on the effects of IL-6R blockade in patients with T1D, but the results of a clinical trial to assess the potential efficacy of anti-IL-6 therapy on beta cell responses in children and adolescents with new-onset T1D are awaited with interest (<https://www.extendstudy.org/about-extend>).
RA and Mood and Sleep Disturbances {#Sec30}
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Many patients with RA suffer from mood disorders, particularly depression and anxiety \[[@CR120]\]. A meta-analysis of 72 studies in \> 13,000 patients with RA found the prevalence of depression to be 38% \[[@CR120]\], and despite the clinical focus on depression among people with arthritis, anxiety can be more common than depression \[[@CR178]\]. In RA, mood disorders are associated with pain, disability, and impaired quality of life, and can even adversely affect adherence to therapy \[[@CR93], [@CR179], [@CR180]\].
Although the link between mood disorders and RA is certainly multifactorial, evidence points toward IL-6 being one of these key factors. Dowlati et al. \[[@CR181]\] performed a meta-analysis that showed significantly higher serum concentrations of TNFα and IL-6 in patients with major depression compared with control subjects. An updated meta-analysis by Haapakoski et al. \[[@CR182]\] continued to show higher mean levels of IL-6 in patients with major depression compared with non-depressed controls, but found that the association between TNFα and risk of depression was uncertain due to heterogeneity in study-specific estimates and inconsistencies between subgroups. In healthy individuals, low serum levels of IL-6 predict earlier resolution of negative mood following psychosocial distress, and administration of IL-6 results in significantly depressed self-reported mood \[[@CR183], [@CR184]\]. A "low-IL-6" synthesizing genotype associated with lower levels of depression has also been identified \[[@CR185]\], and animal studies have shown that IL-6R blockade can induce long-lasting antidepressant effects in susceptible mice after social-defeat stress \[[@CR186]\].
The HPA axis is the major endocrine system regulating the physiologic response to stress, and although the mechanisms by which IL-6 affects mood have not been fully elucidated, effects on the HPA axis have been implicated \[[@CR187], [@CR188]\]. Positive temporal correlations between plasma levels of IL-6 and HPA hormones, adrenocorticotropic hormone, and cortisol have been demonstrated \[[@CR187], [@CR188]\]. Given that dysregulation of the HPA axis has been associated with both depressive and anxiety disorders in RA and other conditions, such as cancer \[[@CR188], [@CR189]\], the IL-6--HPA axis interaction is a plausible explanation for the clinical effects on mood that are seen.
Another prevalent complaint of patients with RA is poor sleep quality, which has been associated with depression, pain, fatigue, and functional disability \[[@CR190], [@CR191]\]. Polysomnographic studies have also confirmed that chronic pain is associated with poor sleep continuity and reduced total sleep time in other populations, although it is also hypothesized that sleep disturbance might drive RA-related pain \[[@CR192]\].
In healthy subjects, elevated IL-6 is negatively correlated with sleep quality and positively correlated with ineffective interrupted sleep \[[@CR190], [@CR191]\]. IL-6 is also involved in normal sleep regulation. In healthy individuals, quantity of sleep correlates negatively with the overall daytime secretion of IL-6, and individuals deprived of sleep have daytime oversecretion of IL-6 \[[@CR193]\]. SC administration of IL-6 into healthy individuals significantly alters sleep structure, and promotes manifestations of somnolence and fatigue \[[@CR183], [@CR193]\]. Research has implicated the link between IL-6 and the HPA axis in poor sleep; IL-6-induced HPA axis activation in patients with RA results in transient hypercortisolemia during the early hours of sleep, which may explain the poor sleep quality during this period \[[@CR194]\].
### IL-6R Blockade and Effects on Mood Disorders and Sleep {#Sec31}
In patients with RA, IL-6R blockade with tocilizumab and sarilumab has previously been reported to be associated with improvements in sleep. Most recently, in a subanalysis of Italian data from the TOZURA multicenter phase IIIb/IV trial, Bazzichi et al. \[[@CR195]\] reported a significant improvement in sleep quality after 24 (but not 12) weeks of tocilizumab treatment using the Pittsburgh Sleep Quality Index questionnaire. Previously, Strand et al. \[[@CR196]\] reported a clinically significant improvement in sleep after 24 weeks of sarilumab treatment using a sleep visual analog scale (VAS), with a decrease in score of − 16.9 from a baseline of 54.1.
Evidence indicating that IL-6R blockers have positive effects on mood in patients with RA is discussed in more detail in "The importance of IL-6R blockade from a patient's perspective" section below.
RA and Infections {#Sec32}
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Disease activity associated with RA is a risk factor for infection explained by the pathobiologic immune system disturbances of RA itself, the impact of chronic comorbid conditions, and sequelae of immunosuppressive treatment. Individuals with RA have a twofold increased adjusted risk of hospitalized infection compared with those without, an observation that was first identified over 50 years ago and has been confirmed in recent years \[[@CR118], [@CR119]\]. Upper and lower respiratory tract infections are often the most common infections, and a history of serious infections and/or comorbidities, increased glucocorticoid dose, and older age are important risk factors of serious infections in patients treated with bDMARDs.
The risk of serious infections with bDMARDs targeting TNFα is higher compared with the use of csDMARDs, particularly during the first 6 months of treatment \[[@CR197]--[@CR199]\], and the addition of MTX to bDMARDs does not appear to increase the risk of serious infection \[[@CR200]\]. However, it is interesting to note that the risk of sepsis or mortality may be lower in patients exposed to bDMARDs compared with csDMARDs at the time of serious infection \[[@CR201]\], which suggests that successful immunosuppression may prevent the unregulated host response to serious infection. Further research is obviously warranted, but such findings highlight the complexity of the mechanisms involved in immunomodulation and infection.
### IL-6R Blockade and Infection in RA {#Sec33}
Given the increased infection risk with other bDMARDs, and since IL-6 has a pivotal role in the recruitment and antiapoptosis of T lymphocytes, and in B and T cell differentiation, the impact of IL-6R blockade on the risk of infections is of considerable interest. In the clinical studies MOBILITY, TARGET, and MONARCH, and in the recently published integrated safety analysis of 2887 patients receiving sarilumab in combination with csDMARDs or as monotherapy (8188 and 812 PY, respectively), the risk of infections was found to be increased compared with placebo but in line with other bDMARDs \[[@CR39]--[@CR41], [@CR163]\]. IL-6 blockade with tocilizumab and sarilumab has been shown to cause a decrease in neutrophil levels \[[@CR163], [@CR202]--[@CR204]\]. However, the reduction in absolute neutrophil count (ANC) observed with sarilumab is not associated with an increased risk of infection or serious infection in clinical studies, and a "margination" hypothesis has been described to explain these observations \[[@CR205]\] (discussed further in the "Safety and tolerability of IL-6 blockade" section of this article).
RA and Malignancy {#Sec34}
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The association between RA and cancer has been a clinical concern, and focus of research efforts, since links between RA and cancer (as well as between RA treatments and cancer) were first identified. Epidemiologic studies have generally demonstrated that hematopoietic, lung, and skin cancers can be increased in patients with RA, while breast and colon cancers are decreased, and that there is a very slight overall increase in all cancers \[[@CR206]--[@CR208]\]. There have been various hypotheses for the differences in the increased risk of certain malignancies in patients with RA. Inflammatory responses play pivotal roles in cancer development, including tumor initiation, promotion, progression, and metastasis \[[@CR122]\]. Inflammation is believed to play a key role in the risk of lymphoma in particular, and evidence suggests that it is the disease activity associated with RA that confers the risk of lymphoma \[[@CR122]\].
IL-6 is highly upregulated in many cancers, and considered one of the most important cytokines associated with tumorigenesis and metastasis \[[@CR209]\]. A high serum concentration of IL-6 is a prognostic indicator of poor outcome in patients with various cancers, including gastric, pancreatic, melanoma, breast, colorectal, myeloma, and lung cancers \[[@CR209]\]. As well as acting directly on tumor cells, IL-6 can act on other cells within the complex tumor microenvironment to sustain a protumor setting, and acting through STAT3, IL-6 also supports tumor cell survival \[[@CR210]\]. The role of IL-6 signaling in the activation of downstream pathways in cancer has been reviewed extensively \[[@CR211]--[@CR215]\] and is therefore not further expanded here.
### IL-6R Blockade and Malignancy in RA {#Sec35}
Unlike some other DMARDs used to treat RA, the prescribing information for IL-6R blockers does not have a warning regarding malignancies \[[@CR11]--[@CR14]\]. It is acknowledged that malignancies have been reported in clinical studies, but analyses indicate that IL-6 blockade with sarilumab and tocilizumab does not increase cancer risk significantly compared with treatment-naïve groups \[[@CR163], [@CR164], [@CR216]\]. The overall rates of malignancy of 0.7/100 PY for sarilumab combination therapy, 0.6/100 PY for sarilumab monotherapy \[[@CR163]\], and 1.1--1.2/100 PY with tocilizumab \[[@CR164], [@CR216]\] are comparable with the rate of 1.3/100 PY observed in a contemporary large US cohort of patients with RA (\> 40,000 PY), in which \> 60% of patients were treated with anti-TNFα bDMARDs \[[@CR217]\].
RA and Interstitial Lung Disease {#Sec36}
--------------------------------
Interstitial lung disease (ILD) is the most common pulmonary complication in patients with RA, with a reported lifetime risk of developing ILD of 7.7% for patients with RA compared with 0.9% for those without RA. \[[@CR117]\] There has been growing interest in the overlap of these two conditions in recent years, particularly since prognosis is so poor, with a mean of 2.6 years' survival after diagnosis \[[@CR117]\]. Indeed, certain drugs used to treat RA, such as MTX and potentially (although data are conflicting) anti-TNFα bDMARDs, have been associated with the development or progression of ILD \[[@CR117]\].
A recent report has shown that active RA is associated with an increased risk for developing RA-ILD, with a hazard ratio of 2.22 for patients with moderate/high disease activity compared with those with LDA or in remission \[[@CR218]\], thus providing the link with systemic inflammation, of which IL-6 is a key driver. However, while elevated levels of serum IL-6 (\> 7.67 pg/ml) have been shown to be predictive of negative outcomes in ILD associated with systemic sclerosis (SSc-ILD) \[[@CR219]\], and elevated serum interleukin-18 levels have recently been shown to be associated with the presence of ILD in patients with RA \[[@CR220]\], there is a paucity of research investigating the role of IL-6 in RA-ILD \[[@CR221], [@CR222]\].
### IL-6R Blockade and ILD {#Sec37}
Although primary endpoints were not met in the phase II faSScinate \[[@CR223]\] and phase III focuSSced trials conducted in patients with SSc-ILD, there was some evidence of reduced lung function decline with the anti-IL-6R agent tocilizumab. In addition, case series have also reported modest effects in patients with SSc-ILD, with approximately 50% of patients achieving an improvement or stabilization of pulmonary function \[[@CR224]\]. However, to date there is limited information on the effects of IL-6 blockade on ILD in patients with RA, with evidence limited to case reports describing anecdotal benefits regarding the off-label use of tocilizumab in patients with RA and ILD \[[@CR225]--[@CR227]\].
The Importance of IL-6r Blockade from a Patient's Perspective {#Sec38}
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While the clinical endpoints (discussed in the "Effect of sarilumab and tocilizumab on clinical endpoints in RA" section above) are valuable from a clinical perspective and help guide treatment decisions, they are of little direct relevance to patients themselves. In fact, RA is no different from other conditions in that there is often a disconnect between the treatment goals of patients and those of their physicians. In surveys conducted between 2014 and 2016, of approximately 1800 patients with RA whose RA was primarily managed by a rheumatologist and a similar number of physicians managing patients with RA, while 90% of physicians were satisfied with their communication with their patients regarding RA treatment, 61% of patients felt uncomfortable raising concerns or fears with their physician \[[@CR228]\]. Over one-half of patients responding felt that improved dialogue/discussion with their physician would optimize their RA management, and over two-thirds of physicians wished that they and their patients talked more about RA goals and treatment \[[@CR228]\]. The European League Against Rheumatism (EULAR) 2016 RA treatment recommendations were designed, in part, based on recognition of a need for improved dialogue surrounding RA manifestations \[[@CR60]\], such as is reported here. As such, the first overarching principle is that best care for patients must be aimed for, and that such care should be based on shared decisions made between the patient and their rheumatologist \[[@CR60]\].
Indeed, factors influencing treatment decisions differ between rheumatologists and patients \[[@CR229]\]. Physicians are more likely to escalate treatment based on DAS28 scores, the number of swollen joints, levels of CRP, and progression of joint erosion, while patients rate the number of painful joints, fatigue, morning stiffness, and level of physical function as more important factors \[[@CR230]\]. A recent review of patient perspectives also highlighted routes of administration as an important attribute influencing treatment preferences \[[@CR231]\]. Studies have documented a preference for newer autoinjectors over prefilled syringes, consistent with high satisfaction rates with the sarilumab autoinjector pen \[[@CR232]\].
Table [3](#Tab3){ref-type="table"} lists the key phase III studies for IV and SC tocilizumab, SC sarilumab, and patient-reported outcomes investigated \[[@CR233]\], and the following sections describe how these measures provide more information on the beneficial effects of anti-IL-6R bDMARDs on some of the comorbid conditions and extra-articular manifestations associated with RA.Table 3Overview of phase III studies with tocilizumab IV and SC, and sarilumab SC, on individual patient-reported outcome endpointsStudy populationTreatment armsHAQ-DISF-36FatiguePainMorning stiffnessSarilumab combination studies MOBILITYMTX-IR (*n* = 1197)S 150 mg SCS 200 mg SCPlacebo SCQ2W 52 weeksCo-primary endpoint: change from baseline W16Not reportedNot reportedSecondary endpoint: change from baseline VAS W24Not reported\[[@CR39]\] <https://clinicaltrials.gov/ct2/show/NCT01061736>Patients also received MTX TARGETTNF-IR (*n* = 546)S 150 mg SCS 200 mg SCPlacebo SCQ2W 24 weeksCo-primary endpoint: change from baseline W12Secondary endpoint: change from baseline W24Secondary endpoints: change from baseline SF-36 physical W24; change from baseline SF-36 mental W24Secondary endpoints: change from baseline FACIT-F W24; also measured in RAID domain (change from baseline W12, W24)Secondary endpoints: change from baseline VAS W24; also measured in RAID domain (change from baseline W12, W24)Secondary endpoint: change from baseline VAS W24\[[@CR40]\] <https://clinicaltrials.gov/ct2/show/NCT01709578>Patients also received csDMARDsSarilumab monotherapy studies MONARCHMTX-IR (*n* = 369)S 200 mg SCA 40 mg SCPlacebo SCQ2W 24 weeksSecondary endpoint: change from baseline W24Secondary endpoints: change from baseline SF-36 physical W24; change from baseline SF-36 mental W24Secondary endpoints: change from baseline FACIT-F W24; also measured in RAID domain (change from baseline W24)Secondary endpoints: change from baseline VAS W24; also measured in RAID domain (change from baseline W24)Secondary endpoint: change from baseline VAS W24\[[@CR41]\] <https://clinicaltrials.gov/ct2/show/NCT02332590>SC tocilizumab studies SUMMACTADMARDs-IR (*n* = 1262)T 162 mg SC QWT 8 mg/kg IV Q4W24 weeksSecondary endpoint: proportion with ≥ 0.3 change HAQ-DI ≥ 0.3 W24, W97Not reportedNot reportedNot reportedNot reported\[[@CR42]\] <https://clinicaltrials.gov/ct2/show/NCT01194414> BREVACTADMARDs-IR (*n* = 656)T 162 mg SCPlacebo SCQ2W24 weeksSecondary endpoint: change from baseline W24; proportion with ≥ 0.3 change W24, W97Secondary endpoint: change from baseline SF-36 W24Not reportedSecondary endpoint: change from baseline VAS W24Not reported\[[@CR43]\] <https://clinicaltrials.gov/ct2/show/NCT01232569>IV tocilizumab combination studies LITHEMTX-IR (*n* = 1196)T 4 mg/kg IVT 8 mg/kg IVPlacebo IVQ4W52 weeksCo-primary endpoint: change from baseline in AUC W52, W104; proportion with ≥ 0.3 change W104Secondary endpoint: change from baseline SF-36 W24, W52, W104Secondary endpoints: change from baseline FACIT-F W24, W52, W104Secondary endpoint: change from baseline VAS W52, W104Not reported\[[@CR44]\] <https://clinicaltrials.gov/ct2/show/NCT00106535>Patients also receive MTX OPTIONcsDMARD-IR (*n* = 623)T 8 mg/kg IVT 4 mg/kg IVPlacebo IVQ4W24 weeksAdditional endpoint: change from baseline W24Additional endpoint: difference from placebo group SF-36 physical W24; SF-36 mental W24Additional endpoint: FACIT-F score, difference from placebo group W24Additional endpoint: change from baseline VAS W24Not reported\[[@CR45]\] <https://clinicaltrials.gov/ct2/show/NCT00106548>Patients also receive MTX TOWARDcsDMARD-IR (*n* = 1220)T 8 mg/kg IVPlacebo IVQ4W24 weeksSecondary endpoint: change from baseline W24Secondary endpoint: change from baseline SF-36 W24Secondary endpoint: change from baseline FACIT-F W24Not reportedNot reported\[[@CR46]\] <https://clinicaltrials.gov/ct2/show/NCT00106574>Patients also receive csDMARDsRADIATETNF-IR (*n* = 499)T 8 mg/kg IVT 4 mg/kg IVPlacebo IVQ4W24 weeksAdditional endpoint: change from baseline W24; proportion with ≥ 0.22 change W24Additional endpoint: change from baseline SF-36 physical and mental W24Additional endpoint: change from baseline FACIT-F W24Additional endpoint: change from baseline; patient's assessment of pain by VAS W24Not reported\[[@CR47]\] <https://clinicaltrials.gov/ct2/show/NCT00106522>Patients also receive MTXIV tocilizumab monotherapy studies U-ACT-EARLYNewly diagnosed DMARD-naïve (*n* = 317)T 8 mg/kg IV + MTXT 8 mg/kg IVPlacebo + MTXQ4W104 weeksNot reportedSecondary endpoint: change from baseline SF-36 W12, W24, W52, W104Secondary endpoint: change from baseline FACIT-F W12, W24, W52, W104Secondary endpoint: change from baseline; patient's assessment of pain by VAS W12, W24, W52, W104Not reported\[[@CR48]\] <https://clinicaltrials.gov/ct2/show/NCT01034137> FUNCTIONMTX-naïve patients with early progressive RA (*n* = 1162)T 8 mg/kg IV + MTXT 8 mg/kg IVT 8 mg/kg + placeboPlacebo + MTXQ4W104 weeksSecondary endpoint: change from baseline W24, W52Secondary endpoint: change from baseline SF-36 physical and mental W24, W52Not reportedNot reportedNot reported\[[@CR49]\] <https://clinicaltrials.gov/ct2/show/NCT01007435> ACT-RAYMTX-IR (*n* = 556)T 8 mg/kg IV + MTXT 8 mg/kg IV104 weeksSecondary endpoint: change from baseline W24, W52Not reportedNot reportedNot reportedNot reported\[[@CR50]\] <https://clinicaltrials.gov/ct2/show/NCT00810199> ADACTAMTX-INT (*n* = 326)T 8 mg/kg IV Q4WA 40 mg SC Q2W24 weeksNot reportedChange from baseline W24Change from baseline W24Not reportedNot reported\[[@CR51]\] <https://clinicaltrials.gov/ct2/show/NCT01119859>*A* adalimumab, *AUC* area under the curve, *csDMARD* conventional synthetic disease-modifying antirheumatic drug, *DMARD* disease-modifying antirheumatic drug, *FACIT-F* Functional Assessment of Chronic Illness Therapy-Fatigue, *HAQ-DI* Health Assessment Questionnaire Disability Index, *INT* intolerant, *IR* inadequate response, *IV* intravenous, *MTX* methotrexate, *n* number of patients, *Q2W* every 2 weeks, *Q4W* every 4 weeks, *QW* weekly, *RA* rheumatoid arthritis, *RAID* rheumatoid arthritis impact of disease, *S* sarilumab, *SC* subcutaneous, *SF-36* Short Form (36 item) Health Survey, *T* tocilizumab, *TNF* tumor necrosis factor, *VAS* visual analog scale, *W* week
Combination Therapy with Sarilumab and Tocilizumab {#Sec39}
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### Physical Functioning {#Sec40}
The Health Assessment Questionnaire Disability Index (HAQ-DI) is often the measure used to assess the physical disability component of the ACR core set and, for sarilumab, was evaluated in MOBILITY at week 16 \[[@CR39]\] and TARGET at week 12 \[[@CR40]\], with change from baseline included as co-primary endpoints (Table [2](#Tab2){ref-type="table"}). In the MOBILITY study, significant improvement was observed at weeks 16, 24, and 52 of the study, and in the TARGET clinical study, the mean change in HAQ-DI score after week 12 of the study was significantly increased versus the placebo groups \[[@CR39], [@CR40]\]. Treatment with tocilizumab has also been found to cause improvements in HAQ-DI scores. In the SUMMACTA study, mean HAQ-DI score improvements with SC tocilizumab were observed to be maintained at approximately − 0.6 compared with baseline values from week 24 through to week 97 \[[@CR53]\]. In the LITHE study, the proportion of patients receiving treatment who maintained a HAQ-DI improvement score of ≥ 0.3 from the baseline level to week 24 of the study was numerically higher with IV tocilizumab than in the untreated control group \[[@CR44]\]. At week 24 in the TOWARD study \[[@CR46]\], 60% of treated patients were reported to exhibit clinically meaningful HAQ-DI score improvements compared with 34% in the untreated control group, with baseline mean change also significantly greater in the tocilizumab-treated versus the control group. The RADIATE study reported that HAQ-DI values improved by − 0.31 and 0.39 (tocilizumab 4 mg/kg and 8 mg/kg doses, respectively) versus − 0.05 in treated compared with control groups \[[@CR47]\].
### Effects of Sarilumab and Tocilizumab on Mood and Depressive Manifestations {#Sec41}
In post hoc analyses, approximately 60% of patients enrolled into MOBILITY and TARGET were classified at baseline as having probable major depressive disorder (PMDD; according to the Short Form \[36-item\] Health Survey \[SF-36\] mental health \[MH\] domain score ≤ 56), and approximately 50% were classified as having probable depressed mood and anhedonia (PDMA; score ≤ 10 on both items of the MH domain: "Have you felt downhearted and depressed?" and "Have you felt so down in the dumps that nothing could cheer you up?"). In both studies, sarilumab provided clinically meaningful improvements in most domains of health status compared with placebo. In particular, MH scores for PMDD and PDMA subgroups were higher (better) for sarilumab 200 mg Q2W versus placebo \[[@CR234]\].
Outside the phase III studies, tocilizumab use has been associated with decreased depressive manifestations (using the Hospital Anxiety and Depression Scale, which comprises two subscales \[one measuring depression and the other anxiety\] of seven items) in a small study of patients with RA \[[@CR235]\].
### Effect of Sarilumab and Tocilizumab on Fatigue {#Sec42}
In MOBILITY, 24 weeks' treatment with sarilumab 200 mg Q2W resulted in improvement from baseline by week 24 in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores that were clinically meaningful and persisted until week 52 \[[@CR236]\]. In TARGET, improvements in the FACIT-F scores with sarilumab 200 mg Q2W were seen 2 weeks after the start of treatment, and greater improvements versus placebo at week 12 were maintained at week 24 \[[@CR237]\]. Similar results have been seen with tocilizumab in the OPTION \[[@CR45]\] and TOWARD studies \[[@CR46]\].
### Effect of Sarilumab and Tocilizumab on Pain {#Sec43}
Improvements in the pain VAS with sarilumab 200 mg Q2W were approximately double those obtained with placebo in MOBILITY and TARGET by week 12 (− 30 vs. − 15) \[[@CR39], [@CR40]\]. Overall, with sarilumab 200 mg Q2W in MOBILITY and TARGET, pain was improved by ≥ 30% in 50--60% of patients \[[@CR39], [@CR40]\]. A recent post hoc analysis reported the proportions of patients achieving ≥ 30%/ ≥ 50%/ ≥ 70% pain VAS improvements and median time to first pain VAS ≥ 50% improvement in MOBILITY and TARGET \[[@CR238]\]. Median time to first pain ≥ 50% improvement was 12 weeks in patients receiving sarilumab 200 mg Q2W compared with 24 weeks in patients receiving placebo \[[@CR238]\].
### Effect of Sarilumab and Tocilizumab on Morning Stiffness {#Sec44}
The effects of sarilumab on morning stiffness were measured using a VAS in TARGET, and showed an improvement in scores of − 30 at week 12 (versus − 13 with placebo) and − 34 at week 24 (versus − 22 with placebo) \[[@CR237]\]. Morning stiffness was not measured in the tocilizumab phase III program, but in a German open-label study (TAMARA), major improvements in morning stiffness were observed in the first 4 weeks of treatment with IV tocilizumab 8 mg/kg Q4W, with further improvement until week 24 \[[@CR239]\].
Monotherapy with Sarilumab or Tocilizumab {#Sec45}
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### Sarilumab Monotherapy {#Sec46}
The MONARCH study compared the effects of sarilumab 200 mg Q2W and adalimumab 40 mg Q2W on a variety of patient-reported outcomes \[[@CR240]\]. After 24 weeks of treatment, and compared with adalimumab, sarilumab resulted in significantly greater improvements in HAQ-DI (decreases from 1.6 at baseline of − 0.61 and − 0.43, respectively). By week 24, 65% of patients had an improvement of HAQ-DI ≥ 0.22 and 62% had an improvement ≥ 0.3 (54% and 48% with adalimumab, respectively). Sarilumab also resulted in larger improvements in Patient Global Assessment, pain VAS, and SF-36 Physical Component Score (PCS), although, overall, between-group differences in FACIT-F and SF-36 Mental Component Score (MCS) were not significant. Improvements in four of eight SF-36 domains were significantly greater with sarilumab than with adalimumab (physical functioning, body pain, and role-physical, and social functioning). Greater changes were also reported for sarilumab versus adalimumab in RA impact of disease, a measure with seven weighted domains covering pain, functional disability, fatigue, emotional well-being, sleep, coping, and physical well-being \[[@CR241]\]. A recent post hoc analysis of MONARCH reported that the median time to first pain ≥ 50% improvement in MONARCH was 12 weeks in patients receiving sarilumab 200 mg Q2W, compared with 24 weeks in patients receiving placebo \[[@CR238]\]. Morning stiffness was also evaluated using a VAS severity scale (0 mm \[no problem\] to 100 mm \[major problem\]) \[[@CR240]\]. At week 24, improvements in morning stiffness VAS were greater with sarilumab treatment than with adalimumab, and more patients (73.9% vs. 62.2%) reported improvements greater than or equal to the morning stiffness minimal clinically important differences (MCID) of ≥ 10 units.
### Tocilizumab Monotherapy {#Sec47}
The effects of IV tocilizumab monotherapy on patient-reported outcomes have been reported from AMBITION (compared with MTX) and ADACTA (compared with adalimumab) over 24 weeks \[[@CR242]\]. In AMBITION, tocilizumab-treated patients reported significantly greater mean improvements in FACIT-F (8.7 vs. 5.7; SF-36 PCS: 9.8 vs. 7.8) and five SF-36 domains (physical functioning, bodily pain, vitality, social functioning, and mental health) than with MTX \[[@CR242]\].
The proportions of patients reporting improvements above the MCID depended on the outcome measured. In AMBITION, 24--44% of tocilizumab-treated patients reported scores at least equal to normative values across HAQ-DI, FACIT-F, and SF-36 PCS/MCS, and 30--52% across SF-36 domains at week 24 compared with 15--42% and 21--45% of MTX-treated patients, respectively \[[@CR242]\].
In ADACTA, tocilizumab-treated patients reported significantly greater improvements in Patient Global Assessment (− 42.3 vs. − 31.8), pain (− 40.1 vs. − 28.7), SF-36 MCS (7.9 vs. 5.0), and three SF-36 domains than with adalimumab (role-physical, vitality, and social functioning) \[[@CR242]\]. Overall, 58--83% of tocilizumab-treated patients reported improvements at least equal to the MCID. The proportion of tocilizumab-treated patients reporting scores at least equal to normative values ranged between 22--49% for HAQ-DI, FACIT-F, and SF-36 PCS/MCS (14--38% with adalimumab), and 23--41% across SF-36 domains at week 24 (17--33% with adalimumab).
Safety and Tolerability of Il-6 Blockade {#Sec48}
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Overall safety profiles of sarilumab and tocilizumab are consistent with IL-6R blockade and the route of administration, and in ASCERTAIN, no clinically meaningful differences in adverse events were seen between SC sarilumab and IV tocilizumab over 24 weeks \[[@CR204]\]. The most useful clinical perspectives on the safety of any pharmacologic intervention develop over time after the completion of the phase III studies, and more patients are treated for longer periods of time in clinical practice in addition to clinical studies. For sarilumab, Fleischmann et al. \[[@CR163]\] have reported an integrated safety analysis of 9000-PY exposure to sarilumab: the overall incidence rates of serious adverse events were 9.4/100 and 6.7/100 PY, respectively, in the combination and monotherapy groups. For tocilizumab, similar integrated and long-term analyses have also been published \[[@CR164], [@CR243]\]. Mohan et al. \[[@CR243]\] showed that the overall rate of serious adverse events in the integrated clinical trial population of \> 22,000 PY was 14.2/100 PY, and in a global postmarketing population included \> 600,000 patients; the overall spontaneous reporting rate of adverse events of special interest was 9.4 cases/100 patients.
In addition to the insights from these postmarketing studies, a number of real-world and registry-based studies provide additional insight into the safety profile of these agents in the wider population of patients with RA. While data from some registries have suggested an increased risk of infections, including serious infections, with agents that inhibit IL-6 signaling \[[@CR244]--[@CR247]\], a comparative head-to-head analysis of the safety of tocilizumab and TNF inhibitors in the Japanese REAL registry did not find a higher risk for serious adverse events or serious infections with tocilizumab compared with TNF inhibitors after adjustment for potentially confounding factors. The use of oral corticosteroids in patients receiving tocilizumab, however, was a significant risk factor for both serious adverse events and serious infections \[[@CR248]\].
In a Japanese 26-week, real-world observational study among \> 1000 patients with RA, the safety profile of SC tocilizumab was consistent with that in clinical trials and for IV tocilizumab. Infections and infestations were the most commonly reported adverse events (7.4% of patients) and accounted for the majority of serious adverse events (1.7% of patients; 2 cases of pneumonia and 2 cases of bacterial pneumonia) \[[@CR249]\].
The most frequent laboratory parameter changes reported in sarilumab/tocilizumab trials were decreased ANC and increases in liver transaminase levels (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) \[[@CR163], [@CR164]\], hence it is recommended that ANC counts, AST/ALT levels, and platelet counts are monitored after starting therapy and regularly thereafter. Lipid changes are also observed as described in the "RA and CVD" section above, although there is no increased risk of major CV events with IL-6R blockade versus anti-TNFα bDMARDs \[[@CR162]\]. Therefore, lipid parameters should be assessed 4--8 weeks following initiation of treatment and regularly thereafter.
As highlighted in the "RA and Infections" section above, the risk of infections is an ongoing clinical consideration in all patients with RA, irrespective of treatment mechanism of action. Patients should therefore be closely monitored for the development of signs and manifestations of infection during treatment with IL-6R. This is particularly true in elderly patients, in whom more infections are seen in general, irrespective of disease or treatment \[[@CR250]\]. IL-6R blockers should not be administered during an active infection, and if a serious infection develops, the IL-6R blockers should be temporarily discontinued until the infection is controlled \[[@CR11]--[@CR14]\].
Sarilumab studies have shown that neutropenia is not associated with a higher incidence of infections, including serious infections \[[@CR163]\], and a margination hypothesis has been postulated \[[@CR205]\]. In this model, "margination" is explained as the redistribution of the neutrophils from the vascular compartment into the vascular wall or other tissues (such as bone marrow), without change in their functionality. The marginated neutrophils remain available in case of an infection and can "demarginate" to mount a host response. Lok et al. \[[@CR202]\] showed that tocilizumab did not affect neutrophil function, activation, or apoptosis ex vivo and, using radiolabeled neutrophils injected into human subjects, that tocilizumab affects neutrophil trafficking to the bone marrow.
Gastrointestinal (GI) perforation has been reported primarily as a complication of diverticulitis in patients with RA. An integrated safety analysis reported 26 cases of GI perforation (2.8/1000 PY) in patients who received tocilizumab compared with no cases in control csDMARD groups; 18 of these perforations occurred in the colon \[[@CR164]\]. An analysis of the global postmarketing database for tocilizumab, which included data for 606,937 patients, identified 632 cases of GI perforation translating to a rate of 0.1 cases/100 patients \[[@CR243]\]. An integrated analysis of sarilumab reported an incidence of GI perforation of 0.1/100 PY with sarilumab in combination with csDMARDs, but no cases with sarilumab monotherapy with 812 PY follow-up \[[@CR163]\].
Hypofibrinogenemia has been noted as a potential adverse effect during tocilizumab treatment in a small case series of seven patients \[[@CR251]\]. This small group of patients (median age 60 years) received tocilizumab 8 mg/kg over a 1-year period and all exhibited low levels of plasma fibrinogen despite normal routine coagulation tests and no evidence of liver failure or disseminated intravascular coagulation (DIC). The authors suggest that, while low fibrinogen levels in the context of normal coagulation tests do not warrant discontinuation of treatment, liver function tests are warranted to rule out DIC or hemophagocytic lymphohistiocytosis.
All bDMARDs have the potential to induce an immunogenic response resulting in the formation of antidrug antibodies (ADAs). ADAs to mAbs may be neutralizing or non-neutralizing, or demonstrate a transient or persistent response; those that are neutralizing and persistent ADAs are more likely to be clinically relevant than transient and/or non-neutralizing ADAs \[[@CR252]\]. ADA incidences cannot be compared across different bDMARDs, partly because of the different assays needed for different products; however, the development of ADAs has been reported with sarilumab \[[@CR41]\] and tocilizumab \[[@CR253]\] treatment. Any impact of an ADA can be compared with different agents and, importantly, unlike infliximab and adalimumab, with IL-6R inhibitors the presence of ADAs has not been associated with a lack or loss of efficacy relative to ADA-negative patients \[[@CR254]\].
Conclusions {#Sec49}
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RA is a chronic, debilitating autoimmune disorder characterized by inflammation of the synovial joint tissues. RA pathogenesis is driven by a complex network of proinflammatory cells and cytokines, and among the actors involved in the network of RA, IL-6 seems to be the most pleiotropic cytokine with the greatest number of downstream influences. IL-6 can bind to various cell types around the body, and increased production of IL-6 can lead to heightened activation of cells within the joint, contributing to the RA disease state. However, beyond the joint, IL-6 is also known to contribute to various extra-articular manifestations and life-threatening comorbidities tightly linked to an existing RA condition.
IL-6R blockade treatments have been shown to cause clinically important improvements in RA clinical endpoints in patients with mild to severe active RA. The leading approved IL-6R inhibitors, sarilumab and tocilizumab, have produced statistically significant improvements in the signs and manifestations of RA when used as monotherapy or in combination with csDMARDs, as defined by the ACR, CRP and ESR, CDAI, and radiographic progression measures, cementing IL-6R blockade as a robust treatment option for RA. However, beyond the joint, the extra-articular manifestations linked to RA including anemia, morning stiffness, pain, weight and body composition, and comorbidities linked to RA that include osteoporosis, CVD and pulmonary disease, infections, depression, T2D, and malignancies have also previously been investigated as IL-6 treatment targets. Clinical evidence in a range of clinical studies has indicated that use of IL-6R blockade with sarilumab or tocilizumab can improve these IL-6-linked conditions to varying extents, to ultimately improve patient disease states and quality of life. To this end, such findings indicate that sarilumab and tocilizumab can be supported as important treatments for certain extra-articular manifestations and comorbidities of RA, in addition to manifestations within the joint. The impacts of IL-6R blockade treatment effects can be observed when explored from both a clinician's perspective through clinical efficacy outcome measures, and also when viewed from a patient's perspective through the use of patient-reported outcome assessments, which measure variables including pain, physical functioning, and sleep disturbance.
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Funding {#FPar1}
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This review was funded by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA). The Rapid Service Fee was funded by Sanofi Genzyme.
Medical Writing Assistance {#FPar2}
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Medical writing support (Matthew Howes, PhD, of Adelphi Communications Ltd, Macclesfield, UK) under the direction of the author was provided by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA) in accordance with Good Publication Practice (GPP3) guidelines.
Authorship {#FPar3}
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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosures {#FPar4}
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Ennio G. Favalli has received consulting fees and/or speaking engagements from AbbVie, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Sanofi Genzyme, and Union Chimique Belge.
Compliance with Ethics Guidelines {#FPar5}
=================================
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data Availability {#FPar6}
=================
Data sharing is not applicable to this article as no datasets were generated or analyzed.
Open Access {#d30e4072}
===========
This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\'s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\'s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit <http://creativecommons.org/licenses/by-nc/4.0/>.
| {
"pile_set_name": "PubMed Central"
} |
On this website you will find lots of information about this exciting picture book.
Click around to see what surprises you find.
For up-to-date news, book signings, and author events, please follow these links:
Abraham's Facebook Author Page: www.Facebook.com/TheGentlemanBat
Ripple Grove Press Events Page: www.RippleGrovePress.com/new-events
Sign up for Abraham's Mailing List!
Piotr Parda's beautiful solo book is now available!
Look for Graduation Day, a sweet, beautiful, wordless picture book,
for anyone who has graduated from anything, or anyone who has ever faced bullying with beauty,
written and illustrated by Piotr Parda, wherever books are sold!
Abraham Schroeder's second book is now available!
Check out this zany story written by Abraham Schroeder and illustrated by Micah Monkey.
Sign up for Abraham's Mailing List! | {
"pile_set_name": "OpenWebText2"
} |
Since the Duterte administration crafted its first budget in 2017, the OP has been allotted a total of P2.5 billion for its sensitive activities. But it came as a shock to lawmakers and critics, as the OP's allocation is 400% more than the previous administration's confidential and intelligence funds. The Aquino administration kept a much lower budget of P500 million a year. | {
"pile_set_name": "OpenWebText2"
} |
Yesterday, Japanese RPG specialist Square Enix published a new Final Fantasy IV trailer on its YouTube channel.
Pretty unexciting, right? Wrong. In fact, you couldn't be more wrong.
"The Final Fantasy mobile revolution begins... Final Fantasy V and more...," a brief message at the end of said video (see below) reads. Those cryptic cats.
So, what does it all mean?
Well, it looks as though Squeenix is planning to port excellent SNES adventure Final Fantasy V and several other titles from its award-winning catalogue over to the iPhone, iPad, and Android-powered devices.
Fingers crossed we can all play Final Fantasy IV: The After Years and Crisis Core: Final Fantasy VII on our smartphones in the near future. | {
"pile_set_name": "Pile-CC"
} |
The benefits of school-based condom availability: cross-sectional analysis of a comprehensive high school-based program.
Abstract
OBJECTIVES:
To analyze the benefits of a school-based condom availability program relative to the risks that such a program may incur.
METHODS:
A confidentially-administered survey instrument was completed by 152 randomly selected high-school students (approximately 14% of the entire student population).
RESULTS:
The respondents had a mean age of 15.9 years (range: 14-19 years) and a proportionate gender distribution. Ninety-three percent of all respondents had "heard of" the school's program and knew from whom they could receive condoms. Twenty-six percent of the respondents had received condoms from the program with 67% using them. Of those receiving condoms but not using them, more than half did not need them, owing to absence of anticipated sexual activity. Of the nonreceivers, 53% had never had sexual intercourse and 27% received condoms from other sources. The benefit of the program by aiding a sexually-active student was found to be more than three times as great as the risk of encouraging a nonsexually active student to have sexual intercourse (RR = 3.2; 95% C.I. = 2.1, 4.9). The prevalence of sexual activity among all respondents was not significantly higher than the state's average based on gender and age (59.8% vs. 54.5%; z = 1.24, p > .05, n.s.).
CONCLUSION:
Given the lack of increased sexual activity and the favorable benefit-risk ratio, we conclude that school-based condom availability is successfully utilized by sexually-active adolescents and may be an effective means to reduce potentially harmful outcomes, such as unintended pregnancy and sexually-transmitted diseases. | {
"pile_set_name": "Pile-CC"
} |
Inception and validation of a pressure ulcer risk scale in oncology.
To create and validate a specific tool to evaluate the pressure ulcer risk in cancer patients. The Pressure Ulcer Scale in Oncology (PUSO) was developed and subsequently validated against the Norton and Braden scales in order to efficiently and reliably evaluate the pressure ulcer risk in adult cancer patients, with various sites and stages of the illness (both curative and palliative phases). Two series of prevalence surveys (three surveys over two days, at two-month intervals) were conducted in one and then two French Cancer Centres in 2002 and 2009, respectively. The surveys investigated a total of 933 patients. Multivariate logistic regression analysis identified three key items as being predictive of the development of pressure ulcers in cancer patients (mobility, incontinence and moisture/shearing), all with similar odds ratio weighting. A score was defined using this logistic model, the PUSO score (0-3)=bedridden/chair-ridden + incontinence + moisture/shearing. The extreme simplicity of this scale may appear disconcerting, but the PUSO is a simple, reliable and validated tool, which allows standardised evaluation of each patient's risk and, thereby, rapid introduction of appropriate measures. | {
"pile_set_name": "PubMed Abstracts"
} |
Q:
How do i make my windows command line more user friendly for running Ruby on rails?
I am new to RoR and am looking for a way, if possible, to make the Windows command line more user friendly like the mac system. Specifically an easier way to copy and paste, such as using short cut keys, but other suggestions are welcome to. So far I have managed to re-size the window and change the font and font size.
Please keep in mind that i am not technically proficient in this area and answers with steps would be greatly appreciated.
Thanks
A:
Download GitBash :D
Here's a link: GitBash installation links and howto
It'll use bash instead of window's CLI, and makes stuff like GIT or SSH a breeze.
How to copy and paste the output of commands/files to clipboard with gitbash
Link
| {
"pile_set_name": "StackExchange"
} |
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<dependencies>
<plugIn identifier="com.apple.InterfaceBuilder.IBCocoaTouchPlugin" version="13104.12"/>
<capability name="Safe area layout guides" minToolsVersion="9.0"/>
<capability name="documents saved in the Xcode 8 format" minToolsVersion="8.0"/>
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<scene sceneID="tne-QT-ifu">
<objects>
<viewController id="BYZ-38-t0r" customClass="ViewController" customModuleProvider="target" sceneMemberID="viewController">
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<viewLayoutGuide key="safeArea" id="6Tk-OE-BBY"/>
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| {
"pile_set_name": "Github"
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Kristy, Shelly Wels - Sapphic Pleasures (2014) HD
Two horny cuties, one couch and a lot of free time at hand. Kristy and Shelly make the best out of the situation, licking, fingering and kissing each other. Rock-hard nipples rub together, wiggly tongues explode wet folds and in general the girls have a fantastic time in this Sapphic half an hour.
Название: Sapphic PleasuresГод выхода: 2014Выпущено: ClubSandy/21sexturyЖанр: LesbiansВ ролях: Kristy, Shelly WelsПродолжительность: 21mn 5s | {
"pile_set_name": "Pile-CC"
} |
Opinion
Hot Topics:
HICKS: Election flier wrong on many levels
Posted:
11/19/2012 10:45:47 AM EST
Updated:
11/19/2012 11:00:59 AM EST
T here's already enough about the electoral/political process I don't like; I certainly don't need more to add to my list.
Yet there it was a few days before Election Day, a letter from Americans for Limited Government, a self-described non-partisan network committed to promoting free-market reforms, private property rights and basic American liberties.
Its main focus is on tax and spending reforms, property rights, political term limits and limiting the size of government.
I am not a member, nor have I ever been a member.
But to be honest, after reading about the organization on its website, I agree with much of what it seems to stand for.
If only it hadn't sent the pre-election letter.
Because now I don't trust them any farther than I can throw them, and that's not more than 10 or 12 feet.
The letter, sent to my home and the homes of six of my immediate neighbors in Shiloh, is thanking us for our "dedication to voting in past presidential elections."
And then it pats us on the back: "Our American democracy is stronger because of civic-minded citizens like you."
So far, so good. If only it had stopped right there.
It didn't.
Instead, it followed with this: "We have conducted an audit of public voting records in your neighborhood, and wanted to present you with findings of past civic participation in your community."
What followed was a chart titled "Vote History Audit," which included first and last names, street addresses, and whether we voted in the 2004 and 2008 presidential elections.
This was all about politics. National politics at that.
My first reaction, even though the information is a matter of public record available to anyone who wants to take the time to research it, was that it felt like an invasion of my privacy.
To what end? I asked myself out loud. What purpose does this audit and mailing serve?
The ALG further advised it would be updating its records after the Tuesday, Nov. 6, 2012, general election, and it would be sending "an updated vote history audit to (me) and my neighbors with the results."
Did ALG think it was twisting my arm to vote? Did it think it was providing some necessary pressure to push me in the direction of a voting booth? Was it performing some useful community service?
None of the above. All it did was tick me off.
And what I was most ticked off about is the information they were sending hither and yon to all my neighbors and goodness knows who else, is wrong. It's just not accurate. It says I didn't vote in 2004, when I did.
To the best of my knowledge I've never missed a vote in my adult life.
Just to make sure of that, I called the York County Department of Elections and Voter Registration and spoke to Lisa. I explained to her the reason for my call and was surprised when she said the elections bureau had received a bunch of complaints from York countians about the ALG mailer.
They, too, were irate about the inaccuracy of the information in the mailing.
Just to be sure, I said, could you check to see what my voting record is? She could and she did. Since 1990, which is as far back as the county records go on computer, I have not missed voting in any primary or general election.
So Lisa suggested I contact the Pa. Department of State Division of Elections and Voter Registration. I did, and guess what? It had received tons of calls, as well, from disgruntled citizens protesting the inaccuracy of the mailer.
So then I contacted ALG down in Fairfax, Va., and poor Robert got to listen to me rail on about the inaccuracy of the information as it related to me personally.
Robert said the purpose of the mailer was to encourage people to vote on Election Day.
But that didn't fly with me.
If you're going to mail this thing out at such great expense, I said, then why not make sure it's accurate? What's the point of being wrong when you could just as easily be right?
Because now I can't take anything in it seriously, I told him. If the information is wrong about me, I must assume it's wrong about everyone in my neighborhood.
Robert listened. He said he'd take my name off the mailing list.
More research on this mailing by ALG shows York County and other areas of Pennsylvania weren't the only recipients. As it turns out similar mailings were made to voters in 19 states -- all battleground states, I'll betcha.
And apparently they were just as inaccurate in the other 18 states as they were in Pennsylvania and York County. Almost 3 million people received the mailing, according to an ALG official.
This mailing is said to have cost $1 billion. That's a total waste of money, funds that could have been put to much better use -- reducing the national debt, for example.
Worse, it's about peer pressure, shaming people into voting because they don't want their neighbors to think badly of them.
On so many levels, it's wrong.
And it's just one more thing on a long list of things that leave a bad taste in my mouth about the political process. | {
"pile_set_name": "Pile-CC"
} |
Um Rawaba District
Um Rawaba is a district of North Kordofan state, Sudan.
References
Category:Districts of Sudan | {
"pile_set_name": "Wikipedia (en)"
} |
Dataflow machine is a computer in which the primitive operations are triggered by the availability of inputs or operands. It is different from classical von Neumann machines, where there is the concept of sequential flow of control, and an operation (i.e. instruction) is performed when flow of control reaches that operation. Today dataflow machines may not be fully leveraged, in particular, with respect to execution of nested program loops. | {
"pile_set_name": "USPTO Backgrounds"
} |
Q:
Protect cell depending on other cell's value
I have an Excel spreadsheet where I want to protect cells in column I if the respective cell of column H <> "yes".
I found a code but it will protect all the cells of column I.
Option explicit
Sub unprotected
Me.unprotect password:= "abc"
End sub
Sub protect
Me.protect userinterfaceonly:= true ,password:= "abc"
End sub
Private Sub Worksheet_change(ByVal Target As Range)
Dim Crow as Long
Call Unprotected
xrow = Target.Row
If not (intersect(Target, range("H3:H1000")) is nothing then
Cells(xrow, "I").locked = (Ucase(trim(cells(xrow, "H").value))<>"yes")
End if
Call protect
End sub
A:
Try this:
Option Explicit
Const PW As String = "abc" '<< use a constant for fixed/shared values
Private Sub Worksheet_change(ByVal Target As Range)
Dim rng As Range, c As Range
'find changed cells in range of interest
Set rng = Application.Intersect(Target, Me.Range("H3:H1000"))
If Not rng Is Nothing Then
UnprotectMe
'process each cell
For Each c In rng.Cells
Me.Cells.Cells(c.Row, "I").Locked = _
(UCase(Trim(Me.Cells(c.Row, "H").Value)) <> "YES")
Next c
ProtectMe
End If
End Sub
Sub UnprotectMe()
Me.Unprotect Password:=PW
End Sub
Sub ProtectMe()
Me.protect userinterfaceonly:=True, Password:=PW
End Sub
| {
"pile_set_name": "StackExchange"
} |
Tiger wrote:and is nobody on this board ever going to criticize the Sedins? 3 penalties .. and no scoring? Ballard ? wtf.. Defence? Other than Garrison and Alberts it sucks
No. You don't criticize the Sedins. It's an unwritten law. I used to break it on the old site, got ripped for it.
Personally I think that the coach(es) has to take responsibility here. The Twins are great players, but the aren't effective right now. A good coach, worth his salt, can get players to shoot and take advantage of golden opportunities rather than just passing endlessly in an attempt to make the pretty play that fools everyone and look so smart. If a regular player doesn't respond to a coach, and they still aren't scoring, then generally the player is moved. If it is a star player, then generally the coach is moved. Neither has happened here. So in this, I will defer to RD and point the finger at Gillis as well as Vigneault and the Sedins. But I will still fault Vigneault and Gillis more than the players. Vigneault for not holding EVERY player accountable and making them earn their minutes. Gillis for not axing Vigneault.
Meds wrote:While I'm typing and giving Ballard some credit tonight, he combines with Burrows to screw up and it's in our net.
How many games now is this where we've watched the Canucks play the majority of their game trying to get the puck out?
Is it the players or is the "system" just ineffective against hard forechecking and aggressive attackers?
Considering AV put Ballard on almost immediately, I think there's culpability on both Burr and Ballard.
Nobody is having a good game including Schneider who looks completely out of sorts.
Sorry, never mind.
Geezes fucking christ man. These are your Canucks at their absolute worst. I'd love to say, forget this one and move on but this is really fucking bad...
These are the Canucks as they have been ALL SEASON LONG. The difference has been the goaltending of Roberto Luongo, first, and then Cory Schneider. Tonight they didn't get the goaltending. This is what happens. Every night this year where they have not gotten all-star goaltending the Canucks have looked worse than the Edmonton Oilers and Calgary Flames.
Obviously it's very hard to win when you aren't getting any shots on net, but when you are getting 37+ shots through and only scoring one goal.....something is very wrong.
3 of the goals that Dallas scored Cory gets a pass on. 2 of them he could have had. Doesn't matter. His team is only scoring 1 goal. | {
"pile_set_name": "Pile-CC"
} |
Q:
Report labels match a dropdown in report builders
I have a report that is designed to allow users who aren't proficient in Tableau visualize data in the form of a bar graph. There are some drop downs on the side that allow them to select some dimensions. These dimensions then populate the graph. The labels in the graph, however, do not match the dimension name selected, and I was curious how to do this. So for instance on the right hand side Dimension 1 is set to Item Subcategory, and I'd like it to say that in the graph as well, instead of being labeled Dimension 1.
The drop downs on the right are generated from this code in the dimension itself:
If anyone has any ideas on how to do this, I'd really appreciate it. Thanks!
A:
The way I would do this would be to hide the column headers on the sheet itself, or edit their aliases to just a bunch of spaces so it appears blank.
You can then create a sheet with the Dimension 1 parameter on the Text shelf, formatted to look like a column header (or formatted however you want it to look), and add that sheet to the dashboard as a floating sheet. Repeat for the other two dimension parameters, position the sheet above the column so it looks like the header, and there you go! Whenever the parameter changes, the column header will change to match too.
I would note that this only works if the sheet is on a fixed-size dashboard, since floating sheets don't usually play nice with auto-sizing dashboards.
| {
"pile_set_name": "StackExchange"
} |
1671 in music
The year 1671 in music involved some significant musical events.
Events
March 3 – Opening of the Paris Opera, with an opera by Robert Cambert.
Philippe Quinault, Molière and Pierre Corneille, collaborate with Jean-Baptiste Lully on a court entertainment.
Arcangelo Corelli settles in Rome after spending four years studying violin in Bologna.
Maurizio Cazzati is dismissed from his post as Maestro di Cappella in San Petronio, Bologna, as a result of controversy over his alleged failure to enforce the rules of counterpoint, and returns to Mantua where he spends the rest of his career as Maestro di Cappella da Camera to Duchess Isabella.
Ignazio Albertini arrives in Vienna with a letter of recommendation from Johann Heinrich Schmelzer.
Published popular music
Classical music
Johann Georg Ahle – Neues Zehn Geistlicher Arien
Giovanni Legrenzi – Op. 8, a collection of sonatas
Andreas Hammerschmidt – Sechsstimmige Fest- und Zeit-Andachten
Guilliaume-Gabriel Nivers – Antiphonarium romanum
Heinrich Schütz – Meine Seele erhebt den Herren, SWV 494
Denis Gaultier – Pièces de Luth sur trois différents modes nouveaux
Opera
Robert Cambert – Pomone
Antonio Pietro Degli – L'inganno fortunato
Antonio Draghi – L'avidità di Mida
Domenico Freschi & Gasparo Sartorio – Iphide greca
Births
February 19 – Charles-Hubert Gervais, composer (died 1744)
May 21 – Azzolino Bernardino della Ciaja, organist, harpsichordist, composer and organ builder (died 1755)
June 8 – Tomaso Albinoni, composer (died 1751)
June 16 – Johann Christoph Bach, musician and composer (died 1721)
June 30 – Teodorico Pedrini, priest, missionary, musician and composer (died 1746)
September – Antoine Forqueray, viola da gamba virtuoso and composer (died 1745)
probable – Robert Valentine, recorder player and composer (died 1747)
Deaths
date unknown – Daniel Farrant, composer, viol player and instrument maker (born 1575)
References
Music
Category:17th century in music
Category:Music by year | {
"pile_set_name": "Wikipedia (en)"
} |
The Cullin-RING ubiquitin E3 ligase (CRLs) super-family is responsible for much of the signal-dependent protein turnover in eukaryotes. CRL specificity derives from the identity of the substrate adaptor, which often interacts with the substrate in a modification-dependent manner. With more than 200 distinct CRL substrate adaptor proteins for the 7 human cullins, the CRL system controls many facets of biology that impinge on disease and aging. However, our understanding of CRL-substrate relationships is largely limited to a few well- studied adaptors, with many CRL adaptors remaining unstudied. We have taken a multi-pronged approach that uses Global Protein Stability (GPS) profiling, quantitative diGLY capture proteomics, and substrate capture by interaction proteomics using specific CRL substrate adaptors to identify more than 600 high priority candidate CRL substrates. Nevertheless, thus far only a portion of the human proteome has been sampled for substrates and that vast majority of candidate CRL substrates have yet to be paired with the appropriate CRL substrate adaptor protein (such as an F-box protein). To address these major limitations, we propose the following aims: 1) AIM 1 will provide a more comprehensive database of candidate CRL substrates in human cells through further development and screening of a v3.0 GPS system, thereby accessing components of the proteome that are not accessible through the current v2.0 system. Improvements will include new C-terminally tagged GPS libraries, bar-coding, as well as Next-gen sequencing of sorted libraries, thereby avoiding limitations of microarray hybridization methods currently employed. 2) AIM 2 will utilize focused high throughput screening and quantitative diGLY proteomics to specifically link high priority candidate substrates to specific cullins and will use both GPS and RNAi screening, as well as interaction proteomics, to link CRL1 substrates with specific F-box protein adaptors, followed by extensive validation. This analysis will provide the first large-scale analysis of the CRL1-F-box system in mammals. 3) AIM 3 will produce a web-based database for dissemination and analysis of CRL-substrate relationships by the community. In addition, selected high priority candidate substrates and the corresponding F-box adaptor proteins will be analyzed through biochemical and cell biological methods to place these proteins into regulatory and physiological pathways with an initial focus on a BACH1, a signal-dependent transcriptional repressor of NRF2-dependent genes and a novel substrate of SCFFBXL17 discovered via our proteomics platform. Together, this work will substantially improve our understanding of the CRL-substrate landscape and will set the stage for in-depth studies that further define signals that dynamically control the proteome via CRLs. | {
"pile_set_name": "NIH ExPorter"
} |
Q:
What should I be trying my hand at to practice composing?
I don't really know how to play any instrument, but I do have some USB keys that I have plinked with in Garageband.
I'm not interested so much in learning to perform my works. I enjoy and am inspired by the chiptune musical aesthetic. I can get my head around how to enter notes into samplers and multitrackers (such as Milkytracker, Nanoloop, and the ilk). I have experience using Reaper for podcast editing also. I am confident I can USE the tools. I am interested in learning music theory too, and have got resources to learn that stuff as I need it.
I know my first stuff will 'suck' but like Jake the Dog said, sucking at something is the first step to being sorta good at something.
What I'm asking here is this: With all that in place, what should I be attempting to do with all my tools and knowledge? What should I try my hand at? What exercises should I be doing?
A:
I recall an interview with Jack Black in which he was asked advice for people who wanted to play rock music. His advice was (paraphrasing) "Copy from the masters. Learn the classics".
His advice was for guitarists - learn to play some Led Zep songs, by whatever means you can -- analysing recordings and videos yourself, looking at guides from guitar magazines, experimenting. By doing that you'll learn how that style of music fits together - how the rhythm, harmony and melody all work.
Then you'll be able to use what you've learned to put together your own original compositions.
I don't know whether Jack Black is a great musical role-model, but I do think that's good advice, and I think it applies to your chiptune ambitions.
Take a piece of music you like, and sequence your own version in the tool of your choice. You can try and make it as faithful to the original as possible, or you can adapt it with your own choice of instruments and arrangement.
It's probably worth reading a theory book early on. It will help you recognise structural elements of the piece you're working on.
A:
Finale is a great sheet-music based music composition program. It offers playback with decent sounding virtual instruments. I've heard good things about Sibelius. Both have free versions. Check out this wikipedia list for similar programs.
As far as learning to compose, I would give species counterpoint a try. While it may seem distant from your ultimate musical interests, a basic understanding of counterpoint can clear up a lot of confusion about the cooperation of harmony and melody. Employing any amount of counterpoint will make your music much stronger (frankly, it's far under-appreciated in popular music). I used Norton's Fundamental Counterpoint as an introduction to species counterpoint, and still use it as a reference. Giovanni Dettori's Art of counterpoint series was a good watch, focusing less on the details of strict counterpoint and giving a good overview with a nice little example fugue constructed at the end. A basic understanding of harmony, as can be found all over, will be useful for these studies. One big thing to take away from counterpoint is how to avoid cluttering your music with too many clashing melodies.
Depending on how interested in harmony you are, try the following noodle-tactics (definitely take your time). Mess around with chord progressions on your keyboard. Start with the chords of the diatonic scale. Play chords in the left hand, running melodies (in the diatonic scale) on your right. C major is nicely contained in the white keys. Try focusing on root motion in fourths, seconds, and sixths. For example, play C to F (fourth) to G (second) to Emin(sixth) to Amin (fourth) to Dmin (fourth) to G (fourth) to C (fourth). Motion up a fourth is especially powerful. Try adding in extra notes from your scale to your triads. When you play the dominant chord of a scale, try throwing in the subdominant note, making a dominant seventh chord. As a way to become familiar with all keys, move down the circle of fiths by moving up perfect fourths, playing the major chord of each. So, Cmaj to Fmaj to Bbmaj to Ebmaj, etc. Experiment with making some of them dominant seventh chords, and some of them minor chords. Focus on the sound of each device.
Try just messing with single line melody (diatonic at first, slowly trying out accidentals). It may seem really boring at first, but getting an ear for how melody works without accompaniment makes your melodies more robust for adaptation to your various harmonies.
Get a feel for how rhythm affects all these things. Syncopation is fun.
Afraid I don't know much on how to best use the electronics! The sound of an instrument affects a lot though. Try not to over-complicate your sound with too much chorus-like effects and distortion.
When it comes to composing and being creative (which you always occasionally be doing), use the cool stuff you've experimented with, but check in with your heart every so often. Try composing to some simple forms. Make a chorus and a verse and put them together. Or don't think of them as choruses and verses and experiment combining pieces into bigger objects in general. Even simple melodies are made of pieces. Consciously mess with structure and get a feel for overall flow. Every so often, stop and just listen to what you've got with a clear head.
Play to your dog. If you're outside, play to the trees. When you play for your crush, keep it simple, stupid, and make up some gushy lyrics.
| {
"pile_set_name": "StackExchange"
} |
Hu Bo
Hu Bo (, 20 July 1988 – 12 October 2017), also known by his pen name Hu Qian (), was a Chinese novelist and film director, best known for his only feature film An Elephant Sitting Still (2018). He died by suicide on 12 October 2017 at the age of 29, soon after he finished that film.
Personal life
Born in 1988 in Jinan, Shandong, China, Hu Bo graduated from Beijing Film Academy with a degree in Film Directing in 2014. His short film Distant Father (2014) won Best Director at the 4th Golden Koala Chinese Film Festival.
His two novels Huge Crack and Bullfrog, both published in 2017, caused a sensation in China.
The production of his first feature An Elephant Sitting Still (2018), based on a story with the same title from his 2017 novel Huge Crack, began in July 2016. He took his own life soon after finishing the film on 12 October 2017 at the age of 29, making it his first and last feature film. According to reports, his death was due to the conflicts with his producers Liu Xuan and Wang Xiaoshuai.
Novels
Huge Crack (大裂) (2017)
Bullfrog (牛蛙) (2017)
Farewell to the Faraway (远处的拉莫) (2018)
Filmography
Distant Father (short, 2014)
Night Runner (short, 2014)
Man in the Well (short, 2017)
An Elephant Sitting Still (2018)
Awards
2014 - 4th Golden Koala Chinese Film Festival: Best Director (Distant Father)
2018 - 55th Golden Horse Awards: Best Adapted Screenplay (An Elephant Sitting Still)
References
External links
Category:1988 births
Category:2017 deaths
Category:Film directors from Shandong
Category:Screenwriters from Shandong
Category:Writers from Jinan
Category:Film directors who committed suicide
Category:Suicides in the People's Republic of China
Category:People's Republic of China novelists | {
"pile_set_name": "Wikipedia (en)"
} |
Q:
How to get the index of the element by class that is clicked
I have this code:
<button class="remove" value="1" />
<button class="remove" value="2" />
<button class="remove" value="3" />
$(document).on('click', ".remove", function(e) {
alert($(this).index());
});
It is always alerting 0. If the user clicked the button that has a value of 2, it must alert 1 but in my code it alerts 0.
A:
depending on what you want to finally achieve and assuming that:
<button class="remove" value="34" data-myval="a"/>
<button class="remove" value="33" data-myval="b"/>
<button class="remove" value="32" data-myval="c"/>
if you want to get the value of 'value':
$(document).on('click', ".remove", function(e) {
alert($(this).val());
});
if you want to get the index of what was clicked:
$(document).on('click', ".remove", function(e) {
alert($(this).index());
});
if you want to get a custom value:
$(document).on('click', ".remove", function(e) {
alert($(this).data('myval'));
});
| {
"pile_set_name": "StackExchange"
} |
Mexico national handball team
La selección mexicana de balonmano es la selección nacional de Mexico. Participa en competiciones internacionales de balonmano.
Campeonato Panamericano Puestos
1979: 6to lugar
1981: 5to lugar
1983: 5to lugar
1985: 4to lugar
1989: 5to lugar
1994: 5to lugar
1996: 6to lugar
1998: 7mo lugar
2000: 7mo lugar
2002: 7mo lugar
2004: 8vo lugar
2006: 7mo lugar
Juegos Centroamericanos y del Caribe
Copa caribeña de Handball
Campeonato NOR.CA
References
External links
Official website
IHF profile
Handball
Category:National handball teams | {
"pile_set_name": "Wikipedia (en)"
} |
Search form
Wind will increase fire activity throughout the Interior
A major wind event is forecast to hit the Cariboo and southern British Columbia today, bringing gusts of up to 70 kilometres per hour to some areas.
These winds are expected to persist well into Sunday.
Given the current wildfire situation throughout the Interior, the BC Wildfire Service anticipates that this weather system will lead to a substantial increase in wildfire activity throughout the region.
This wind could cause significant growth of current wildfires and new fires may burn and spread aggressively. Firefighting crews have spent the last few days preparing for this wind event, but containment efforts will be challenged by hot and dry conditions and gusting winds.
Given the proximity of existing wildfires to communities, infrastructure and transportation corridors, people throughout the Cariboo region and the southern Interior should be prepared for potential evacuations.
Provincial parks and recreation sites in the Cariboo are already closed to the public. The BC Wildfire Service urges everyone to also stay out of the backcountry in the affected areas, given the potential for extreme fire behaviour.
For up-to-date information on current evacuation alerts and evacuation orders, check your local government's website or the Emergency Management BC website at: www.emergencyinfobc.gov.bc.ca
For the most recent information on highway conditions and road closures, check: www.DriveBC.ca (http://www.drivebc.ca/)
To report a wildfire or open burning violation, call 1 800 663-5555 toll-free or *5555 on a cell phone. For the latest information on current wildfire activity, burning restrictions, road closures and air quality advisories, visit: http://www.bcwildfire.ca | {
"pile_set_name": "Pile-CC"
} |
REMEMBER THAT CONFIDENCE YOU JUST HAD THAT YOU DELETED YOUR HISTORY BEFORE YOU GAVE YOUR GIRLFRIEND YOUR LAPTOP? HERE, LET ME GET RID OF THAT FOR YOU
219 shares | {
"pile_set_name": "OpenWebText2"
} |
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