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Introduction:Allergic diseases affect both children and adults, but generation-specific prevalence rates are unclear.Methods:An online questionnaire was used from December 2021 to January 2022 to survey the prevalence of allergic diseases among staff and their families of designated allergic disease medical hospitals in Japan. In this study, bronchial asthma (BA), atopic dermatitis (AD), food allergies (FAs), allergic rhinitis (AR), allergic conjunctivitis (AC), metal allergies (MAs), and drug allergies (DAs) were the allergic diseases surveyed.Results:In total, 18,706 individuals were surveyed (median age, 36 years; quartile range, 18-50). Allergic disease was reported in 62.2% of respondents. Across all ages, prevalence rates were as follows: BA (14.7%), AD (15.6%), FAs (15.2%), AR (47.4%), AC (19.5%), MAs (1.9%), and DAs (4.6%). The prevalence of BA and AR was higher in male children, whereas that of FAs and AC was higher in adult females. The prevalence of MAs and DAs peaked during adulthood and predominated among females.Conclusions:Our results suggest that approximately two-thirds of the Japanese population may have an allergic disease, with AR being the most prevalent.
The loss of cardiomyocytes (CMs) after myocardial infarction (MI) is widely acknowledged to initiate the development of heart failure (HF). Herein, we found that circCDYL2 (583 nt) derived from chromodomain Y-like 2 (Cdyl2) is significantly upregulated in vitro (oxygen-glucose deprivation (OGD)-treated CMs) and in vivo (failing heart post-MI) and can be translated into a polypeptide termed Cdyl2-60aa (~7 kDa) in the presence of internal ribosomal entry sites (IRES). Downregulation of circCDYL2 significantly decreased the loss of OGD-treated CMs or the infarcted area of the heart post-MI. Additionally, elevated circCDYL2 significantly accelerated CM apoptosis via Cdyl2-60aa. We then discovered that Cdyl2-60aa could stabilize protein apoptotic protease activating factor-1 (APAF1) and promote CM apoptosis; heat shock protein 70 (HSP70) mediated APAF1 degradation in CMs by ubiquitinating APAF1, which Cdyl2-60aa could competitively block. In conclusion, our work substantiated the claim that circCDYL2 could promote CM apoptosis via Cdyl2-60aa, which enhanced APAF1 stability by blocking its ubiquitination by HSP70, suggesting that it is a therapeutic target for HF post-MI in rats.
BackgroundNo universally accepted guidelines exist for treatment of patients with colorectal cancer peritoneal metastases (CRPM) undergoing cytoreductive surgery and intraperitoneal chemotherapy (CRS/IPC). Several uncertainties remain concerning almost every aspect of this treatment modality, resulting in marked variability in patient management and likely outcomes. This survey aimed to define variations and trends in clinician decision making more clearly.MethodsA 41-question web-based survey was distributed electronically via the Peritoneal Surface Oncology Group International (PSOGI), the International Society for the Study of Pleura and Peritoneum (ISSPP) as well as via social media (particularly Twitter). The survey sought to address and record clinician responses regarding patient workup/assessment, selection for preoperative systemic therapy, preoperative and intraoperative selection for CRS/IPC, and consideration of prognosis and complications.ResultsComplete responses were received from 60 clinicians from 45 centres in 22 countries. Upon assessment of survey responses, several interesting trends were noted in each section of the survey. Significant variability in surgeon practice and opinion were identified concerning almost every aspect of the treatment modality.ConclusionThis international survey provides the most comprehensive insight into clinician decision-making trends regarding patient assessment, selection and management. This should allow areas of variability to be more clearly defined and could potentially prompt development of initiatives for achieving consensus and standardisation of care in the future.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-022-12794-5.
BackgroundSleep disorders are one of the most common problems in children with Autism Spectrum Disorder (ASD). However, they often tend to be underdiagnosed and incorrectly treated in clinical practice. This study aims to identify sleep disorders in preschool children with ASD and to explore their relationship with the core symptoms of autism, the child’s developmental and cognitive level as well as the psychiatric comorbidities.MethodsWe recruited 163 preschool children with a diagnosis of ASD. The Children’s Sleep Habits Questionnaire (CSHQ) assessed sleep conditions. Multiple standardized tests were used to evaluate intellectual abilities, the presence of repetitive behaviors (through the Repetitive Behavior Scale-Revised), as well as the emotional-behavioral problems and the psychiatric comorbidities (through the Child Behavior Checklist -CBCL 11/2-5).ResultsThe results showed that poor disorders had consistently higher scores in all areas assessed by the CSHQ and on the CBCL across all domains. The correlational analysis showed that severe sleep disorders were associated with higher scores in internalizing, externalizing, and total problems at the CBCL syndromic scales, and in all DSM-oriented CBCL subscales. Moreover, we found that the association between sleep disorders and restricted and repetitive behaviors (RRBs) is explained by the anxiety-related symptoms.ConclusionBased on these findings, the study recommends that screening for sleep problems followed by early intervention should constitute a routine part of clinical practice for children with ASD.
BackgroundPregnancy-induced hypertension is the new onset of high blood pressure after 20 weeks of gestation in women with previously normal blood pressure. To the best of our knowledge, no study has been conducted in our country to investigate the association between this pregnancy problem and iron-folic acid supplementation. The aim of this study was to determine the association between iron-folic acid supplementation and pregnancy-induced hypertension (PIH) in pregnant women at public hospitals in the Wolaita Sodo zone.MethodsAn institution-based case–control study was conducted among pregnant women who visited public hospitals in the Wolaita Sodo zone from March 3, 2022, to August 30, 2022. A consecutive sampling method was used to select the study participants. The total sample size was 492, of which 164 were cases and 328 were controls. The data were collected by conducting face-to-face interviews and measurements. The data were entered into EpiData version 4.6 and exported to STATA 14 for analysis. Those variables with ap-value less than 0.05 were considered statistically significant. Descriptive statistics and odds ratios were presented using texts, tables, and figures.ResultsA total of 471 women participated in this study, yielding a response rate of 96%. The cases had a mean age of 25 ± 4.43, while the controls had a mean age of 25 ± 3.99. The mean age at first pregnancy among cases was 20 ± 2.82 and among controls was 20 ± 2.97. The average number of deliveries for cases and controls was 1.97 ± 1.41 and 1.95 ± 1.38, respectively. There is no significant association between iron-folic acid supplementation and PIH. Pregnant women with high hemoglobin levels had higher odds of PIH as compared to those without it (AOR = 3.65; 95% CI: 1.0–12.9). Eating kocho (AOR = 14.4; 95% CI: 1.2–16.7) was positively associated with PIH.ConclusionsThere is no association between iron-folic acid supplementation during pregnancy and pregnancy-induced hypertension. Pregnant women with high hemoglobin levels had higher odds of PIH as compared to those without it. There is an association between kocho consumption and PIH. More research should be done using stronger designs.
IntroductionBreast angiosarcoma is a rare malignancy of endovascular origin, accounting for less than 1% of all mammary cancers. Our aim was to explore clinicopathological features and the factors associated with prognosis.MethodsWe extracted information from the Surveillance, Epidemiology, and End Results Program (SEER) for all patients with breast angiosarcoma between 2004 and 2015. Chi-square analysis was used to compare the clinicopathological features in all patients. Overall survival (OS) was assessed using the Kaplan and Meier method. Univariate and multivariate analyses were performed to evaluate the factors associated with prognosis.ResultsA total of 247 patients were included in the analyses. The median OS of patients with primary breast angiosarcoma (PBSA) and secondary breast angiosarcoma (SBAB) was 38 months and 42 months, respectively. The 1-, 3- and 5-year OS with PBSA was 80%, 39%, and 25%, respectively, and the 1-, 3- and 5-year OS with SBAB was 80%, 42%, and 34%, respectively. Multivariate analysis revealed that tumor size (p= 0.001), tumor grade (p< 0.001), tumor extension (p= 0.015), and tumor spread (p< 0.001) were statistically significant factors for OS. Partial mastectomy with radiation (HR = 0.160, 95% CI, 0.036–0.719,p= 0.016), partial mastectomy with chemotherapy (HR = 0.105, 95% CI, 0.011–1.015,p= 0.052), and partial mastectomy (HR = 0.125, 95% CI, 0.028–0.583,p= 0.007) were related to significantly better OS outcomes in primary angiosarcoma.ConclusionPrimary breast angiosarcoma has a better clinical phenotype than secondary breast angiosarcoma. Although overall survival was not statistically significant, primary breast angiosarcoma was better than secondary breast angiosarcoma with systemic therapy. Depending on the outcome of survival, partial mastectomy is effective in treating primary breast angiosarcoma.
ObjectiveTo identify prognostic factors for patients with advanced persistent, recurrent, or 2nd primary oral cavity squamous cell carcinoma (OCSCC) potentially unsuitable for salvage surgery with free tissue flap (FTF) reconstruction.Materials and methodsA population-based cohort of 83 consecutive patients with advanced OCSCC who underwent salvage surgery with FTF reconstruction at a tertiary referral centre between 1990 and 2017. Retrospective uni- and multivariable analyses were performed to identify factors affecting all-cause mortality (ACM), i.e., overall survival (OS), as well as disease-specific mortality (DSM), i.e., disease-specific survival (DSS) after salvage surgery.ResultsMedian disease-free interval until recurrence was 15 months with recurrent stage I/II in 31% and III/IV in 69%. Median age at salvage surgery was 67 years (range 31–87) and the median follow-up (alive patients) 126 months. At 2, 5, and 10 years after salvage surgery, respectively, DSS rates were 61%, 44%, and 37% and OS rates 52%, 30%, and 22%. Median DSS was 26 and OS 43 months. Multivariable analysis identified recurrent clinical regional (cN-plus) disease [HR 3.57;p< .001] and elevated gamma-glutamyl transferase (GGT) [HR 3.30;p= .003] as independent pre-salvage predictors for poor OS after salvage, whereas initial cN-plus [HR 2.07;p= .039] and recurrent cN-plus disease [HR 5.14;p< .001] predicted poor DSS. Among post-salvage factors, extranodal extension according to histopathology [HR ACM 6.11; HR DSM 9.99;p< .001] as well as positive [HR ACM 4.98; DSM 7.51;p< 0.001] and narrow surgical margins [HR ACM 2.12; DSM HR 2.80;p< 0.01] emerged as independent factors for poor survival.ConclusionWhile salvage surgery with FTF reconstruction is the primary curative option for patients with advanced recurrent OCSCC, the present findings may help guide discussions with patients who have advanced recurrent regional disease and high GGT preoperatively, especially if there is a small chance of reaching surgical radicality.
PurposeMammography (MG) is the standard imaging in surveillance of women with a personal history of breast cancer or DCIS (PHBC), supplemented with ultrasound. Contrast Enhanced Mammography (CEM) has higher sensitivity than MG and US. We report the performance of CEM compared with MG ± US.MethodsA retrospective study of patients undergoing their first surveillance CEM in an Australian hospital setting between June 2006 and October 2020. Cases where a patient was recalled for assessment were identified, recording radiology, pathology and treatment details. Blinded re-reading of recalled cases was performed to determine the contribution of contrast. Use of surveillance US across the board was assessed for the period.Results73/1191 (6.1%) patients were recalled. 35 (48%) were true positives (TP), with 26 invasive cancers and 9 cases of DCIS, while 38 (52%) were false positive (FP) with a positive predictive value (PPV) 47.9%. 32/73 were recalled due to MG findings, while 41/73 were only recalled due to Contrast. 14/73 had ‘minimal signs’ with a lesion identifiable on MG with knowledge of the contrast finding, while 27/73 were visible only with contrast. 41% (17/41) recalled due to contrast were TP. Contrast-only TPs were found with low and high mammographic density (MD). Screening breast US reduced by 55% in the year after CEM was implemented.ConclusionCompared to MG, CEM as a single surveillance modality for those with PHBC has higher sensitivity and comparable specificity, identifying additional malignant lesions that are clinically significant. Investigation of interval cancer and subsequent round outcomes is warranted.
AbstractClubroot is a soil-borne disease in cabbage (Brassica oleraceaL. var.capitataL.) caused byPlasmodiophora brassicae, which poses a great threat to cabbage production. However, clubroot resistance (CR) genes inBrassica rapacould be introduced into the cabbage via breeding to make it clubroot resistant. In this study, CR genes fromB. rapawere introduced into the cabbage genome and the mechanism of gene introgression was explored. Two methods were used to create CR materials: (i) The fertility of CR Ogura CMS cabbage germplasms containingCRawas restored by using an Ogura CMS restorer. After cytoplasmic replacement and microspore culture,CRa-positive microspore individuals were obtained. (ii) Distant hybridization was performed between cabbage andB. rapa,which contained three CR genes (CRa, CRb, andPb8.1). Finally, BC2individuals containing all three CR genes were obtained. Inoculation results showed that bothCRa-positive microspore individuals and BC2individuals containing three CR genes were resistant to race 4 ofP. brassicae. Sequencing results fromCRa-positive microspore individuals with specific molecular markers and genome-wide association study (GWAS) showed penetration at the homologous position of the cabbage genome by a 3.42 MbCRacontaining a fragment fromB. rapa; indicating homoeologous exchange (HE) as the theoretical basis for the introgression of CR resistance. The successful introduction of CR into the cabbage genome in the present study can provide useful clues for creating introgression lines within other species of interest.
A fundamental goal in the organogenesis field is to understand how cells organize into tubular shapes. Toward this aim, we have established the hydro-vascular organ in the sea starPatiria miniataas a model for tubulogenesis. In this animal, bilateral tubes grow out from the tip of the developing gut, and precisely extend to specific sites in the larva. This growth involves cell migration coupled with mitosis in distinct zones. Cell proliferation requires FGF signaling, whereas the three-dimensional orientation of the organ depends on Wnt signaling. Specification and maintenance of tube cell fate requires Delta/Notch signaling. Moreover, we identify target genes of the FGF pathway that contribute to tube morphology, revealing molecular mechanisms for tube outgrowth. Finally, we report that FGF activates the Six1/2 transcription factor, which serves as an evolutionarily ancient regulator of branching morphogenesis. This study uncovers distinct mechanisms of tubulogenesis in vivo and we propose that cellular dynamics in the sea star hydro-vascular organ represents a key comparison for understanding the evolution of vertebrate organs.
BackgroundThe growing population of older adults worldwide is associated with an extended life expectancy and an increasing proportion of older adults with dynapenia. Most research on dynapenia has involved only populations of older adults living in the community; little research has examined the effects of risk factors on sleep quality among older adults with dynapenia residing in assisted living facilities.AimThis study examined the relationships among physical function, nutrition, cognitive function, depression, and sleep quality among older adults with dynapenia residing in assisted living facilities.MethodsIn this cross-sectional study, data on physical function, nutrition, cognitive function, depression, and sleep quality was collected from 178 older adults with dynapenia residing in assisted living facilities, who were selected using purposive sampling. Descriptive statistical analysis, independent-samplettests, chi-squared tests, and logistic regression analysis were performed using SPSS 25.0.ResultsThe statistical analyses revealed correlations between sleep quality and age (t= 2.37,p< 0.05), level of education (χ2= 3.85,p< 0.05), grip strength (t= 3.40,p< 0.01), activities of daily living (t= 4.29,p< 0.001), instrumental activities of daily living (t= 2.23,p< 0.001), calf circumference (t= 2.89,p< 0.01), Mini Nutritional Assessment scores (t= 2.29,p< 0.05), Mini Mental State Exam (MMSE) scores (t= 4.50,p< 0.001), and Geriatric Depression Scale (GDS) scores (t= − 4.20,p< 0.001). Calf circumference (OR = 0.8, 95% CI = 0.650.97,p< 0.05), GDS score (OR = 1.42, 95% CI = 1.05–1.92,p< 0.05), and MMSE score (OR = 0.85, 95% CI = 0.73–0.97,p< 0.05) were related to sleep quality among the sample population.ConclusionPhysical function, nutrition, cognitive function, and depression affect the sleep quality of older adults with dynapenia residing in assisted living facilities. Facility nurses must regularly assess these aspects of their patients to ensure that facility-dwelling older adults can maintain their physical function and improve their health to improve the quality of their sleep.
PurposeCurrently used classification systems and measurement methods are insufficient to assess fracture displacement. In this study, a novel 3D measure for fracture displacement is introduced and associated with risk on conversion to total knee arthroplasty (TKA).MethodsA multicenter cross-sectional study was performed including 997 patients treated for a tibial plateau fracture between 2003 and 2018. All patients were contacted for follow-up and 534 (54%) responded. For all patients, the 3D gap area was determined in order to quantify the degree of initial fracture displacement. A cut-off value was determined using ROC curves. Multivariate analysis was performed to assess the association of 3D gap area with conversion to TKA. Subgroups with increasing levels of 3D gap area were identified, and Kaplan–Meier survival curves were plotted to assess survivorship of the knee free from conversion to TKA.ResultsA total of 58 (11%) patients underwent conversation to TKA. An initial 3D gap area ≥ 550 mm2was independently associated with conversion to TKA (HR 8.4;p= 0.001). Four prognostic groups with different ranges of the 3D gap area were identified: excellent (0–150 mm2), good (151–550 mm2), moderate (551–1000 mm2), and poor (> 1000 mm2). Native knee survival at 10-years follow-up was 96%, 95%, 76%, and 59%, respectively, in the excellent, good, moderate, and poor group.ConclusionA novel 3D measurement method was developed to quantify initial fracture displacement of tibial plateau fractures. 3D fracture assessment adds to current classification methods, identifies patients at risk for conversion to TKA at follow-up, and could be used for patient counselling about prognosis.Level of evidencePrognostic Level III.
Pancreatic cancer (PC) is a malignant tumor of the digestive system that has a bad prognosis. N6-methyladenosine (m6A) is involved in a wide variety of biological activities due to the fact that it is the most common form of mRNA modification in mammals. Numerous research has accumulated evidence suggesting that a malfunction in the regulation of m6A RNA modification is associated with various illnesses, including cancers. However, its implications in PC remain poorly characterized. The methylation data, level 3 RNA sequencing data, and clinical information of PC patients were all retrieved from the TCGA datasets. Genes associated with m6A RNA methylation were compiled from the existing body of research and made available for download from the m6Avar database. The LASSO Cox regression method was used to construct a 4-gene methylation signature, which was then used to classify all PC patients included in the TCGA dataset into either a low- or high-risk group. In this study, based on the set criteria of \|cor\| > 0.4 andpvalue < 0.05. A total of 3507 gene methylation were identified to be regulated by m6A regulators. Based on the univariate Cox regression analysis and identified 3507 gene methylation, 858 gene methylation was significantly associated with the patient's prognosis. The multivariate Cox regression analysis identified four gene methylation (PCSK6, HSP90AA1, TPM3, and TTLL6) to construct a prognosis model. Survival assays indicated that the patients in the high-risk group tend to have a worse prognosis. ROC curves showed that our prognosis signature had a good prediction ability on patient survival. Immune assays suggested a different immune infiltration pattern in patients with high- and low-risk scores. Moreover, we found that two immune-related genes, CTLA4 and TIGIT, were downregulated in high-risk patients. We generated a unique methylation signature that is related to m6A regulators and is capable of accurately predicting the prognosis for patients with PC. The findings might prove useful for therapeutic customization and the process of making medical decisions.
BackgroundAlthough hospitalization can be a burdensome experience for all patients, research into the sources of this distress and potential protective factors has so far been scattered, specifically among the broad hospitalized population across all disease types and inpatient units. The present study explores the frequency and nature of the foremost experienced hassles among a sample of Lebanese hospitalized patients, tracing their correlations with depression and anxiety while also investigating positive coping (i.e., perceived social support and spiritual well-being) as potential moderator of these relationships.MethodsA total of 452 Lebanese inpatients from all medical units filled a survey composed of a list of 38 stressors experienced during hospitalization and other measures assessing depression, anxiety, perceived social support, and spiritual well-being.ResultsPain was the most common stressor experienced by the patients (88.9%), followed by the feeling of being overwhelmed (80.3%). When conducting a factor analysis, 18 stressors loaded on 4 distinct factors, hence yielding 4 main stressor groups (i.e., Illness Apprehension, Hopelessness/Uselessness, Social Isolation, and Spiritual Concerns). The multivariable analysis showed that increased illness apprehension (Beta = 0.69) and hopelessness (Beta = 1.37), being married (Beta = 1.17) or divorced (Beta = 1.38) compared to single, being admitted in a two-bed room compared to one-bed (Beta = 1.59), higher financial burden (Beta = 0.24), and lower socio-economic status (Beta = 1.60) were significantly associated with higher anxiety. Additionally, increased hopelessness (Beta = 0.82) and being married (Beta = 0.79) compared to single were significantly associated with higher depression. However, among patients experiencing high levels of stressors, those with high spiritual well-being and perceived social support had lower depressive/anxiety symptoms.ConclusionOur study characterized the principal stressors encountered during hospitalization, underscoring their associations with Lebanese inpatients’ mental health. On the other hand, as perceived social support and spiritual well-being acted as negative moderators of these associations, intervention programs aimed at enhancing such adaptive coping techniques are strongly called upon to palliate the psychological distress of patients in hospital settings.
Gambling disorder is a high comorbid disorder in substance abusers which conjunct appearance is related to worse symptomatology and evolution. Nevertheless, the research on the risk factors that may explain this comorbidity is scarce. We build of the self-regulation theory of attachment and addiction to examine if insecure attachment is related to gambling comorbidity in substance abuse disorder and the mediating role of alexithymia in this process. A cross-sectional study was carried out with 369 clinical patients with substance use disorder of which 69 presented comorbid gambling disorder diagnosed with the DSM-5 criteria. Results showed that insecure attachment was more prevalent in the group with comorbid gambling. In this group, the alexithymia levels were also higher and mediated the relationship in between attachment and gambling disorder comorbidity even controlling for several sociodemographic variables. This research indicates that insecure attachment enhances the risk of gambling comorbidity on substance abusers due to the detrimental effect on the self-regulation of emotion. Thus, interventions directed to increase the identification, expression and awareness of emotions might help to reduce comorbidity of gambling of substance use disorders.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10899-022-10154-2.
BackgroundHigh sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood.MethodsWe employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints.ResultsIn total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes.ConclusionsWe have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13073-023-01184-5.
It is estimated that approximately 280 million people worldwide suffer from depression. Depression is a common disease to us all, and the socioeconomic loss caused by depression is very large. However, there is currently a problem that many depressed patients do not respond to existing antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Therefore, novel and effective therapeutic agents are highly desirable. It has been reported that exercise has preventive effects on depression (antidepressant effects) and that serotonin, whose release increases in the brain with exercise, is involved in exercise-induced antidepressant effects. We focused on the action of serotonin and investigated its role in the antidepressant effect of exercise using gene knockout mice, and then, we found that serotonin type 3 (5-HT3) receptors play an essential role in the antidepressant effect of exercise. We then further investigated the antidepressant effects mediated by 5-HT3 receptors. Our detailed analyses revealed that neurons expressing 5-HT3 receptors are abundant in the subgranular zone of the hippocampal dentate gyrus and produce insulin-like growth factor-1 (IGF-1). In addition, we newly found that the stimulation of 5-HT3 receptors by agonists promotes IGF-1 release in the hippocampus and increases hippocampal neurogenesis via the IGF-1 signaling pathway, resulting in antidepressant effects. Furthermore, we further showed that a 5-HT3 receptor agonist increases hippocampal neurogenesis and exhibits antidepressant effects in mice with depressive-like behavior. A comparison with the effects of existing antidepressant SSRIs revealed that the 5-HT3 receptor-mediated antidepressant action is a new therapeutic mechanism that differs from existing drugs. Our findings suggest a novel 5-HT3 receptor-IGF-1 mechanism, which could lead to the development of new antidepressant drugs for depression based on the molecular mechanism of exercise-induced antidepressant effects and could bring significant benefits to many depressed patients who do not respond to existing drugs such as SSRIs.
Backgroundaccompanied to the spreading of coronavirus disease 2019 (Covid-19) in the world, identifying factors related to the severity of the disease is one of the interests of physician and medical researchers. We hypothesized that interleukin 6 serum level is associated with severe outcome.MethodsIn this longitudinal prospective cohort study we enrolled 208 confirmed COVID-19 patients who were admitted to the Tohid Hospital (Sanandaj, Iran). Patients were classified into two groups based on IL-6 value in the first day of admission, elevated (n = 107) or not elevated/normal (n = 101), and followed until the occurrence of final outcome (death or discharge from the hospital). Data were analyzed using univariate methods, Chi-squared and independent two sample T test. The relationship between the independent variables and our interesting outcomes were investigated by multiple linear and penalized logistic regression modeling.ResultsA total of 208 patients, 51% female and mean age 53.6 ± 16.3 years, including 107 elevated and 101 non-elevated IL-6 patients, were followed. No significant difference was observed between the two groups in demographic and clinical characteristics. Although not significant, logistic regression results showed that the chance of death occurrence among patients with elevated IL-6 are 3.91 times higher. According to the multiple linear regression modeling, elevated IL-6 significantly increased the duration of hospital stay (P = 0.02). Frequency of ICU admission (P = 0.04) and mean of ICU stay (P = 0.8) are also higher in elevated IL-6 group.ConclusionThis study revealed that elevated IL-6 is significantly related to prolongation of hospital stay in Covid-19 patients. Although not significant, the occurrence of death among patients who had increased IL-6 in the time of admission was higher than patients with normal or lower serum levels of IL-6.
Type-2 low asthma affects 30-50% of people with severe asthma and includes a phenotype characterized by sputum neutrophilia and resistance to corticosteroids. Airways inflammation in type-2 low asthma or COPD is potentially driven by persistent bacterial colonization of the lower airways by bacteria such as non-encapsulatedHaemophilus influenzae(NTHi). Although pathogenic in the lower airways, NTHi is a commensal of the upper airways. It is not known to what extent these strains can invade airway epithelial cells, persist intracellularly and activate epithelial cell production of proinflammatory cytokines, and how this differs between the upper and lower airways. We studied NTHi infection of primary human bronchial epithelial cells (PBECs), primary nasal epithelial cells (NECs) and epithelial cell lines from upper and lower airways. NTHi strains differed in propensity for intracellular and paracellular invasion. We found NTHi was internalized within PBECs at 6 h, but live intracellular infection did not persist at 24 h. Confocal microscopy and flow cytometry showed NTHi infected secretory, ciliated and basal PBECs. Infection of PBECs led to induction of CXCL8, interleukin (IL)-1β, IL-6 and TNF. The magnitude of cytokine induction was independent of the degree of intracellular invasion, either by differing strains or by cytochalasin D inhibition of endocytosis, with the exception of the inflammasome-induced mediator IL-1β. NTHi-induced activation of TLR2/4, NOD1/2 and NLR inflammasome pathways was significantly stronger in NECs than in PBECs. These data suggest that NTHi is internalized transiently by airway epithelial cells and has capacity to drive inflammation in airway epithelial cells.
RGB cameras and LiDAR are crucial sensors for autonomous vehicles that provide complementary information for accurate detection. Recent early-level fusion-based approaches, flourishing LiDAR data with camera features, may not accomplish promising performance ascribable to the immense difference between two modalities. This paper presents a simple and effective vehicle detection method based on an early-fusion strategy, unified 2D BEV grids, and feature fusion. The proposed method first eliminates many null point clouds through cor-calibration. It augments point cloud data by color information to generate 7D colored point cloud, and unifies augmented data into 2D BEV grids. The colored BEV maps can then be fed to any 2D convolution network. A peculiar Feature Fusion (2F) detection module is utilized to extract multiple scale features from BEV images. Experiments on the KITTI public benchmark and Nuscenes dataset show that fusing RGB image with point cloud rather than raw point cloud can lead to better detection accuracy. Besides, the inference time of the proposed method reaches 0.05 s/frame thanks to its simple and compact architecture.
Cisplatin resistance is a crucial factor affecting ovarian cancer patient's survival rate, but the primary mechanism underlying cisplatin resistance in ovarian cancer remains unclear, and this prevents the optimal use of cisplatin therapy. Maggot extract (ME) is used in traditional Chinese medicine for patients with comas and patients with gastric cancer when combined with other drug treatments. In this study, we investigated whether ME enhances the sensitivity of ovarian cancer cells to cisplatin. Two ovarian cancer cells—A2780/CDDP and SKOV3/CDDP—were treated with cisplatin and ME in vitro. SKOV3/CDDP cells that stably expressed luciferase were subcutaneously or intraperitoneally injected into BALB/c nude mice to establish a xenograft model, and this was followed by ME/cisplatin treatment. In the presence of cisplatin, ME treatment effectively suppressed the growth and metastasis of cisplatin-resistant ovarian cancer in vivo and in vitro. RNA-sequencing data showed that HSP90AB1 and IGF1R were markedly increased in A2780/CDDP cells. ME treatment markedly decreased the expression of HSP90AB1 and IGF1R, thereby increasing the expression of the proapoptotic proteins p-p53, BAX, and p-H2AX, while the opposite effects were observed for the antiapoptotic protein BCL2. Inhibition of HSP90 ATPase was more beneficial against ovarian cancer in the presence of ME treatment. In turn, HSP90AB1 overexpression effectively inhibited the effect of ME in promoting the increased expression of apoptotic proteins and DNA damage response proteins in SKOV3/CDDP cells. Inhibition of cisplatin-induced apoptosis and DNA damage by HSP90AB1 overexpression confers chemoresistance in ovarian cancer. ME can enhance the sensitivity of ovarian cancer cells to cisplatin toxicity by inhibiting HSP90AB1/IGF1R interactions, and this might represent a novel target for overcoming cisplatin resistance in ovarian cancer chemotherapy.
AbstractBackgroundTalazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor approved for the treatment of adult patients with deleterious or suspected deleterious germlineBRCA-mutated (gBRCAm), HER2-negative, locally advanced or metastatic breast cancer (LA/mBC), with approval based on the EMBRACA trial. To date, there are no published data on talazoparib use in the real-world United States (USA) setting.Patients and MethodsCharacteristics, treatment patterns, and clinical outcomes of real-world US patients with gBRCAm HER2-negative LA/mBC treated with talazoparib monotherapy were collected via retrospective chart review and summarized using descriptive statistics.ResultsAmong 84 eligible patients, 35.7% had hormone receptor-positive tumors and 64.3% had triple-negative LA/mBC (TNBC). At talazoparib initiation, 29.8% had ECOG PS of ≥2 and 19.0% had brain metastasis. Mutations in gBRCA1or2were detected among 64.3% and 35.7% of patients, respectively. Talazoparib was given as 1st-line therapy in 14.3% of patients, 2nd-line in 40.5%, and 3rd- or 4th-line in 45.2%. Median time to talazoparib treatment failure was 8.5 months (95% CI, 8.0-9.7), median progression-free survival was 8.7 months (95% CI, 8.0-9.9), the median time from initiation to chemotherapy was 12.2 months (95% CI, 10.5-20.1), and the overall response rate was 63.1%. No differences in clinical outcomes were observed between patients with HR-positive/HER2-negative LA/mBC and patients with TNBC by using unadjusted statistical comparisons. Brain metastasis and ECOG PS ≥2 at talazoparib initiation were associated with treatment failure and progression or mortality.ConclusionOverall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.
BackgroundIn this study, we report the case of a 14-month-old female patient transferred from another hospital to our hospital with a 9-day history of fever and worsening dyspnea.Case Report. The patient tested positive for influenza type B virus 7 days before being transferred to our hospital but was never treated. The physical examination performed at presentation revealed redness and swelling of the skin at the site of the peripheral venous catheter insertion performed at the previous hospital. Her electrocardiogram revealed ST segment elevations in leads II, III, aVF, and V2–V6. An emergent transthoracic echocardiogram revealed pericardial effusion. As ventricular dysfunction due to pericardial effusion was not present, pericardiocentesis was not performed. Furthermore, blood culture revealed methicillin-resistantStaphylococcus aureus(MRSA). Thus, a diagnosis of acute pericarditis complicated with sepsis and peripheral venous catheter-related bloodstream infection (PVC-BSI) due to MRSA was made. Frequent bedside ultrasound examinations were performed to evaluate the outcomes of the treatment. After administering vancomycin, aspirin, and colchicine, the patient's general condition stabilized.ConclusionsIn children, it is crucial to identify the causative organism and provide appropriate targeted therapy to prevent worsening of the condition and mortality due to acute pericarditis. Moreover, it is important to carefully monitor the clinical course for the progression of acute pericarditis to cardiac tamponade and evaluate the treatment outcomes.
BackgroundDuring the COVID-19 pandemic, a variable percentage of patients with SARS-CoV-2 infection failed to elicit humoral response. This study investigates whether patients with undetectable SARS-CoV-2 IgG are able to generate SARS-CoV-2 memory T cells with proliferative capacity upon stimulation.MethodsThis cross-sectional study was conducted with convalescent COVID-19 patients, diagnosed with a positive real-time PCR (RT-PCR) from nasal and pharyngeal swab specimens. COVID-19 patients were enrolled ≥3 months after the last PCR positive. Proliferative T-cell response after whole blood stimulation was assessed using the FASCIA assay.ResultsA total of 119 participants (86 PCR-confirmed COVID-19 patients and 33 healthy controls) were randomly filtered from an initial cohort. Of these 86 patients, 59 had detectable (seropositive) and 27 had undetectable (seronegative) SARS-CoV-2 IgG. Seropositive patients were subclassified as asymptomatic/mild or severe according to the oxygen supplementation requirement. SARS-CoV-2 CD3+ and CD4+ T cells showed significantly lower proliferative response in seronegative than in seropositive patients. The ROC curve analysis indicated that ≥ 5 CD4+ blasts/μL of blood defined a “positive SARS-CoV-2 T cell response”. According to this cut-off, 93.2% of seropositive patients had a positive T-cell response compared to 50% of seronegative patients and 20% of negative controls (chi-square; p < 0.001).ConclusionsThis proliferative assay is useful not only to discriminate convalescent patients from negative controls, but also to distinguish seropositive patients from those with undetectable SARS-CoV-2 IgG antibodies. Memory T cells in seronegative patients are able to respond to SARSCoV-2 peptides, although at a lower magnitude than seropositive patients.
PurposeTo analyze the risk of postoperative hemorrhage in tonsil surgery with different surgical methods, instruments, indications, and age groups. Monopolar diathermy compared to bipolar diathermy was of particular interest.MethodsThe data from tonsil surgery patients were retrospectively collected between 2012 and 2018 in the Hospital District of Southwest Finland. The surgical method, instruments, indication, sex and age and their association with a postoperative hemorrhage were analyzed.ResultsA total of 4434 patients were included. The postoperative hemorrhage rate for tonsillectomy was 6.3% and for tonsillotomy 2.2%. The most frequently used surgical instruments were monopolar diathermy (58.4%) cold steel with hot hemostasis (25.1%) and bipolar diathermy (6.4%) with the overall postoperative hemorrhage rates 6.1%, 5.9% and 8.1%, respectively. In tonsillectomy patients, the risk for a secondary hemorrhage was higher with bipolar diathermy compared to both monopolar diathermy (p = 0.039) and the cold steel with hot hemostasis technique (p = 0.029). However, between the monopolar and the cold steel with hot hemostasis groups, the difference was statistically non-significant (p = 0.646). Patients aged > 15 years had 2.6 times higher risk for postoperative hemorrhage. The risk of a secondary hemorrhage increased with tonsillitis as the indication, primary hemorrhage, tonsillectomy or tonsillotomy without adenoidectomy, and male sex in patients aged ≤ 15 years.ConclusionBipolar diathermy increased the risk for secondary bleedings compared to both monopolar diathermy and the cold steel with hot hemostasis technique in tonsillectomy patients. Monopolar diathermy did not significantly differ from the cold steel with hot hemostasis group regarding the bleeding rates.
BackgroundTo summarize the characteristics and treatment, and analyze the prognosis of large number of infants with retinoblastoma (RB) in China through a multicenter, 10-year retrospective analysis.MethodsThe data of RB infants were collected from multiple centers. The characteristics and survival prognosis were analyzed. The overall survival (OS) rate was estimated by the Kaplan–Meier method. Multivariate Cox survival analysis was to evaluate the independent risk factors affecting the prognosis of RB infants.ResultsA total of 373 RB infants (202 boys and 171 girls) were included, the median age was 6.22 months (10 days to 11.93 months). The median follow-up time of RB infants was 18.4 (1.02–122.81 months). After excluding the lost to follow-up cases, the OS rate was 97.7% (345/353). Kaplan–Meier survival analysis indicated that 9 cases died and the median survival time was not reached. Univariate analysis of prognostic factors revealed eye affected, presenting signs, left eye stage and recurrence to be poor prognostic factors for OS rate in RB infants (allP< 0.05). Multivariate Cox regression analyses for OS showed recurrence (HR = 1.376, 95% CI: 0.878–2.156,P= 0.048) was an independent factor for prognosis of infants with RB. The median survival time of infants underwent chemotherapy + intra-arterial chemotherapy (IAC) + enucleation + vitrectomy was the longest than other treatments (n= 9, 47.64 months, OS = 100%, allP< 0.05). There was a history of RB in 17 infants' lineal relatives. Kaplan-merier survival analysis indicated 1 case died and the median survival time was not reached.ConclusionRecurrence is an independent factor for prognosis of RB infants, which still needs attention after treatment. Early screening, comprehensive treatments and follow-up of patients may lead to improvements of prognosis of RB infants.
PurposeTo explore the therapeutic efficiency of acupuncture and the related molecular mechanism of neural plasticity in depression.MethodsChronic unpredictable mild stress- (CUMS-) induced rats were established for the depression animal model. There were a total of four rat groups, including the control group, the CUMS group, the CUMS+acupuncture group, and the CUMS+fluoxetine group. The acupuncture group and the fluoxetine group were given a 3-week treatment after the modeling intervention. The researcher performed the open-field, elevated plus maze, and sucrose preference tests to evaluate depressive behaviors. The number of nerve cells, dendrites' length, and the prefrontal cortex's spine density were detected using Golgi staining. The prefrontal cortex expression, such as BDNF, PSD95, SYN, and PKMZ protein, was detected using the western blot and RT-PCR.ResultsAcupuncture could alleviate depressive-like behaviors and promote the recovery of the neural plasticity functions in the prefrontal cortex, showing the increasing cell numbers, prolonging the length of the dendrites, and enhancing the spine density. The neural plasticity-related proteins in the prefrontal cortex, including BDNF, PSD95, SYN, and PKMZ, were all downregulated in the CUMS-induced group; however, these effects could be partly reversed after being treated by acupuncture and fluoxetine (P< 0.05).ConclusionAcupuncture can ameliorate depressive-like behaviors by promoting the recovery of neural plasticity functions and neural plasticity-related protein upregulation in the prefrontal cortex of CUMS-induced depressed rats. Our study provides new insights into the antidepressant approach, and further studies are warranted to elucidate the mechanisms of acupuncture involved in depression treatment.
The local communities living around national parks or areas like World Heritage Site (WHS) are crucial stakeholders to such settings. Their well-being needs to be unraveled so that the holistic management of the national park is in good condition to stabilize its status as WHS through the support and empowerment of the community. Numerous studies have been conducted on the biodiversity and geology of Gunung Mulu National Park (GMNP), but the community psychology aspect that is the foundation of conservation efforts has not been addressed. Therefore, this study aims to examine the community well-being dimensions in terms of environment, economics, social aspects as well as authority intervention based on the perspective of the local community and professionals with an emphasis on the current issues in GMNP. Quantitative and qualitative approaches were used in this study through a questionnaire to 99 local communities, and individual interviews that were conducted in GMNP and four nearby villages. Data were analyzed descriptively with four themes: environment; economics; social; and authority intervention. The findings showed that locals were satisfied in residing area in terms of environmental conditions. However, it does not reflect the actual situation, i.e., river water cloudiness, wildlife threat, degradation of wetlands, and solid waste issues are still happening. The constraints of the COVID-19 pandemic portrayed that they were very dissatisfied with their monthly income, which is very low compared to before. In terms of social, the services and facilities, especially treated water and electricity need improvement. It also noted that authority intervention especially related to road proposal, financial and skills assistance, and community conflicts could influence locals’ support for the planning and policies implemented in the national parks or WHS areas. This study suggests that relevant stakeholders should emphasize bottom-up approaches by considering aspects of community well-being that stem from multiple dimensions in order to achieve holistic national park management.
Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution.
AbstractRadiopharmaceuticals have been utilized for men with advanced prostate cancer for decades. Older agents, seldom used today, provided palliation for bone metastatic pain. In 2013, the alpha emitter radium-223 provided a catalyst for the field by prolonging survival in men with metastatic castrate-resistant prostate cancer (mCRPC). Recently radioisotopic therapies have gained further interest with the development and FDA approval of 177 lutetium (177Lu)-PSMA-617 (also known as lutetium Lu-177 vipivotide tetraxetan). This agent targets the prostate-specific membrane antigen (PSMA) expressed on the cell surface of prostate cancer cells with a beta-emitting isotope (177Lu). This clinical review summarizes key data reported from 177Lu-PSMA-617 clinical trials, including data from the phase III VISION trial which were pivotal for regulatory approval in heavily pretreated PSMA-PET-positive patients with mCRPC. The current field of radiopharmaceuticals is in a rapid state of flux. Additional phase III trials are now ongoing in patients with mCRPC and in patients with metastatic castrate-sensitive prostate cancer. The results from these potential practice-changing trials are highly anticipated. Earlier phase trials (I/II) are in progress examining combination therapies, radiolabeled monoclonal antibodies, and novel compounds. Studies of PSMA-targeted therapies using both beta emitters such as 177Lu and novel alpha emitters such 225 actinium are in progress. During the next decade, radiopharmaceuticals will likely play a central role in the management of patients with advanced prostate cancer.
Background:Health literacy is related to a variety of health outcomes, including disease control, health-related quality of life, and risk for death. Few studies have investigated the relation of electronic health literacy (e-health literacy) to outcomes or the mechanism by which they may be related.Methods:Secondary data were drawn from participants in a larger study on chronic disease self-management who were age 40 years and older, had at least one chronic health condition and a health literacy score of 8th grade or below on the validated short form of the Rapid Estimate of Adult Literacy in Medicine. Participants completed the e-Health Literacy Scale (eHEALS), the Multidimensional Health Locus of Control scale, a modified version of the Attitudes Toward Health Care Providers Scale (ATHCPS), the Wake Forest Physician Trust Scale (WFPTS), and the Gonzalez-Lu adherence questionnaire. Hypothesized relations were evaluated in a bootstrapped path analytic model using the Mplus statistical software.Key Results:Participants included 334 individuals (mean age: 57.5 years; 173 women and 161 men) with Black, Indigenous, and People of Color accounting for 83.3% of the participants and White individuals making up 16.7% of the participants. Model results showed that after controlling for age, education, gender, and race, the eHEALS score was significantly related to the ATHCPS and WFPTS but not to the Gonzalez-Lu adherence questionnaire (p< .05). The eHEALS score was significantly related to the Multidimensional Health Locus of Control scale. Analysis of indirect effects showed that a portion of the relation between e-health literacy and patient attitude and adherence was mediated by internal locus of control (allp< .05).Conclusions:In this study, e-health literacy was related to important patient attitude and behavior variables via locus of control. This finding has implications for the importance of improving patients' ability to use the internet to access and effectively use health information. [HLRP: Health Literacy Research and Practice. 2023;7(2):e80–e88.]
Iron (Fe) is an essential micronutrient for plant growth and development, participating in many significant biological processes including photosynthesis, respiration, and nitrogen fixation. Although abundant in the earth’s crust, most Fe is oxidized and difficult for plants to absorb under aerobic and alkaline pH conditions. Plants, therefore, have evolved complex means to optimize their Fe-acquisition efficiency. In the past two decades, regulatory networks of transcription factors and ubiquitin ligases have proven to be essential for plant Fe uptake and translocation. Recent studies inArabidopsis thaliana(Arabidopsis) suggest that in addition to the transcriptional network, IRON MAN/FE-UPTAKE-INDUCING PEPTIDE (IMA/FEP) peptide interacts with a ubiquitin ligase, BRUTUS (BTS)/BTS-LIKE (BTSL). Under Fe-deficient conditions, IMA/FEP peptides compete with IVc subgroup bHLH transcription factors (TFs) to interact with BTS/BTSL. The resulting complex inhibits the degradation of these TFs by BTS/BTSL, which is important for maintaining the Fe-deficiency response in roots. Furthermore, IMA/FEP peptides control systemic Fe signaling. By organ-to-organ communication in Arabidopsis, Fe deficiency in one part of a root drives the upregulation of a high-affinity Fe-uptake system in other root regions surrounded by sufficient levels of Fe. IMA/FEP peptides regulate this compensatory response through Fe-deficiency-triggered organ-to-organ communication. This mini-review summarizes recent advances in understanding how IMA/FEP peptides function in the intracellular signaling of the Fe-deficiency response and systemic Fe signaling to regulate Fe acquisition.
PurposeThis study aims to evaluate the pain relief function of chemical sphincterotomy in patients undergoing haemorrhoid surgery and compare, through a meta-analysis, the different drugs used to treat this condition.MethodsWe conducted a search in databases including PubMed, EMBASE and Web of Science. The methodological quality was evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (ROB2). The pain score was assessed using a visual analogue scale (VAS) on day 1, day 2, and day 7, and a meta-analysis was conducted based on the use of random effects models. In addition, the subgroup analysis was evaluated based on the kind of experimental drugs. Heterogeneity and publication bias were assessed.ResultsFourteen studies with a total of 681 patients were included in this meta-analysis, and all studies were randomized controlled trials RCTs. Chemical sphincterotomy showed better pain relief function than placebo on day 1 (SMD: 1.16, 95% CI 0.52 to 1.80), day 2 (SMD: 2.12, 95% CI 1.37 to 2.87) and day 7 (SMD: 1.97, 95% CI 1.17 to 2.77) after surgery. In the subgroup meta-analysis, we found that different drugs for chemical sphincterotomy provided different pain relief.ConclusionChemical sphincterotomy effectively relieves pain after haemorrhoidectomy, and calcium channel blockers have the best effect.
ObjectiveThe aim of this study was to systematically explore the inclination of the lower central incisor and symphysis in alveolar bone in severe skeletal class III patients.Materials and methodsA total of 198 severe skeletal class III patients (ANB ≤ -4°) who underwent combined orthodontic and orthognathic treatment were divided into three groups based on the mandibular plane angle (MP-SN). Pretreatment lateral cephalograms were analysed and compared among the three groups. We also assessed cone-beam computed tomography (CBCT) images of 11 samples to investigate the reliability of the cephalometric analysis.ResultsANOVA showed no statistically significant differences in the angle between the long axis of the mandibular symphysis and the long axis of the lower central incisor (MIA) among the low-angle, normal-angle and high-angle groups (P> 0.05), while significant differences were found in the angle between the axis of the lower incisor and the mandibular plane (IMPA) among the three groups (P< 0.001). The mean IMPA decreased with increasing MP-SN in the 198 patients. The mean MIA in the low-angle and normal-angle groups was 3.70° and 3.52°, respectively, while the value (2.33°) was smaller in the high-angle group. Paired-samples t test showed no statistically significant differences between the cephalometric and CBCT measurements of the MP-SN, the angle between the mandibular plane and the Frankfort plane (FH-MP) and the MIA (P> 0.05).ConclusionsIn severe skeletal class III patients, the long axis of the lower central incisor was highly consistent with the long axis of the mandibular symphysis, which was more obvious in the high-angle subjects. The MIA reflects the physiological inclination of the lower central incisor better than the IMPA.
AbstractBackgroundA proportion of COVID19 survivors may present with long‐COVID, which is persistent symptoms lasting four or more weeks post SARS‐CoV‐2 infection. These symptoms may be mild to severe, and may affect different organ‐systems of the body.AimsThe main objective of this study was to determine the demographic, clinical and immunological factors associated with long COVID.Materials & MethodsWe conducted a nested case control study, with a total of 94 study participants initially included, and 64 participants matched for age and sex for biomarker analyses.Results32/94 (34.1%) of all the participants had long COVID. Respiratory symptoms were the most common (59.5%) followed by the musculoskeletal symptoms (28.1%). HIV was an independent predictor of long COVID (adjusted odds ratio = 2.7;p= .037). In all the 64 matched cases and controls, IFN‐β was significantly higher among controls than cases. After stratifying by HIV, IL6 was significantly higher among cases than controls in the HIV‐ group (2.06 vs. 0.81 pg/mL;p= .02). On the other hand, IFN‐β was significantly higher among controls than cases in the HIV+ group (251 vs. 0 pg/mL;p= .01).ConclusionHIV infection is a risk factor for long COVID, and inflammatory markers associated with long COVID may be slightly different for HIV− and HIV+ individuals.
Synthesized in the liver from cholesterol, the bile acids (BAs) primary role is emulsifying fats to facilitate their absorption. BAs can cross the blood-brain barrier (BBB) and be synthesized in the brain. Recent evidence suggests a role for BAs in the gut-brain signaling by modulating the activity of various neuronal receptors and transporters, including the dopamine transporter (DAT). In this study, we investigated the effects of BAs and their relationship with substrates in three transporters of the solute carrier 6 family. The exposure to obeticholic acid (OCA), a semi-synthetic BA, elicits an inward current (IBA) in the DAT, the GABA transporter 1 (GAT1), and the glycine transporter 1 (GlyT1b); this current is proportional to the current generated by the substrate, respective to the transporter. Interestingly, a second consecutive OCA application to the transporter fails to elicit a response. The full displacement of BAs from the transporter occurs only after exposure to a saturating concentration of a substrate. In DAT, perfusion of secondary substrates norepinephrine (NE) and serotonin (5-HT) results in a second OCA current, decreased in amplitude and proportional to their affinity. Moreover, co-application of 5-HT or NE with OCA in DAT, and GABA with OCA in GAT1, did not alter the apparent affinity or the Imax, similar to what was previously reported in DAT in the presence of DA and OCA. The findings support the previous molecular model that suggested the ability of BAs to lock the transporter in an occluded conformation. The physiological significance is that it could possibly avoid the accumulation of small depolarizations in the cells expressing the neurotransmitter transporter. This achieves better transport efficiency in the presence of a saturating concentration of the neurotransmitter and enhances the action of the neurotransmitter on their receptors when they are present at reduced concentrations due to decreased availability of transporters.
PurposePediatric tibial fractures have been described internationally as mainly caused by fall during leisure activities and organized sports and showing a higher incidence in boys. Still, most studies are single center studies or have a small sample size. This study aimed to analyze sex and age distribution, seasonal variation, injury mechanisms and treatment of pediatric tibial fractures based on the nationwide Swedish Fracture Register (SFR).MethodsAll tibial fractures in patients < 16 years at injury and registered in 2015–2019 were extracted from the SFR. We analyzed patient characteristics such as sex and age, injury mechanism, fracture location and treatment.ResultsThe study cohort consisted of 5828 pediatric tibial fractures in 5719 patients. Median age of the patients was 7 years and 58% were boys. Shaft fractures were most common, followed by the distal and proximal tibia. The lowest incidence was observed during autumn. The most common cause of injury was fall mostly involving winter sports, stumbles and fall from play equipment. Play/free time and sports were the most common activities, common places of injury were sports facility and home. 1% were open fractures. 78% were treated non-surgically. Screw fixation was performed in 52% of surgically treated fractures, predominantly in the distal segment.ConclusionInjury mechanism differs between age groups; play/free time injuries are common in younger children compared with sport activities in older children. Most patients are treated non-surgically. Open fractures are rare. Information on injury patterns is useful working preventively, for example safety work in playgrounds.
A uniform prognostic marker is needed for nontuberculous mycobacterial pulmonary disease (NTM-PD) due to the diverse clinical course. We aimed to seek the utility of the BACES score, originally derived to predict all-cause mortality, for various outcomes. To calculate the BACES score, one point was given for each of the following factors: body mass index < 18.5 kg/m2,age ≥ 65 years, presence ofcavities, elevatederythrocyte sedimentation rate, or malesex. The study included 681 patients, of whom 97 (14.2%), 189 (27.7%), 192 (28.2%), 143 (21.0%), 47 (6.9%), and 13 (1.9%) had BACES scores of 0 to 5. Those with greater BACES scores were more likely to experience dyspnea, body weight loss, and anorexia. With severe disease, the risk of disease progression increased while the rate of treatment culture conversion decreased. After adjustment of comorbidities, higher BACES score was independently associated with the risk of mortality from respiratory causes or infection. As a simple and efficient bedside tool for assessing the severity of NTM-PD, the BACES score has the potential to be utilized as a surrogate marker for uniform severity assessment.
PurposeDifferent surgical techniques to manage cartilage defects are available, including microfracture (MFx), autologous chondrocyte implantation (ACI), osteoarticular auto- or allograft transplantation (OAT), autologous matrix-induced chondrogenesis (AMIC). This study investigated the patient-related prognostic factors on the clinical outcomes of surgically treated knee and ankle cartilage defects.MethodsThis study followed the PRISMA statement. In May 2022, the following databases were accessed: PubMed, Google Scholar, Embase, and Scopus. All the studies investigating the outcomes of surgical management for knee and/or talus chondral defects were accessed. Only studies performing mesenchymal stem cells transplantation, OAT, MFx, ACI, and AMIC were considered. A multiple linear model regression analysis through the Pearson Product–Moment Correlation Coefficient was used.ResultsData from 184 articles (8905 procedures) were retrieved. Female sex showed a positive moderate association with visual analogue scale at last follow-up (P= 0.02). Patient age had a negative association with the American Orthopaedic Foot and Ankle Score (P= 0.04) and Lysholm Knee Scoring Scale (P= 0.03). BMI was strongly associated with graft hypertrophy (P= 0.01). Greater values of VAS at baseline negatively correlate with lower values of Tegner Activity Scale at last follow-up (P< 0.0001).ConclusionThe clinical outcomes were mostly related to the patients’ performance status prior surgery. A greater BMI was associated with greater rate of hypertrophy. Female sex and older age evidenced fair influence, while symptom duration prior to the surgical intervention and cartilage defect size evidenced no association with the surgical outcome. Lesion size and symptom duration did not evidence any association with the surgical outcome.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00068-022-02155-y.
BackgroundMatrix metalloproteinase-7 (MMP7) is markedly expressed in patients with chronic kidney disease; its expression in dialysate and role in patients undergoing peritoneal dialysis (PD) have not been well established.MethodsParticipants undergoing PD from June 1st, 2015, to June 30th, 2020, were involved and were followed up every 3 months for the first year and every 6 months thereafter until death, PD withdrawal, or the end of the study. Data at each follow-up point were collected and analyzed for the association with congestive heart failure (CHF), PD withdrawal, and combined endpoint.ResultsA total of 283 participants were included in this study. During a median follow-up of 21 months, 20 (7%) participants died, 93 (33%) withdrew from PD, and 105 (37%) developed CHF. A significantly increased level of serum and dialysate MMP7 was observed at baseline. Dialysate MMP7 presented a good linearity with serum MMP7. Baseline serum and dialysate MMP7 levels were associated with CHF in multivariable Cox proportional hazards regression models. After categorization, participants with high baseline MMP7 levels had a higher incidence of CHF (42%), and the hazard ratios (95% confidence intervals) were 1.595 (1.023-2.488). Interestingly, participants with higher serum MMP7 levels were trended to use dialysate with higher glucose concentration. However, the ultrafiltration volumes were not significantly increased. Higher MMP7 levels were also positively associated with PD withdrawal and combined endpoint.ConclusionsThe expression of MMP7 in serum and dialysate was markedly increased and was tightly associated with the risk of CHF in PD patients. This finding suggests that the measurement of MMP7 may inform strategies for managing CHF at an earlier stage.
AbstractAnthocyanins are a valuable source of antioxidants in the human diet and contribute to fruit coloration. In red-skinned pears, anthocyanin biosynthesis can be induced by light, in which the MYB–bHLH–WDR complex plays a critically important role in transcriptional regulation. However, knowledge of WRKY-mediated transcriptional regulation of light-induced anthocyanin biosynthesis is scarce in red pears. This work identified and functionally characterized a light-inducing WRKY transcription factor, PpWRKY44, in pear. Functional analysis based on overexpressed pear calli showed that PpWRKY44 promoted anthocyanin accumulation. Also, transiently overexpressedPpWRKY44in pear leaves and fruit peels significantly enhanced the accumulation of anthocyanin, whereas silencingPpWRKY44in pear fruit peels impaired induction of the accumulation of anthocyanin by light. By chromatin immunoprecipitation and electrophoretic mobility shift assay coupled to a quantitative polymerase chain reaction, we found that PpWRKY44 boundin vivoandin vitroto thePpMYB10promoter, revealing it as a direct downstream target gene. Moreover,PpWRKY44was activated by PpBBX18, a light signal transduction pathway component. Our results explained the mechanism mediating the impacts of PpWRKY44 on the transcriptional regulation of anthocyanin accumulation, with potential implications for fine-tuning the fruit peel coloration triggered by light in red pears.
AbstractIntroductionCheckpoint blockade has improved the response rate and survival in metastatic melanoma. Elective treatment discontinuation appears to be reasonable in most patients who have achieved a confirmed complete remission. It seems crucial to understand whether restarting immune checkpoint inhibitor therapy can induce additional responses or remissions in rare patients who relapse.MethodsA retrospective analysis identified only 10 patients who relapsed after elective treatment discontinuation after a radiologically confirmed remission. These patients were retreated with single-agent PD-1 or combined CTLA-4 plus PD-1-directed monoclonal antibodies.ResultsWe found an initial complete response rate of 20% (2 patients) following retreatment. With a median follow-up of 26 months, the addition of individualized salvage therapies converted an additional 4 patients to a 2nd remission. All 6 of these patients have again discontinued therapy. Three patients have died of metastatic melanoma, while another is receiving salvage therapy. Six of our 10 patients experienced grades 2-3 retreatment-related toxicity. There were no hospitalizations or fatalities.DiscussionRetreatment of relapsing patients resulted in 20% complete responses with checkpoint inhibitors. The planned addition of other treatment modalities converted another 4 patients (40%) to a durable 2nd remission. This sequential approach merits further exploration in prospective clinical trials.
ObjectiveFor patients with diabetes, high-frequency and -amplitude glycemic variability may be more harmful than continuous hyperglycemia; however, there is still a lack of screening indicators that can quickly and easily assess the level of glycemic variability. The aim of this study was to investigate whether the glycemic dispersion index is effective for screening high glycemic variability.MethodsA total of 170 diabetes patients hospitalized in the Sixth Affiliated Hospital of Kunming Medical University were included in this study. After admission, the fasting plasma glucose, 2-hour postprandial plasma glucose, and glycosylated hemoglobin A1c were measured. The peripheral capillary blood glucose was measured seven times in 24 h, before and after each of three meals and before bedtime. The standard deviation of the seven peripheral blood glucose values was calculated, and a standard deviation of > 2.0 was used as the threshold of high glycemic variability. The glycemic dispersion index was calculated and its diagnostic efficacy for high glycemic variability was determined by the Mann–Whitney U test, receiver operating characteristic (ROC) curve and, Pearson correlation analysis.ResultsThe glycemic dispersion index of patients with high glycemic variability was significantly higher than that of those with low glycemic variability (p< 0.01). The best cutoff value of the glycemic dispersion index for screening high glycemic variability was 4.21. The area under the curve (AUC) was 0.901 (95% CI: 0.856–0.945) and had a sensitivity of 0.781 and specificity of 0.905. It was correlated with the standard deviation of blood glucose values (r= 0.813,p< 0.01).ConclusionsThe glycemic dispersion index had good sensitivity and specificity for screening high glycemic variability. It was significantly associated with the standard deviation of blood glucose concentration and is simple and easy to calculate. It was an effective screening indicator of high glycemic variability.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13098-023-01077-y.
AbstractType I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN‐stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN‐β also activates an inflammatory gene expression program in contrast to IFN‐λ3, a type III IFN, which elicits only the common antiviral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis, we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus‐specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK–STAT/IRF signaling network that may produce distinct biological responses and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it.
Asciminib is approved for patients with Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia (CML-CP) who received ≥2 prior tyrosine kinase inhibitors or have the T315I mutation. We report updated results of a phase 1, open-label, nonrandomized trial (NCT02081378) assessing the safety, tolerability, and antileukemic activity of asciminib monotherapy 10–200 mg once or twice daily in 115 patients with CML-CP without T315I (data cutoff: January 6, 2021). After ≈4-year median exposure, 69.6% of patients remained on asciminib. The most common grade ≥3 adverse events (AEs) included increased pancreatic enzymes (22.6%), thrombocytopenia (13.9%), hypertension (13.0%), and neutropenia (12.2%); all-grade AEs (mostly grade 1/2) included musculoskeletal pain (59.1%), upper respiratory tract infection (41.7%), and fatigue (40.9%). Clinical pancreatitis and arterial occlusive events (AOEs) occurred in 7.0% and 8.7%, respectively. Most AEs occurred during year 1; the subsequent likelihood of new events, including AOEs, was low. By data cutoff, among patients without the indicated response at baseline, 61.3% achievedBCR::ABL1≤ 1%, 61.6% achieved ≤0.1% (major molecular response [MMR]), and 33.7% achieved ≤0.01% on the International Scale. MMR was maintained in 48/53 patients who achieved it and 19/20 who were in MMR at screening, supporting the long-term safety and efficacy of asciminib in this population.
AbstractEarly‐life stress can result in life‐long effects that impact adult health and disease risk, but little is known about how such programming is established and maintained. Here, we show that such epigenetic memories can be initiated in theDrosophilaembryo before the major wave of zygotic transcription, and higher‐order chromatin structures are established. An early short heat shock results in elevated levels of maternal miRNA and reduced levels of a subgroup of zygotic genes in stage 5 embryos. Using aDicer‐1mutant, we show that the stress‐induced decrease in one of these genes, the insulator‐binding factor Elba1, is dependent on functional miRNA biogenesis. Reduction in Elba1 correlates with the upregulation of early developmental genes and promotes a sustained weakening of heterochromatin in the adult fly as indicated by an increased expression of the PEVwm4hreporter. We propose that maternal miRNAs, retained in response to an early embryonic heat shock, shape the subsequentde novoheterochromatin establishment that occurs during early development via direct or indirect regulation of some of the earliest expressed genes, including Elba1.
Purpose: This study intended to determine, and non-invasively evaluate, sternal intraosseous oxygen saturation (SsO2) and study its variation during provoked hypoxia or hypovolaemia. Furthermore, the relation between SsO2and arterial (SaO2) or mixed venous oxygen saturation (SvO2) was investigated. Methods: Sixteen anaesthetised male pigs underwent exsanguination to a mean arterial pressure of 50 mmHg. After resuscitation and stabilisation, hypoxia was induced with hypoxic gas mixtures (air/N2). Repeated blood samples from sternal intraosseous cannulation were compared to arterial and pulmonary artery blood samples. Reflection spectrophotometry measurements by a non-invasive sternal probe were performed continuously. Results: At baseline SaO2was 97.0% (IQR 0.2), SsO273.2% (IQR 19.6) and SvO252.3% (IQR 12.4). During hypovolaemia, SsO2and SvO2decreased to 58.9% (IQR 16.9) and 38.1% (IQR 12.5), respectively, p < 0.05 for both, whereas SaO2remained unaltered (p = 0.44). During hypoxia all saturations decreased; SaO271.5% (IQR 5.2), SsO239.0% (IQR 6.9) and SvO222.6% (IQR 11.4) (p < 0.01), respectively. For hypovolaemia, the sternal probe red/infrared absorption ratio (SQV) increased significantly from baseline (indicating a reduction in oxygen saturation) + 5.1% (IQR 7.4), p < 0.001 and for hypoxia + 19.9% (IQR 14.8), p = 0.001, respectively. Conclusion: Sternal blood has an oxygen saturation suggesting a mixture of venous and arterial blood. Changes in SsO2relate well with changes in SvO2during hypovolaemia or hypoxia. Further studies on the feasibility of using non-invasive measurement of changes in SsO2to estimate changes in SvO2are warranted.
BackgroundGordon Holmes syndrome (GHS) is a rare autosomal recessive disorder characterized by hypogonadotropic hypogonadism, cognitive decline, and cerebellar ataxia. Mutations in the Ring Finger Protein 216 (RNF216) gene have been known to be associated with GHS therewithalRNF216mutations have been detected in cases with Huntington-like disease, 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism), and congenital hypogonadotropic hypogonadism.Case presentationHere we report a novel homozygous frameshift mutation inRNF216gene c.1860_1861dupCT (p.Cys621SerfsTer56) in a patient with hypogonadotropic hypogonadism, ataxia, and cognitive decline diagnosed with GHS also co-occurrence of parkinsonism and dystonia which was not reported before.ConclusionsWe report an extremely rare case of GHS. The core features of GHS are well defined, but genotype–phenotype correlations are still limited. To understand the pathophysiology of different phenotypes, the type and localization of novel mutations need to be defined, and the effect of these different variants on clinical features needs to be determined. Further studies should explain the factors of phenotypic variability present in GHS patients withRNF216mutations.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-023-01529-4.
BackgroundDetermining the cause of visual deterioration in idiopathic intracranial hypertension (IIH) patients is of clinical necessity. This study aimed to study the effect of chronic increased ICP on the retina and optic nerve through objective electrophysiological measures in chronic IIH patients.MethodsThirty patients with chronic IIH and thirty age and sex-matched healthy controls were included in this study. Papilledema grade and CSF pressure were evaluated in the patients’ group. Both groups were submitted to visual evoked potentials (VEP) and multifocal electroretinogram (mfERG).ResultThe mean value of P100 latencies of the right and left on two check sizes, 1 deg and 15ṁ in chronic IIH patients, was significantly delayed than controls (P-value < 0.001 for each). Chronic IIH patients showed a significantly lower amplitude of the right and left R1, R2, R3, R4 & R5 compared to controls (P-value < 0.001, < 0.001) (P-value < 0.001, < 0.001) (P-value < 0.001, < 0.001) (P-value < 0.001, = 0.001) (P-value = 0.002, < 0.001), respectively. Also, patients showed a significantly delayed peak time of the right and left R1 and R2 compared to controls (P-value < 0.001, < 0.001) (P-value = 0.001, = 0.009), respectively. There was a significant positive correlation between each of CSF pressure and papilledema grade with right and left PVEP latencies. In contrast, there was no statistically significant correlation between either CSF pressure or papilledema grade and PVEP amplitudes in both eyes.ConclusionIn chronic IIH patients, both optic nerve dysfunction and central retinal changes were identified, supported by VEP and the mfERG findings.
BackgroundCervical pregnancy, an uncommon type of ectopic pregnancy, can lead to devastating consequences if not diagnosed and treated early. Despite this, there are no specific guidelines on how to treat such pregnancies especially in advanced gestational ages (GAs).CaseThis is a 35-year-old patient who presented to our hospital at 13 weeks GA after failing systemic multidose methotrexate therapy for a cervical ectopic pregnancy. Given desire to preserve fertility, a minimally invasive conservative approach was taken involving potassium chloride (KCl) and methotrexate injections into the gestational sac, followed by immediate Cook intracervical double balloon placement under direct ultrasound visualization, with removal of the balloon after 72 hours, and ultimately resolution of the pregnancy 12 weeks after the removal.ConclusionAdvanced first trimester cervical ectopic pregnancy after failure of methotrexate therapy was managed successfully with minimally invasive KCl and methotrexate injections in combination with cervical ripening balloon.
ObjectiveThe aim of this study was to investigate the physiological impact of airway pressure release ventilation (APRV) on patients with early moderate-to-severe acute respiratory distress syndrome (ARDS) by electrical impedance tomography (EIT).MethodsIn this single-center prospective physiological study, adult patients with early moderate-to-severe ARDS mechanically ventilated with APRV were assessed by EIT shortly after APRV (T0), and 6 h (T1), 12 h (T2), and 24 h (T3) after APRV initiation. Regional ventilation and perfusion distribution, dead space (%), shunt (%), and ventilation/perfusion matching (%) based on EIT measurement at different time points were compared. Additionally, clinical variables related to respiratory and hemodynamic condition were analyzed.ResultsTwelve patients were included in the study. After APRV, lung ventilation and perfusion were significantly redistributed to dorsal region. One indicator of ventilation distribution heterogeneity is the global inhomogeneity index, which decreased gradually [0.61 (0.55–0.62) to 0.50 (0.42–0.53),p< 0.001]. The other is the center of ventilation, which gradually shifted towards the dorsal region (43.31 ± 5.07 to 46.84 ± 4.96%,p= 0.048). The dorsal ventilation/perfusion matching increased significantly from T0 to T3 (25.72 ± 9.01 to 29.80 ± 7.19%,p= 0.007). Better dorsal ventilation (%) was significantly correlated with higher PaO2/FiO2(r = 0.624,p= 0.001) and lower PaCO2(r = -0.408,p= 0.048).ConclusionsAPRV optimizes the distribution of ventilation and perfusion, reducing lung heterogeneity, which potentially reduces the risk of ventilator-induced lung injury.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04469-8.
IntroductionLimonium(L.)tetragonum(Thunb.) A. A. Bullock, a halophyte that grows all over the southwest coast of Korea, is a medicinal plant with various pharmacological effects. The salt defense mechanism stimulates the biosynthesis of various secondary metabolites and improves functional substances. In this study, we investigated the optimal NaCl concentration for the growth and enhancement of secondary metabolites in hydroponically grownL. tetragonum.MethodsThe seedlings grown for 3 weeks in a hydroponic cultivation system were treated with 0-, 25-, 50-, 75-, and 100-mM NaCl in Hoagland’s nutrient solution for 8 weeks. No significant effect on the growth and chlorophyll fluorescence was observed for the NaCl concentrations below 100-mM.Results and discussionsThe increase in the NaCl concentration resulted in the decrease in the water potential of theL. tetragonumleaves. The Na+content accumulated in the aerial part increased rapidly and the content of K+, which acts as an antagonist, decreased with the increase in NaCl concentrations in hydroponics. The total amino acid content ofL. tetragonumdecreased compared to the 0-mM NaCl, and most of the amino acid content decreased as the NaCl concentration increased. In contrast, the content of urea, proline (Pro), β-alanine, ornithine, and arginine was increased with an increase in NaCl concentration. The Pro content at 100-mM NaCl accounted for 60% of the total amino acids and was found to be a major osmoregulator as an important component of the salt defense mechanisms. The top five compounds identified in theL. tetragonumwere classified as flavonoids while the flavanone compound was detected only in the NaCl treatments. A total of four myricetin glycosides were increased in comparison to the 0-mM NaCl. Among the differentially expressed genes, a significantly large change in Gene ontology was seen in the circadian rhythm. NaCl treatment enhanced the flavonoid-based substances ofL. tetragonum. The optimum NaCl concentration for the enhancement of secondary metabolites of theL. tetragonumin the vertical farm-hydroponic cultivation system was 75-mM NaCl.
Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disorder, resulting fromMEN1gene abnormalities, which causes tumors mainly in the endocrine glands. We experienced a sporadic case of MEN1 complicated with papillary thyroid carcinoma (PTC) and found a novel missense mutation in the patient’sMEN1gene. Her older sister, who showed no typical symptom of MEN1, had a history of PTC, suggesting the presence of another genetic factor involved in PTC development. This case suggests the importance of an individual’s genetic background in the development of MEN1 complications.
BackgroundRecently, Vacuum formed retainers (VFRs) are preferred as an Orthodontic retention appliance over conventional Begg’s retainers. Very few studies have been conducted between VFRs and Begg’s retainers. Hence, this study aims at assessing the effectiveness, oral hygiene and acceptability between VFRs and Begg’s retainers with a follow up period of 1 year.MethodsEighty patients who completed fixed Orthodontic treatment were included. Retainers were delivered on the same day of debonding. Retainer 1/ R1 stands for VFRs and Retainer 2/ R2 stands for Begg’s retainers. The retainers were randomly allocated to both the arches. 40 VFRs and Begg’s retainers in maxillary and mandibular arch were given respectively.Effectiveness, oral hygiene condition were performed at T0(After debonding), T1(3 months after using retainers), T2(6 months after using retainers), T3(9 months after using retainers), T4(12 months after using retainers) follow up stages, except the feedback form and the breakage of retainers that were filled at T4stage.ResultsBoth R1and R2retainers showed improvement in teeth alignment in both the arches at follow up stages. Interproximal contacts in maxillary and mandibular arch with VFRs and Begg’s retainers improved to 77.5% and 82.5% respectively. Considering the marginal ridge, Begg’s retainers and VFRs showed 95%, 55% increased proportion at T4respectively (p< 0.05). Patients wearing Beggs’s retainers had significantly better (p< 0.05) oral hygiene status.Significant differences were observed with Begg’s retainers in teeth biting, whereas no significant difference was found with fitting of appliance (p= 0.180) and gingival irritation (p= 1.000). VFRs were well accepted aesthetically that was significant. Retainers were prone to breakage but was not significant (p= 0.162).ConclusionBegg’s wrap around retainers maintain good oral hygiene, improve the teeth alignment, interproximal contact and marginal ridges post Orthodontic treatment with better fitting of the appliance. VFRs are also preferred as they are good in maintaining proper teeth alignment with progressive improvement in the interproximal contacts and are aesthetically pleasing.
INTRODUCTIONTobacco smoking poses a significant threat to the health of individuals living with diabetes. Intensive stand-alone smoking cessation interventions, such as multiple or long (>20 minutes) behavioral support sessions focused solely on smoking cessation, with or without the use of pharmacotherapy, increase abstinence when compared to brief advice or usual care in the general population. However, there is limited evidence so far for recommending the use of such interventions amongst individuals with diabetes. This study aimed to assess the effectiveness of intensive stand-alone smoking cessation interventions for individuals living with diabetes and to identify their critical features.METHODSA systematic review design with the addition of a pragmatic intervention component analysis using narrative methods was adopted. The key terms ‘diabetes mellitus’ and ‘smoking cessation’ and their synonyms were searched in 15 databases in May 2022. Randomized controlled trials which assessed the effectiveness of intensive stand-alone smoking cessation interventions by comparing them to controls, specifically amongst individuals with diabetes, were included.RESULTSA total of 15 articles met the inclusion criteria. Generally, the identified studies reported on the delivery of a multi-component behavioral support smoking cessation intervention for individuals with type I and type II diabetes, providing biochemically verified smoking abstinence rates at follow-up at six months. The overall risk-of-bias of most studies was judged to be of some concern. Despite observing inconsistent findings across the identified studies, interventions consisting of three to four sessions, lasting more than 20 min each, were found to be more likely to be associated with smoking cessation success. The additional use of visual aids depicting diabetes-related complications may also be useful.CONCLUSIONSThis review provides evidence-based smoking cessation recommendations for use by individuals with diabetes. Nonetheless, given that the findings of some studies were found to be possibly at risk-of-bias, further research to establish the validity of the provided recommendations is suggested.
BackgroundThe biomaterial integration depends on its interaction with the host immune system. Monocyte-macrophage lineage cells are immediately recruited to the implant site, polarized into different phenotypes, and fused into multinucleated cells, thus playing roles in tissue regeneration. IL-1R-associated kinase 4 (IRAK4) inhibition was reported to antagonize inflammatory osteolysis and regulate osteoclasts and foreign body giant cells (FBGCs), which may be a potential target in implant osseointegration.MethodsInin-vitroexperiments, we established simulated physiological and inflammatory circumstances in which bone-marrow-derived macrophages were cultured on sand-blasted and acid-etched (SLA) titanium surfaces to evaluate the induced macrophage polarization, multinucleated cells formation, and biological behaviors in the presence or absence of IRAK4i. Then, bone marrow stromal stem cells (BMSCs) were cultured in the conditioned media collected from the aforementioned induced osteoclasts or FBGCs cultures to clarify the indirect coupling effect of multinucleated cells on BMSCs. We further established a rat implantation model, which integrates IRAK4i treatment with implant placement, to verify the positive effect of IRAK4 inhibition on the macrophage polarization, osteoclast differentiation, and ultimately the early peri-implant osseointegration in vivo.ResultsUnder inflammatory conditions, by transforming the monocyte-macrophage lineage cells from M1 to M2, IRAK4i treatment could down-regulate the formation and activity of osteoclast and relieve the inhibition of FBGC generation, thus promoting osteogenic differentiation in BMSCs and improve the osseointegration.ConclusionThis study may improve our understanding of the function of multinucleated cells and offer IRAK4i as a therapeutic strategy to improve early implant osseointegration and help to eliminate the initial implant failure.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12903-023-03011-0.
Sources of neurotoxic mercury in forests are dominated by atmospheric gaseous elemental mercury (GEM) deposition, but a dearth of direct GEM exchange measurements causes major uncertainties about processes that determine GEM sinks. Here we present three years of forest-level GEM deposition measurements in a coniferous forest and a deciduous forest in northeastern USA, along with flux partitioning into canopy and forest floor contributions. Annual GEM deposition is 13.4 ± 0.80 μg m−2(coniferous forest) and 25.1 ± 2.4 μg m−2(deciduous forest) dominating mercury inputs (62 and 76% of total deposition). GEM uptake dominates in daytime during active vegetation periods and correlates with CO2assimilation, attributable to plant stomatal uptake of mercury. Non-stomatal GEM deposition occurs in the coniferous canopy during nights and to the forest floor in the deciduous forest and accounts for 24 and 39% of GEM deposition, respectively. Our study shows that GEM deposition includes various pathways and is highly ecosystem-specific, which complicates global constraints of terrestrial GEM sinks.
The aim of this studywas to evaluate the efficiency of local and integral methods of the assessment of the hemostasiological profile in sheep at various stages of implantation of a biodegradable vascular graft.Materials and MethodsThe object of the study was the whole blood of sheep collected at the stage of premedication, during the intraoperative period, and in the early postoperative period. Thromboelastography was used to assess the kinetics of clot formation and changes in its viscoelastic properties in whole blood samples. The thrombin generation test was performed in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) with the assessment of quantitative and temporal parameters. The platelet factor 4 concentration in PRP and PPP was measured by the enzyme immunoassay. The functional activity of platelets in PPP was assessed with inductors and without additional stimulation. Prothrombin complex activity, APTT values, thrombin time, fibrinogen concentration, antithrombin III and protein C activity, soluble fibrin monomer complexes, and fibrinolysis were determined in blood plasma.ResultsMultidirectional changes in the hemostasiological profile at various stages of vascular prosthesis implantation have been revealed. On the one hand, it is an increased prothrombogenic status, on the other hand, it is the development of hypocoagulation. Shortening of theR(blood coagulation time) andK(clot formation time) intervals and an increase in the angle parameter and maximum amplitude on the thromboelastogram in all the studied periods relative to the reference values, a significant increase in platelet factor 4 in PRP and increased platelet aggregation testified in favor of hypercoagulation. However, the quantitative parameters of the thrombin generation test and a number of coagulogram indicators pointed to hypocoagulation in the intraoperative and early postoperative periods.ConclusionThe comparative analysis of local tests characterizing the state of hemostasis and indicators of integral methods demonstrated the advantages of the latter in assessing thrombotic risks during implantation of vascular grafts. Local tests are not sufficient to assess the dynamics of the coagulation process in real time and are not always sensitive to hypercoagulation. The use of integral methods will help to fill these gaps, make a timely diagnosis of hypercoagulability and minimize the risks associated with the implantation of vascular grafts in future.
Outpatient care in Germany is mainly provided in physicians’ private practices. Data from health surveys enable to analyse the utilization of outpatient services from the patient’s perspective, and to identify associations with social determinants and other influencing factors. As part of the GEDA 2014/2015-EHIS study, data was collected for the indicator ‘utilization of outpatient medical care in the last 12 months’. The analysis found that 90.9% of women aged 18 years and over and 84.1% of men had used outpatient medical services within the last 12 months. The utilization of outpatient medical care increases with age: about 94% of people aged 65 or over were provided with outpatient medical treatment in the last 12 months. There were significant differences in utilization between younger men and women, which balance out with age. No differences were identified in relation to educational level or federal state.
Autoimmune blistering diseases such as bullous pemphigoid (BP) and pemphigus vulgaris (PV) are complex, multifactorial, and polygenic diseases, whose exact pathogenesis is difficult to pinpoint. Research aimed at elucidating the associated epidemiologic risk factors of these two diseases has been hampered by their rare disease status. Further, a lack of centralization and standardization of available data makes the practical application of this information challenging. In order to collate and clarify the available literature we comprehensively reviewed 61 PV articles from 37 different countries and 35 BP articles from 16 different countries addressing a range of disease relevant clinical parameters including age of onset, sex, incidence, prevalence, and HLA allele association. The reported incidence of PV ranged from 0.098 to 5 patients per 100,000 people, while BP ranged from 0.21 to 7.63 patients per 100,000. Prevalence of PV ranged from 0.38 to 30 per 100,000 people and BP ranged from 1.46 to 47.99 per 100,000. The mean age of onset in patients ranged from 36.5 to 71 years for PV and 64 to 82.6 years for BP. Female-to-male ratios ranged from 0.46 to 4.4 in PV and 1.01 to 5.1 in BP. Our analysis provides support for the reported linkage disequilibrium of HLA DRB10402 (an allele previously shown to be associated with PV) and DQB10302 alleles in Europe, North America, and South America. Our data also highlight that HLA DQB10503 (also known to be associated with PV) appears in linkage disequilibrium with DRB11404 and DRB11401, mainly in Europe, the Middle East, and Asian countries. The HLA DRB10804 allele was only associated with PV in patients of Brazilian and Egyptian descent. Only two HLA alleles were reported as associated with BP more than twice in our review, DQB10301 and DQA10505. Collectively, our findings provide detailed insights into the variation of disease parameters relevant to PV and BP that can be expected to inform future work aimed at unraveling the complex pathogenesis of these conditions across the globe.
PurposeThe extent of resection (EOR) is an independent prognostic factor for overall survival (OS) in adult patients with Glioma Grade 4 (GG4). The aim of the neuro-oncology section of the Italian Society of Neurosurgery (SINch®) was to provide a general overview of the current trends and technical tools to reach this goal.MethodsA systematic review was performed. The results were divided and ordered, by an expert team of surgeons, to assess the Class of Evidence (CE) and Strength of Recommendation (SR) of perioperative drugs management, imaging, surgery, intraoperative imaging, estimation of EOR, surgery at tumor progression and surgery in elderly patients.ResultsA total of 352 studies were identified, including 299 retrospective studies and 53 reviews/meta-analysis. The use of Dexamethasone and the avoidance of prophylaxis with anti-seizure medications reached a CE I and SR A. A preoperative imaging standard protocol was defined with CE II and SR B and usefulness of an early postoperative MRI, with CE II and SR B. The EOR was defined the strongest independent risk factor for both OS and tumor recurrence with CE II and SR B. For intraoperative imaging only the use of 5-ALA reached a CE II and SR B. The estimation of EOR was established to be fundamental in planning postoperative adjuvant treatments with CE II and SR B and the stereotactic image-guided brain biopsy to be the procedure of choice when an extensive surgical resection is not feasible (CE II and SR B).ConclusionsA growing number of evidences evidence support the role of maximal safe resection as primary OS predictor in GG4 patients. The ongoing development of intraoperative techniques for a precise real-time identification of peritumoral functional pathways enables surgeons to maximize EOR minimizing the post-operative morbidity.
Thefinal infection sizeis defined as the total number of individuals that become infected throughout an epidemic. Despite its importance for predicting the fraction of the population that will end infected, it does not capture which part of the infected population will present symptoms. Knowing this information is relevant because it is related to the severity of the epidemics. The objective of this work is to give a formula for the total number of symptomatic cases throughout an epidemic. Specifically, we focus on different types of structured SIR epidemic models (in which infected individuals can possibly become symptomatic before recovering), and we compute the accumulated number of symptomatic cases when time goes to infinity using a probabilistic approach. The methodology behind the strategy we follow is relatively independent of the details of the model.
ObjectiveAlthough the clinical application value of Aidi injection when treating non-small cell lung cancer (NSCLC) patients is explained only by the effectiveness of a certain literature or the improvement of a certain evaluation index, and the result is not convincing. To evaluate the effect of Aidi injection on life quality and incidence of adverse reactions in patients with NSCLCcompared with traditional chemotherapy.MethodsPubMed, EMBASE, ScienceDirect, Cochrane Library, China Journal full-text Database (CNKI), VIP full-text Database, Wanfang Database and Chinese Biomedical Literature data (CBM), search relevant Chinese and foreign periodicals, conference papers, degree papers, etc. were searched Database and China Biomedical Literature Database (CBM) to search case-control trials of Aidi injection when treating NSCLC patients. The retrieval period begins with the establishment of the database and ends when the database is closed. Cochrane Handbook 5.3 was adopted to assess the bias risk of each contained literature based on independently extracted data by two researchers. A meta-analysis of the collected data was carried out using RevMan5.3 statistical software.Results2306 articles were retrieved by computer database, 1422 articles were harvested by excluding repeated studies, 865 articles were harvested by preliminary reading of article titles and abstracts, and 533 articles were initially contained by excluding unrelated studies, reviews, case reports and uncontrolled articles, and then the full text of the literature was carefully read. Eight clinical controlled studies were finally included, with a total of 784 samples, after excluding 525 literatures with incomplete data and no primary outcome indicators. Data from the contained studies were not noticeably heterogeneous in the meta-analysis of treatment effectiveness. The fixed effect model analysis indicated that the treatment effective rate of the study group was noticeably better, and the difference was statistically significant(P<0.05). The findings of the heterogeneity test were clearly heterogeneous among the contained research data, according to the meta-analysis of the levels of T lymphocyte subsets following treatment. The random effect model analysis indicated that the improvement of the cellular immune function of the research group was obvious, and the difference was statistically significant (P<0.05). According to the meta-analysis of the life quality scores after treatment, data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. The random effect model analysis indicated that the life quality of the study group was noticeably higher, and the difference was statistically significant (P<0.05). The levels of serum vascular endothelial growth factor (VEGF) after treatment were measured by meta. Data from the contained research were evidently heterogeneous, according to results of the heterogeneity test. Random effect model analysis indicated that the level of serum VEGF in the study group was noticeably lower, and the difference was not statistically significant (P>0.05). A meta-analysis was conducted on the incidence of adverse reactions after treatment. The results of the heterogeneity test indicated that data from the contained research were evidently heterogeneous. The incidence was noticeably lower, and the difference was statistically significant (P<0.05). The funnel chart was drawn based on the effective rate of treatment, the level of T lymphocyte subsets, the score of life quality, the level of serum VEGF and the incidence of adverse reactions, and the publication bias analysis was carried out. The results indicated that most of the funnel maps were symmetrical and a small part of them were asymmetrical, suggesting that despite the heterogeneity of the study and the small number of included literatures, a publication bias was apparent in the included literature.ConclusionBased on routine chemotherapy associated with Aidi injection, the therapeutic effect of NSCLC patients can be noticeably enhanced, the effective rate of treatment can be noticeably promoted, the immune function and life quality can be improved, and the incidence of adverse reactions is low, which is worth popularizing in clinical practice, but several studies and follow-ups are needed to improve methodological quality and to verify the results over a longer period of time.
Data on the prevalence of perceived exposure to hazardous working conditions were gathered for the GEDA 2014/2015-EHIS study using a simple graduated question. Approximately one-fifth of people in employment state that they face serious or very serious occupational health hazards. However, women (18.6%) are significantly less likely to have this perception than men (27.0%). The differences between women and men can be explained by the variation in working hours and by the continued gender specific division of the labour market (segregation). There are pronounced differences among men with regard to educational and vocational qualifications, with lower qualified men viewing their employment as posing a higher risk to their health than higher qualified men; no similar differences exist between women. Finally, perceived health risks are highest among women and men in the passenger and freight transport sectors. The results of this study underline the importance of occupational safety and workplace health promotion.
Background:Actions focused on age-friendly environments contribute to promote and maintain older people’s functional ability and may enable them to contribute to their communities and enjoy life. As such, age-friendly practices require collaboration between diverse stakeholders across multiple sectors responsible for natural, built, and social environments, which can be particularly relevant during public health emergencies when socio-ecological vulnerabilities become more salient and may disproportionally affect older people. This paper presents a protocol for a scoping review aiming to investigate the breadth of evidence concerning the development, implementation, and evaluation of age-friendly practices during the COVID-19 pandemic. The protocol sets out the objectives, methods, and dissemination plans for the review.Methods:The scoping review will be conducted in line with the Joanna Briggs Institute (JBI) scoping review methodology. We will search databases (PubMed, Web of Science, Embase, CINAHL, Scopus, PsychNet) and grey literature sources. Publications relating to practices across the 8 domains of the World Health Organization’s age-friendly cities and communities’ framework will be included. A tabular data extraction tool will be used to facilitate a narrative synthesis of results.Ethics and dissemination:Ethical approval is not required as the methods proposed for this scoping review consist of collecting publicly available data. Findings will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) and submitted to a journal for academic dissemination. Lay dissemination plans include an infographic and a blog-style article presenting our core results.Conclusion:The publication of this protocol allows for transparency in the systematic process of a scoping review focused on age-friendly practices during COVID-19. Findings emerging from the scoping review will provide insights into the evidence available regarding age-friendly activities during COVID-19 and may inform future age-friendly practices during public health emergencies and beyond.
We report here the first clinical use of the left atrial appendage (LAA) for epicardial micrograft transplantation during left ventricular assist device (LVAD) implantation. Previously, a sample from the right atrial appendage (RAA) has been available for processing and administering micrograft therapy in cardiac surgery. Both LAA and RAA are rich sources of various types of myocardial cells and are capable of providing both paracrine and cellular support to the failing myocardium. The surgical approach of LAA micrografting facilitates epicardial micrograft therapy dose escalation and treatment of larger myocardial areas than done previously. Moreover, as collection of treated vs. untreated tissues from the recipient heart is possible following LVAD implantation at the time of heart transplantation, the evaluation of the therapy's mechanism of action can be further deciphered at cellular and molecular levels. This LAA modification of the epicardial micrografting technique has the overall potential to facilitate the adoption of cardiac cell therapy during heart surgery.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.
ObjectiveTo evaluate whether the categorization methods of risk stratification systems (RSSs) is a decisive factor that influenced the diagnostic performances and unnecessary FNA rates in order to choose optimal RSS for the management of thyroid nodules.MethodsFrom July 2013 to January 2019, 2667 patients with 3944 thyroid nodules had undergone pathological diagnosis after thyroidectomy and/or US-guided FNA. US categories were assigned according to the six RSSs. The diagnostic performances and unnecessary FNA rates were calculated and compared according to the US-based final assessment categories and the unified size thresholds for biopsy proposed by ACR-TIRADS, respectively.ResultsA total of 1781 (45.2%) thyroid nodules were diagnosed as malignant after thyroidectomy or biopsy. Significantly lowest specificity and accuracy, along with the highest unnecessary FNA rates were seen in EU-TIRADS for both US categories (47.9%, 70.2%, and 39.4%, respectively, allP< 0.05) and indications for FNA (54.2%, 50.0%, and 55.4%, respectively, allP< 0.05). Diagnostic performances for US-based final assessment categories exhibited similar accuracy for AI-TIRADS, Kwak-TIRADS, C-TIRADS, and ATA guidelines (78.0%, 77.8%, 77.9%, and 76.3%, respectively, allP> 0.05), while the lowest unnecessary FNA rate was seen in C-TIRADS (30.9%) and without significant differences to that of AI-TIRADS, Kwak-TIRADS, and ATA guideline (31.5%, 31.7%, and 33.6%, respectively, allP> 0.05). Diagnostic performance for US-FNA indications showed similar accuracy for ACR-TIRADS, Kwak-TIRADS, C-TIRADS and ATA guidelines (58.0%, 59.7%, 58.7%, and 57.1%, respectively, allP> 0.05). The highest accuracy and lowest unnecessary FNA rate were seen in AI-TIRADS (61.9%, 38.6%) and without significant differences to that of Kwak-TIRADS(59.7%, 42.9%) and C-TIRADS 58.7%, 43.9%, allP> 0.05).ConclusionThe different US categorization methods used by each RSS were not determinant influential factors in diagnostic performance and unnecessary FNA rate. For daily clinical practice, the score-based counting RSS was an optimal choice.
Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. However, optimization of these properties is not enough to circumvent unwanted toxicity towards mammalian cells. Hence, herein, we report new isoamphipathic antibacterial molecules (IAMs:1–3) where positional isomerism was introduced as one of the guiding factors for molecular design. This class of molecules displayed good (MIC = 1–8 μg mL−1or μM) to moderate [MIC = 32–64 μg mL−1(32.2–64.4 μM)] antibacterial activity against multiple Gram-positive and Gram-negative bacteria. Positional isomerism showed a strong influence on regulating antibacterial activity and toxicity forortho[IAM-1: MIC = 1–32 μg mL−1(1–32.2 μM), HC50= 650 μg mL−1(654.6 μM)],meta[IAM-2: MIC = 1–16 μg mL−1(1–16.1 μM), HC50= 98 μg mL−1(98.7 μM)] andpara[IAM-3: MIC = 1–16 μg mL−1(1–16.1 μM), HC50= 160 μg mL−1(161.1 μM)] isomers. Co-culture studies and investigation of membrane dynamics indicated thatorthoisomer, IAM-1 exerted more selective activity towards bacterial over mammalian membranes, compared tometaandparaisomers. Furthermore, the mechanism of action of the lead molecule (IAM-1) has been characterized through detailed molecular dynamics simulations. In addition, the lead molecule displayed substantial efficacy against dormant bacteria and mature biofilms, unlike conventional antibiotics. Importantly, IAM-1 exhibited moderatein vivoactivity against MRSA wound infection in a murine model with no detectable dermal toxicity. Altogether, the report explored the design and development of isoamphipathic antibacterial molecules to establish the role of positional isomerism in achieving selective and potential antibacterial agents.
Joint symptoms and pain belong to the most common diseases worldwide that affect people in their usual activities and lead to loss of quality of life. 29.3% of women and 24.4% of men reported acute joint pain, which is defined as pain suffered during the past 24 hours. With age, these figures increase. Women report pain in 3.9 joints on average and men in 3.6. In both genders the joints most affected are the shoulders, knees and hips. Respondents suffering from joint pain significantly more often report medically diagnosed osteoarthritis or rheumatoid arthritis than respondents who were free of pain.
Asthma is a chronic inflammatory disease of the airways affecting people of all ages. The disease is characterised by a variable narrowing of the bronchia, which may be accompanied by symptoms such as wheezing or shortness of breath. In GEDA 2014/2015-EHIS, 6.2% of respondents aged 18 years or older with complete information on the respective indicator (n=22,671) reported having had asthma during the past 12 months. The 12-month prevalence among women (7.1%) is higher than among men (5.4%). Overall, women and men with a low level of education more often reported having had asthma than those with a higher level of education. In analyses stratified by age and gender, differences in asthma prevalence with regard to educational level are evident among women under 30 years of age. In a comparison of federal states, the prevalence of asthma ranges from 3.0% to 9.7% among women and from 2.9% to 7.0% among men.
Visual attention is influenced by the characteristics of the stimuli (bottom-up), their task relevance (top-down), and prior experience (e.g., selection history and learning). However, it is largely unclear how learning and selection history interact with top-down attentional guidance. We combined trial-and-error learning with a spatial cueing protocol to test whether previously learned target-defining features continued to capture attention if participants were instructed to search for a new target feature (Experiment1) or had to learn a new target feature (Experiment2). It turned out that the previously learned feature quickly stopped capturing attention when the target feature changed (Experiment1; even before participants learned the new target-defining feature, in Experiment2). Finally, in Experiment3, in which participants learned to search for targets defined by two redundant features (color and orientation), we found possible reasons for the dominance of the instructed feature over learning. Participants reported using only the target color for their search. Consequently, only cues with a target color captured attention. The unused target orientation only captured attention in participants aware of both target-defining features (13 out of 23) and only if the orientation was presented in the target color. We conclude that knowledge of target-defining features and their use as search criterion is critical for attentional guidance, while previously learned target features either influence attentional guidance only contingent on such deliberately selected top-down based attentional control settings or may influence visual search but not attentional guidance.
BackgroundSpasticity is common among people with multiple sclerosis (MS), but there are few studies of spasticity treatment patterns. We aim to describe associations with spasticity treatment measured primarily by oral baclofen use.MethodsThis cohort study using Swedish registers included 1826 and 3519 people with incident and prevalent MS (pwIMS, pwPMS) respectively, followed from 2005 to 2014. Cox regression assessed factors associated with new baclofen prescriptions and its discontinuation.ResultsA total of 10% of pwIMS and 19% of pwPMS received baclofen, a drug prescribed specifically for spasticity in Sweden, of which many patients had relapsing-remitting course. Prescriptions occurred soon after MS diagnosis: pwIMS received baclofen typically within 6 months of diagnosis, and pwPMS within 3 years. Younger patients compared with older patients were three times more likely to receive baclofen with similar disability level measured using Expanded Disability Severity Scores (EDSS). Patients aged 18–44 years with EDSS 3.0–5.0 have an HR for baclofen use of 5.62 (95% CI 2.91 to 10.85) and EDSS 6+ have an HR of 15.41 (95% CI 7.07 to 33.58) compared with individuals with EDSS 0–2.5. In comparison, patients aged 45+ years with EDSS 3.0–5.0 have an HR of 2.05 (95% CI 1.10 to 3.82) and EDSS 6+ an HR of 4.26 (95% CI 1.96 to 9.17). Baclofen discontinuation was high: 49% (95% CI 0.42 to 0.57) of pwIMS discontinued within 150 days of dispensation, 90% discontinued within 2 years including patients with progressive course or higher EDSS. Associations among pwPMS and sensitivity analyses including additional treatments were similar.ConclusionsYounger patients with MS are more likely to receive baclofen compared with older patients with MS. High rates of baclofen discontinuation highlight the need for more tolerable and efficacious spasticity treatments and monitoring of spasticity among people with MS.
AimThe climate and ecological crises are considered fundamental threats to human health. Healthcare workers in general and doctors in particular can contribute as change agents in mitigation and adaptation. Planetary health education (PHE) aims to harness this potential. This study explores perspectives among stakeholders involved in PHE at German medical schools on the characteristics of high-quality PHE and compares them to existing PHE frameworks.MethodsIn 2021, we conducted a qualitative interview study with stakeholders from German medical schools involved in PHE. Three different groups were eligible: faculty members, medical students actively involved in PHE, and study deans of medical schools. Recruitment was performed through national PHE networks and snowball sampling. Thematic qualitative text analysis according to Kuckartz was used for the analysis. Results were systematically compared to three existing PHE frameworks.ResultsA total of 20 participants (13 female) from 15 different medical schools were interviewed. Participants covered a wide range of professional backgrounds and experience in PHE education. The analysis revealed ten key themes: (1) Complexity and systems thinking, (2) inter- and transdisciplinarity, (3) ethical dimension, (4) responsibility of health professionals, (5) transformative competencies including practical skills, (6) space for reflection and resilience building, (7) special role of students, (8) need for curricular integration, (9) innovative and proven didactic methods, and (10) education as a driver of innovation. Six of our themes showed substantial overlap with existing PHE frameworks. Two of our themes were only mentioned in one of the frameworks, and two others were not explicitly mentioned. Few important elements of the frameworks did not emerge from our data.ConclusionsIn the light of increased attention regarding the connections of the climate and ecological crises and health, our results can be useful for anyone working toward the integration of planetary health into medical schools' and any health professions' curricula and should be considered when designing and implementing new educational activities.
Current research emphasizes the habitual dietary pattern without differentiating eating occasions. We aimed to assess meal-specific dietary patterns and insulin resistance indicators. This cross-sectional study was conducted on 825 Iranian adults. Dietary data were recorded by three 24-h dietary recalls. Dietary patterns were identified using principal component analysis (PCA) on main meals and an afternoon snack. Anthropometric measurements, blood pressure, and laboratory investigation, fasting plasma glucose (FPG), triglyceride, insulin, c-reactive protein (CRP) were done. Homeostatic model assessment for insulin resistance and sensitivity (HOMA-IR and HOMA-IS), Triglycerides and glucose (TyG-index), and Lipid accommodation product index were calculated. We used multivariate analysis of variance (MANOVA) analysis. Two major dietary patterns at the main meals and the afternoon were identified. Higher adherence to “Bread, vegetable, and cheese” dietary pattern at breakfast was related to lower FPG, and “Oil, egg, and cereals” showed a direct association with body mass index, FPG, and TyG-index at breakfast. The “Western” pattern in lunch and dinner directly related to waist circumference (WC) and body mass index, however, it was inversely related to HOMA-IS. This pattern at dinner was related to higher CRP. Higher adherence to “bread, cereals, and oil” pattern at afternoon snack was associated with a lower WC. These results indicated that unhealthy meal-specific dietary patterns are associated with a greater chance of obesity and insulin resistance risk. However, “Bread, vegetable, and cheese” dietary pattern at breakfast was related to lower FPG, and “bread, cereals, and oil” pattern in the afternoon was associated with lower WC.
Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in health and disease. Neutrophils are highly glycolytic when activated, with inhibition of glycolysis associated with functional deficits. There is currently very limited data available assessing metabolism in neutrophils. Extracellular flux (XF) analysis assesses real time oxygen consumption and the rate of proton efflux in cells. This technology allows for the automated addition of inhibitors and stimulants to visualise the effect on metabolism. We describe optimised protocols for an XFe96 XF Analyser to (i) probe glycolysis in neutrophils under basal and stimulated conditions, (ii) probe phorbol 12-myristate 13-acetate induced oxidative burst, and (iii) highlight challenges of using XF technology to examine mitochondrial function in neutrophils. We provide an overview of how to analyze XF data and identify pitfalls of probing neutrophil metabolism with XF analysis. In summary we describe robust methods for assessing glycolysis and oxidative burst in human neutrophils and discuss the challenges around using this technique to assess mitochondrial respiration. XF technology is a powerful platform with a user-friendly interface and data analysis templates, however we suggest caution when assessing neutrophil mitochondrial respiration.
Ultrasound shear wave elastography is a modern method that is based on measuring the shear wave velocity making it possible to determine stiffness of soft biological tissues at an arbitrary point (point elastography) or to construct a two-dimensional color image with a subsequent point measurement of stiffness (two-dimensional elastography) and therefore to compare the stiffness of an object with a medium or objects with each other.The aim of the studyis to develop a new criterion for the comparative assessment of objects with different stiffness during shear wave elastometry: modulus of stiffness difference between object and environment.Materials and MethodsUsing the original technology of building two-dimensional color elastogram, point and two-dimensional shear wave elastography were performed using linear sensors on commercial ultrasound scanners: Aixplorer (SuperSonic Imagine, France), Acuson S2000 (Siemens, Germany), and Verasonics acoustic system (Verasonics Inc., USA) with an open architecture to determine the stiffness values of focal inclusions and compare them with each other with the help of a new comparative elastomeric assessment criterion: modulus of stiffness difference between object and environment. First, the accuracy of the scanners under test was compared on a calibrated Elasticity QA Phantom, model 049 (Computerized Imaging Reference Systems Company, USA) with a known stiffness of various inclusions and thereafter on an uncalibrated BP1901 phantom (Blue Phantom, USA) with unknown stiffness of inclusions. The obtained values were compared to determine the influence of subjective factors on the measurement results.ResultsTo assess the stiffness of the foci and compare the values with each other taking into account the rigidity of the environment, it is proposed to use a new criterion for the comparative assessment — the modulus of stiffness difference between focus and environment, which quantitatively characterizes the difference between these values. According to this criterion, all three ultrasound scanners have been established to show high and comparable accuracy in determining the stiffness of inclusions within the homogeneous medium in the experiments on phantoms. Two-dimensional shear wave elastography has revealed the effect of the control volume size and the correctness of the color scale setting, especially in the heterogeneous objects, on the results of elastometry. Methodological techniques to reduce the influence of subjective factors have also been proposed.ConclusionThe study has showed the possibility of using the modulus of stiffness difference between object and environment as a new criterion for comparative assessment of objects in shear wave elastometry taking into account stiffness of the environment. To reduce operator-dependence, it is necessary to take into consideration both the way of realizing elastometry (point or two-dimensional color elastography) and a number of other methodological factors.
Eye behavior differs between internally and externally directed cognition and thus is indicative of an internal versus external attention focus. Recent work implicated perceptual decoupling (i.e., eye behavior becoming less determined by the sensory environment) as one of the key mechanisms involved in these attention-related eye movement differences. However, it is not yet understood how perceptual decoupling depends on the characteristics of the internal task. Therefore, we systematically examined effects of varying internal task demands on smooth pursuit eye movements. Specifically, we evaluated effects of the internal workload (control vs. low vs. high) and of internal task (arithmetic vs. visuospatial). The results of multilevel modelling showed that effects of perceptual decoupling were stronger for higher workload, and more pronounced for the visuospatial modality. Effects also followed a characteristic time-course relative to internal operations. The findings provide further support of the perceptual decoupling mechanism by showing that it is sensitive to the degree of interference between external and internal information.Supplementary InformationThe online version contains supplementary material available at 10.3758/s13414-023-02688-3.
ObjectiveTo observe the effect of three consecutive intravitreal injections of conbercept in the treatment of neovascular age-related macular degeneration (nAMD), to investigate the correlation between retinal anatomy and retinal function by spectral-domain optical coherence tomography (SD-OCT) and electroretinography (ERG), to evaluate the short-term clinical efficacy of conbercept in the treatment of nAMD, and to explore the value of ERG as a predictor of treatment efficacy.MethodA retrospective investigation was conducted on 36 patients (36 eyes) treated with intravitreal injections of conbercept at 0.5 mg a month for three consecutive courses. Data collected included the best corrected visual acuity (BCVA), central retinal thickness (CRT), retinal pigment epithelium (RPE) elevation volume in 1 mm-diameter (1RV), 3 mm-diameter (3RV), and 6 mm-diameter circles around the fovea (6RV), amplitude density and latency of the P1 wave in the multifocal electroretinography (mf-ERG) R1 ring and amplitude and latency in full-field electroretinography (ff-ERG) at baseline and monthly. The paired t test was used to compare the difference between pre- and posttreatment. Pearson correlation analysis was used to analyze the correlation between macular retinal structure and function. The difference was significant whenp< 0.05.ResultsAt 12 weeks, the BCVA, CRT, 1RV, 3RV, 6RV, the P1 wave amplitude density of the mf-ERG R1 ring and the ff-ERG amplitude parameters were all significantly improved (p< 0.001). The BCVA in logMAR was positively correlated with CRT; 1RV, 3RV, and 6RV were negatively correlated with the amplitude density and latency of the mf-ERG R1 ring P1 wave. There were no severe ocular or systemic complications during the follow-up period.ConclusionConbercept is useful for the short-term treatment of nAMD. It can safely improve the visual acuity of affected eyes and restore the structure and function of the retina. ERG could serve as an objective indicator of function for evaluating the efficacy of and determining the need for retreatment during nAMD treatment.
For a drop on a very hot solid surface, a vapor film will form beneath the drop, which has been discovered by Leidenfrost in 1756. The vapor escaping from the Leidenfrost film causes uncontrollable flows, and actuates the drop to move around. Recently, although numerous strategies have been used to regulate the Leidenfrost vapor, the understanding of surface chemistry for modulating the phase-change vapor dynamics remains incomplete. Here, we report how to rectify vapor by “cutting” the Leidenfrost film using chemically heterogeneous surfaces. We demonstrate that the segmented film cut by a Z-shaped pattern can spin a drop, since the superhydrophilic region directly contacts the drop and vaporizes the water, while a vapor film is formed on the superhydrophobic surrounding to jet vapor and reduce heat transfer. Furthermore, we reveal the general principle between the pattern symmetry design and the drop dynamics. This finding provides new insights into the Leidenfrost dynamics modulation, and opens a promising avenue for vapor-driven miniature devices.
Many birds move fast into dark nest cavities forcing the visual system to adapt to low light intensities. Their visual system takes between 15 and 60 min for complete dark adaptation, but little is known about the visual performance of birds during the first seconds in low light intensities. In a forced two-choice behavioural experiment we studied how well budgerigars can discriminate stimuli of different luminance directly after entering a darker environment. The birds made their choices within about 1 s and did not wait to adapt their visual system to the low light intensities. When moving from a bright facility into an environment with 0.5 log unit lower illuminance, the budgerigars detected targets with a luminance of 0.825 cd m−2on a black background. When moving into an environment with 1.7 or 3.5 log units lower illuminance, they detected targets with luminances between 0.106 and 0.136 cd m−2. In tests with two simultaneously displayed targets, the birds discriminated similar luminance differences between the targets (Weber fraction of 0.41–0.54) in all light levels. Our results support the notion that partial adaptation of bird eyes to the lower illumination occurring within 1 s allows them to safely detect and feed their chicks.
AbstractObjectiveEWS‐FLI1 is the most common oncogenic fusion protein in Ewing's sarcoma family tumors (ESFTs). DAX1, an orphan member of the nuclear receptor superfamily, is up‐regulated by EWS‐FLI1 and plays a key role in the transformed phenotype of ESFTs.MethodsTo discover a functional inhibitor of DAX1 and EWS‐FLI1, we screened small‐molecular inhibitors using a DAX1 reporter assay system.ResultsK‐234 and its derivatives, which were dihydroorotate dehydrogenase (DHODH) inhibitors, showed inhibitory effects in the reporter assay. K‐234 inhibited the growth of Ewing's sarcoma with various fusion types, and K‐234 derivatives altered the expression of EWS‐FLI1‐regulated genes. The DAX1 expression had no effect on the growth inhibitory effect of the K‐234 derivatives, while DHODH overexpression or uridine treatment attenuated their inhibitory effects, suggesting that inhibition by K‐234 derivatives occurs through DHODH inhibition. An in vivo study showed that a K‐234 derivative clearly inhibited tumor growth in an Ewing's sarcoma xenograft mouse model.ConclusionTaken together, the present results suggest that DHODH inhibitors can inhibit the function of DAX1/EWS‐FLI1 in ESFTs and might be a therapeutic agent with potent anti‐tumor activity for Ewing's sarcoma patients.
AbstractBackground and AimPoliovirus is a global health issue that affects children in different parts of the world. Despite the efforts of national, international, and nongovernmental organizations to eradicate the disease, it is re‐emerging in Africa due to poor sanitation, vaccine hesitancy, new ways of transmission, and poor surveillance among others. Circulating vaccine‐derived poliovirus type 2 (cVDPV2) is a major step in eradicating poliovirus and preventing outbreaks in developing countries. Strengthening African healthcare systems, increasing surveillance, hygiene and sanitation, and proper mass vaccination to achieve herd immunity are required in the fight against polio disease. This paper discusses the outbreak of cVDPV2, public health challenges, and recommendations in Africa with a special emphasis on Nigeria.MethodsWe searched for articles documenting the incidence of cVDPV2 in Nigeria and other African countries on Pubmed, Google Scholar, and Scopus.ResultsA total of 68 distinct cVDPV2 genetic emergences were found across 34 nations between April 2016 to December 2020, and in Nigeria, three cVDPV2 emergences were found. Also, 1596 instances of acute flaccid paralysis linked to cVDPV2 outbreaks were reported in four areas of the World Health Organization where Africa contributed 962 cases out of 1596 cases. Available data indicate that Africa has the most cVDPV2 cases and is associated with various challenges like the unidentified virus source, poor sanitation system, and inability to achieve herd immunity of the cVDPV2 vaccine.ConclusionCollaborative efforts of stakeholders are crucial in combating infectious diseases, especially those transmitted via environments such as water and air, like poliovirus. Therefore, a collaboration between environmental health workers, veterinarians, community health workers, laboratory scientists, policymakers, and other professionals is required.
The family Anaplasmataceae includes tick-borne bacteria of major public and veterinary health interest, as best illustrated by members of the generaAnaplasmaandEhrlichia. Recent epidemiological surveys have also reported on the presence of a novel putative genus in the Anaplasmataceae,CandidatusAllocryptoplasma, previously described asCandidatusCryptoplasma in the western black-legged tick,Ixodes pacificus. However, the genetic diversity ofCa.Allocryptoplasma and its phylogenetic relationship with other Anaplasmataceae remain unclear. In this study, we developed a multi-locus sequence typing approach, examining the DNA sequence variation at five genes ofCa.Allocryptoplasma found in ticks. Combining this multi-locus sequence typing and genetic data available on public databases, we found that substantial genetic diversity ofCa.Allocryptoplasma is present inIxodes,AmblyommaandHaemaphysalisspp. ticks on most continents. Further analyses confirmed that theCa.Allocryptoplasma of ticks, theCa.Allocryptoplasma of lizards and someAnaplasma-like bacteria of wild mice cluster into a monophyletic genus, divergent from all other genera of the family Anaplasmataceae.CandidatusAllocryptoplasma appears as a sister genus ofAnaplasmaand, with the generaEhrlichiaandNeoehrlichia, they form a monophyletic subgroup of Anaplasmataceae associated with tick-borne diseases. The detection of genetically distinctCa.Allocryptoplasma in ticks of significant medical or veterinary interest supports the hypothesis that it is an emergent genus of tick-borne pathogens of general concern.
From the clinical standpoint, systemic sclerosis (SSc) is characterized by skin and internal organ fibrosis, diffuse fibroproliferative vascular modifications, and autoimmunity. Clinical presentation and course are highly heterogenous and life expectancy variably affected mostly dependent on lung and heart involvement. SSc touches more women than men with differences in disease severity and environmental exposure. Pathogenetic events originate from altered homeostasis favored by genetic predisposition, environmental cues and a variety of endogenous and exogenous triggers. Epigenetic modifications modulate SSc pathogenesis which strikingly associate profound immune-inflammatory dysregulation, abnormal endothelial cell behavior, and cell trans-differentiation into myofibroblasts. SSc myofibroblasts show enhanced survival and enhanced extracellular matrix deposition presenting altered structure and altered physicochemical properties. Additional cell types of likely pathogenic importance are pericytes, platelets, and keratinocytes in conjunction with their relationship with vessel wall cells and fibroblasts. In SSc, the profibrotic milieu is favored by cell signaling initiated in the one hand by transforming growth factor-beta and related cytokines and in the other hand by innate and adaptive type 2 immune responses. Radical oxygen species and invariant receptors sensing danger participate to altered cell behavior. Conventional and SSc-specific T cell subsets modulate both fibroblasts as well as endothelial cell dysfunction. Beside autoantibodies directed against ubiquitous antigens important for enhanced clinical classification, antigen-specific agonistic autoantibodies may have a pathogenic role. Recent studies based on single-cell RNAseq and multi-omics approaches are revealing unforeseen heterogeneity in SSc cell differentiation and functional states. Advances in system biology applied to the wealth of data generated by unbiased screening are allowing to subgroup patients based on distinct pathogenic mechanisms. Deciphering heterogeneity in pathogenic mechanisms will pave the way to highly needed personalized therapeutic approaches.
BackgroundThe changes which typically occur in molecular causal risk factors and predictive biomarkers for cardiometabolic diseases across early life are not well characterised.MethodsWe quantified sex-specific trajectories of 148 metabolic trait concentrations including various lipoprotein subclasses from age 7 years to 25 years. Data were from 7065 to 7626 offspring (11 702 to14 797 repeated measures) of the Avon Longitudinal Study of Parents and Children birth cohort study. Outcomes were quantified using nuclear magnetic resonance spectroscopy at 7, 15, 18 and 25 years. Sex-specific trajectories of each trait were modelled using linear spline multilevel models.ResultsFemales had higher very-low-density lipoprotein (VLDL) particle concentrations at 7 years. VLDL particle concentrations decreased from 7 years to 25 years with larger decreases in females, leading to lower VLDL particle concentrations at 25 years in females. For example, females had a 0.25 SD (95% CI 0.20 to 0.31) higher small VLDL particle concentration at 7 years; mean levels decreased by 0.06 SDs (95% CI −0.01 to 0.13) in males and 0.85 SDs (95% CI 0.79 to 0.90) in females from 7 years to 25 years, leading to 0.42 SDs (95% CI 0.35 to 0.48) lower small VLDL particle concentrations in females at 25 years. Females had lower high-density lipoprotein (HDL) particle concentrations at 7 years. HDL particle concentrations increased from 7 years to 25 years with larger increases among females leading to higher HDL particle concentrations in females at 25 years.ConclusionChildhood and adolescence are important periods for the emergence of sex differences in atherogenic lipids and predictive biomarkers for cardiometabolic disease, mostly to the detriment of males.
Multigene testing using NGS (next-generation sequencing) provides a large amount of information and can detect multiple molecular alterations. Subsequent clinical interpretation is a time-consuming process necessary to select a treatment strategy. Existing databases often contain inconsistent information and are not regularly updated. The use of ESCAT levels of evidence requires a deep understanding of the nature of alterations and does not answer the question of which therapy option to select when multiple biomarkers with the same level of evidence are detected. To address these issues, we created the Clinical Relevance of Alterations in Cancer (CRAC) database on the relevance of detected alterations in specific genes, which are often analyzed as part of NGS panels. The team of oncologists and biologists assigned a CRAC score from 1 to 10 to each biomarker (a type of genomic alteration characteristic of specific genes) for 15 malignancies; an average score was entered into the database. CRAC scores are a numerical reflection of the following factors: therapy availability and the prospects of drug treatment with experimental drugs for patients with a particular type of tumor. A total of 134 genes and 15 of the most common tumor types have been selected for CRAC. The biomarker–nosology associations with CRAC scores in the range of 1–3 are the most frequent (n=2719 out of 3495; 77.8%), the least frequent ones (n=52 out of 3495; 1.5%) are with the highest CRAC scores 9 and 10. To estimate the practical effectiveness of the CRAC database, 208 reports on comprehensive molecular profiling were retrospectively analyzed; the applicability of CRAC was compared with the ESCAT level of evidence system. The highest CRAC scores corresponded to the ESCAT maximum levels of evidence: the range of scores 8–10 corresponded to evidence levels I and II. No biomarker within the same level of evidence was represented by the same CRAC score; the largest range of CRAC scores was observed for biomarkers of levels evidence IIIA and IV — from 2 to 10 and from 1 to 9, respectively. The use of CRAC scores allowed to identify additional 95 alterations with CRAC scores of 1–5 in the studied patients.The developed database is available at:https://crac.oncoatlas.ru/.
Patients with chemo-refractory metastatic colorectal cancer (mCRC) have poor prognoses. The application of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors encouragingly improved the survival of mCRC patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR). Unfortunately, it was ineffective for mCRC with microsatellite-stable (MSS)/proficient mismatch repair (pMMR), which accounted for 95% of mCRC. Radiotherapy can promote local control by directly killing tumor cells and inducing positive immune activities, which might help synergistically with immunotherapy. We present the report of an advanced MSS/pMMR mCRC patient who had progressive disease (PD) after first-line chemotherapy, palliative surgery and second-line chemotherapy combined with targeted therapy. Then the patient received the therapy of PD-1 inhibitor combined with radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF). According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), the patient showed a complete response (CR) after triple-combined therapy with progression-free survival (PFS) for more than 2 years so far. The patient had no other significant adverse reactions except for fatigue (Grade 1). The triple-combination therapy provided a promising strategy for metastatic chemo-refractory MSS/pMMR mCRC patients.
Questing ticks are usually collected by flagging or dragging. Mostly exophilic tick species are caught, such asIxodes ricinus, the most common tick in Central Europe. In the present study, ticks collected from underground environments in the Grand Duchy of Luxembourg and in the Central German Uplands (Federal States of Hesse, Bavaria, Thuringia, Baden-Wuerttemberg, Rhineland-Palatinate, Saarland and Northrhine-Westphalia) were investigated. Six tick species were revealed among the 396 analyzed specimens:Ixodes ariadnae,Ixodes canisuga,Ixodes hexagonus,I. ricinus,Ixodes trianguliceps, andDermacentor marginatus. Adults and immatures ofI. hexagonusdominated the findings (57% of all specimens), especially in shelters acting as potential resting places of main hosts.Ixodes canisugaandI. triangulicepswere for the first time recorded in Luxembourg, and one nymph of the bat tickI. ariadnaerepresents only the second report for Germany. Collecting ticks in subterranean environments turned out to be a useful approach to increase knowledge about the occurrence of relatively rare tick species, including those that spend most of their lifetime on their hosts, but detach in such environmental settings.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10493-023-00795-2.
Background17q12 microdeletion and microduplication syndromes present as overlapping, multisystem disorders. We assessed the disease phenotypes of individuals with 17q12 CNV in a population-based cohort.MethodsWe investigated 17q12 CNV using microarray data from 450 993 individuals in the UK Biobank and calculated disease status associations for diabetes, liver and renal function, neurological and psychiatric traits.ResultsWe identified 11 17q12 microdeletions and 106 microduplications. Microdeletions were strongly associated with diabetes (p=2×10−7) but microduplications were not. Estimated glomerular filtration rate (eGFR mL/min/1.73 m2) was consistently lower in individuals with microdeletions (p=3×10−12) and microduplications (p=6×10−25). Similarly, eGFR <60, including end-stage renal disease, was associated with microdeletions (p=2×10−9, p<0.003) and microduplications (p=1×10−9, p=0.009), respectively, highlighting sometimes substantially reduced renal function in each. Microduplications were associated with decreased fluid intelligence (p=3×10−4). SNP association analysis in the 17q12 region implicated changes toHNF1Bas causing decreased eGFR (NC_000017.11:g.37741642T>G, rs12601991, p=4×10−21) and diabetes (NC_000017.11:g.37741165C>T, rs7501939, p=6×10−17). A second locus within the region was also associated with fluid intelligence (NC_000017.11:g.36593168T>C, rs1005552, p=6×10−9) and decreased eGFR (NC_000017.11:g.36558947T>C, rs12150665, p=4×10–15).ConclusionWe demonstrate 17q12 microdeletions but not microduplications are associated with diabetes in a population-based cohort, likely caused byHNF1Bhaploinsufficiency. We show that both 17q12 microdeletions and microduplications are associated with renal disease, and multiple genes within the region likely contribute to renal and neurocognitive phenotypes.
Hepatocellular carcinoma (HCC) is the 3rdmost deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressingCyp1b1but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.
Prolonged grief disorder (PGD) is a new mental health disorder, recently introduced in the International Classification of Diseases (ICD-11), World Health Organization Classification of Diseases (WHO). The new ICD-11 guidelines reflect an emerging wave of interest in the global applicability of mental disorders. However, the selection of diagnostic core features in different cultural contexts has yet to be determined. Currently, there is debate in the field over the global applicability of these guidelines. Using semi-structured interviews with 14 key informants, we explored the acceptability of ICD-11 guidelines for PGD according to Japanese health professionals as key informants. The interviews revealed symptoms of grief possibly missing in the ICD-11 PGD guidelines including somatization and concepts such ashole in the heart. Additionally, sociocultural barriers such as stigma and beliefs about the social desirability of emotions may challenge patients’ and clinicians’ acceptance of the new ICD-11 criteria.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11013-022-09781-6.
Background and purposeData on in-stent stenosis (ISS) following the flow diverter (FD) implantation method are scarce and inconsistent. In the present study, we sought to determine the incidence of ISS and identify the factors that predict its severity via the use of ordinal logistic regression.MethodsA retrospective review of our center's electronic database was conducted to identify all patients with intracranial aneurysms (IAs) who received pipeline embolization device (PED) implantation between 2016 and 2020. Patient demographics, aneurysm characteristics, procedural information, and clinical and angiographic outcomes were reviewed. ISS was quantitatively assessed on angiographic follow-ups and graded as mild (<25%), moderate (25–50%), or severe (>50%). Ordinal logistic regression was conducted to determine the predictors of stenosis severity.ResultsA total of 240 patients with 252 aneurysms treated in 252 procedures were enrolled in this study. ISS has been detected in 135 (53.6%) lesions, with a mean follow-up time of 6.53 ± 3.26 months. The ISS was mild in 66 (48.9%) cases, moderate in 52 (38.5%) cases, and severe in 17 (12.6%) cases. All patients were asymptomatic, except for two of them with severe stenosis who presented with symptoms of acute cerebral thrombosis. Ordinal logistic regression identified that younger age and a longer procedure duration were independent predictors of a higher likelihood of ISS.ConclusionISS is a common angiographic finding after PED implantation for IAs and is presented as a largely benign course through long-term follow-up. Patients who were younger in age and had a longer procedure duration were found to be at a greater risk of developing ISS.
Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad’s phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of “seronegative” SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients’ stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns’ interpretation. The gold-standard technique for autoantibodies’ identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.
The aim of the studyis to develop a method for detection of pathological respiratory sound, caused by bronchial asthma, with the aid of machine learning techniques.Materials and MethodsTo build and train neural networks, we used the records of respiratory sounds of bronchial asthma patients at different stages of the disease (n=951) aged from several months to 47 years old and healthy volunteers (n=167). The sounds were recorded with calm breathing at four points: at the oral cavity, above the trachea, on the chest (second intercostal space on the right side), and at a point on the back.ResultsThe method developed for computer-aided detection of respiratory sounds allows to diagnose sounds typical for bronchial asthma in 89.4% of cases with 89.3% sensitivity and 86.0% specificity regardless of sex and age of the patients, stage of the disease, and the point of sound recording.
ObjectivesSevere infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial.MethodsData on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models.ResultsEighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis againstPneumocystis jiroveciiwith trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA.ConclusionsThe use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.
The identification and classification of crystal structures is fundamental in materials science, as the crystal structure is an inherent factor of what gives solid materials their properties. Being able to identify the same crystallographic form from unique origins (e.g.different temperatures, pressures, orin silico-generated) is a complex challenge. While our previous work has focused on comparison of simulated powder diffractograms from known crystal structures, herein is presented the variable-cell experimental powder difference (VC-xPWDF) method to match collected powder diffractograms of unknown polymorphs to both experimental crystal structures from the Cambridge Structural Database andin silico-generated structures from the Control and Prediction of the Organic Solid State database. The VC-xPWDF method is shown to correctly identify the most similar crystal structure to both moderate and “low” quality experimental powder diffractograms for a set of 7 representative organic compounds. Features of the powder diffractograms that are more challenging for the VC-xPWDF method are discussed (i.e.preferred orientation), and comparison with the FIDEL method showcases the advantage of VC-xPWDF provided the experimental powder diffractogram can be indexed. The VC-xPWDF method should allow rapid identification of new polymorphs from solid-form screening studies, without requiring single-crystal analysis.
BackgroundPsilocybin may help treat obsessive–compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with a randomized controlled design. The neural correlates of psilocybin’s effects on OCD have also not been studied.ObjectivesThis first-of-its-kind trial aims to evaluate the feasibility, safety, and tolerability of psilocybin in the treatment of OCD, provide preliminary evidence on the effects of psilocybin on OCD symptoms, and elucidate neural mechanisms that may mediate psilocybin’s effects on OCD.DesignWe use a randomized (1:1), double-blind, placebo-controlled, non-crossover design to examine the clinical and neural effects of either a single dose of oral psilocybin (0.25 mg/kg) or active placebo-control agent (250 mg of niacin) on OCD symptoms.Methods and analysisWe are enrolling 30 adult participants at a single site in Connecticut, USA who have failed at least one trial of standard care treatment (medication/psychotherapy) for OCD. All participants will also receive unstructured, non-directive psychological support during visits. Aside from safety, primary outcomes include OCD symptoms over the past 24 h, assessed by the Acute Yale-Brown Obsessive–Compulsive Scale and Visual Analog Scale ratings. These are collected by blinded, independent raters at baseline and the primary endpoint of 48 h post-dosing. Total follow-up is 12 weeks post-dosing. Resting state neuroimaging data will be collected at baseline and primary endpoint. Participants randomized to placebo will be offered the chance to return for an open-label dose of 0.25 mg/kg.Ethics statementAll participants will be required to provide written informed consent. The trial (protocol v. 5.2) was approved by the institutional review board (HIC #2000020355) and registered withClinicalTrials.gov(NCT03356483).DiscussionThis study may represent an advance in our ability to treat refractory OCD, and pave the way for future studies of neurobiological mechanisms of OCD that may respond to psilocybin.
Idiopathic inflammatory myopathies (IIMs) are a group of acquired muscle diseases with muscle inflammation, weakness, and other extra-muscular manifestations. IIMs can significantly impact the quality of life, and management of IIMs often requires a multi-disciplinary approach. Imaging biomarkers have become an integral part of the management of IIMs. Magnetic resonance imaging (MRI), muscle ultrasound, electrical impedance myography (EIM), and positron emission tomography (PET) are the most widely used imaging technologies in IIMs. They can help make the diagnosis and assess the burden of muscle damage and treatment response. MRI is the most widely used imaging biomarker of IIMs and can assess a large volume of muscle tissue but is limited by availability and cost. Muscle ultrasound and EIM are easy to administer and can even be performed in the clinical setting, but they need further validation. These technologies may complement muscle strength testing and laboratory studies and provide an objective assessment of muscle health in IIMs. Furthermore, this is a rapidly progressing field, and new advances are going to equip care providers with a better objective assessment of IIMS and eventually improve patient management. This review discusses the current state and future direction of imaging biomarkers in IIMs.
Proteases are involved in almost all biological processes, implying their importance for both health and pathological conditions. Dysregulation of proteases is a key event in cancer. Initially, research identified their role in invasion and metastasis, but more recent studies have shown that proteases are involved in all stages of cancer development and progression, both directly through proteolytic activity and indirectly via regulation of cellular signaling and functions. Over the past two decades, a novel subfamily of serine proteases called type II transmembrane serine proteases (TTSPs) has been identified. Many TTSPs are overexpressed by a variety of tumors and are potential novel markers of tumor development and progression; these TTSPs are possible molecular targets for anticancer therapeutics. The transmembrane protease serine 4 (TMPRSS4), a member of the TTSP family, is upregulated in pancreatic, colorectal, gastric, lung, thyroid, prostate, and several other cancers; indeed, elevated expression of TMPRSS4 often correlates with poor prognosis. Based on its broad expression profile in cancer, TMPRSS4 has been the focus of attention in anticancer research. This review summarizes up-to-date information regarding the expression, regulation, and clinical relevance of TMPRSS4, as well as its role in pathological contexts, particularly in cancer. It also provides a general overview of epithelial-mesenchymal transition and TTSPs.

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