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data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1007_en.txt

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+A 51-year-old Japanese man developed gross hematuria. He visited a local hospital where he underwent abdominal computed tomography, which revealed many cysts with calcification inside the left kidney. He was then referred to our hospital for further examination. A blood test showed no abnormal findings. Urinary cytology yielded a pseudo-positive result (class 3). However, dynamic contrast-enhanced computed tomography revealed a mass, which showed enhancement in the early phase and appeared washed out in the late phase, in a cyst at the upper pole of the left kidney . Magnetic resonance imaging revealed a tumor with an abnormal signal on a diffusion-weighted image . Retrograde pyelography showed no wall irregularity at the left renal pelvis, and urinary cytology of samples from the left pelvis and urinary tract yielded negative results. He was diagnosed with left cystic renal cell carcinoma (cT1N0M0) and underwent retroperitoneal laparoscopic nephrectomy. The surgical specimen showed a cystic lesion filled with papillary formation . Microstones and brownish liquid retention were also observed inside the cystic lesion. Pathological examination revealed that the wall of the cystic lesion was covered with urothelial cells and high-grade urothelial carcinoma with renal parenchymal invasion. In immunohistochemical staining, GATA3, p63, and p40 were positive and PAX8 was negative. The definitive pathological diagnosis was urothelial carcinoma originating from the renal pyelocalyceal diverticulum, invasive urothelial carcinoma, high-grade (G3), and pT3. An additional residual ureterectomy and two courses of gemcitabine and cisplatin adjuvant chemotherapy were performed. Pathological examination showed no malignant findings of the residual ureter, and no recurrence was observed during the 12-month follow-up.

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+The present case reports a 37-year-old man suffering from metastatic osteosarcoma originating in the distal part of the left femur. In March 2018, the patient entered the hospital with pain in the left leg as the major symptom. An MRI scan showed a large tumor with extramedullary parts and an intraosseous diameter of 13 cm. The histological examination of the biopsy showed a mostly epithelioid, in part osteoblastic, high-grade osteosarcoma. In the CT scans of the thorax and abdomen, there was no metastasis detectable. Before surgery, the patient was treated with a neoadjuvant regimen analog to the EURAMOS-1 trial with two cycles of doxorubicin and cisplatin and four cycles of high-dose MTX. In the intermediate staging performed by a further CT scan before surgical resection of the tumor, there was still no sign of distant metastasis. In the restaging-MRI of the left thigh the tumor showed a decrease in size. Limb saving surgical resection of the entire tumor (R0) was performed in August 2018. The tumor showed regression with 30% vital tumor cells (grade IV Salzer-Kutschnik).
+Surgery was followed by an adjuvant chemotherapy analog to the EURAMOS-1-protocol containing two cycles of doxorubicin and cisplatin, two further cycles of Doxorubicin and eight cycles of high-dose MTX. The start of adjuvant chemotherapy was delayed for two weeks because of a wound infection.
+The final staging after the last chemotherapy cycle showed two new pulmonary metastases in the CT scan of the lung. Hence, curatively intended surgical resection was performed in April 2019.
+In September 2019, the patient had a seizure and in an MRI of the brain multiple cerebral metastases became visible. A neurosurgical resection of a symptomatic metastasis was performed, followed by a total brain irradiation with a boost on parafalcial and occipital metastases.
+In a systemic restaging performed by a total body FDG-PET-CT scan and an MRI of the brain, the patient then showed a rapid systemic disease-progression with metastases affecting the lung, the mediastinum, the left adrenal gland, the brain, soft tissue, bones, and the skin. (, , )
+In a molecular testing of the most recent tissue sample of the resected brain metastases, the tumor showed a high expression of PD-L1 (TPS 90% CPS 92%) but microsatellite stability (MSS). The patient was still in a good performance state (ECOG 1). A salvage chemotherapy containing the in osteosarcoma therapy established drugs ifosfamide and etoposide was not performed because of an acute kidney failure in the patient’s history and a high amount of cumulative neurotoxicity after the total brain irradiation. Benefit-risk ratio was not considered being favorable for this option. Referring to the case of a patient with advanced osteosarcoma reported by Nuytemans et al. , who reached a stabilization of disease-progression undergoing immunotherapy with nivolumab and ipilimumab, an individual therapy attempt with the same treatment combination was conducted, as there was no further established therapy and no ongoing study available.
+Starting in December 2019, we exposed the patient to the immunotherapy combination of Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg every 3 weeks for four times analog to the established treatment protocol for kidney cancer. In the following restaging performed by a PET-CT scan and an MRI of the brain 3 months after starting the therapy, the patient showed a clear response to the therapy with a profound remission of all tumor lesions (, , ). In some of the lesions, a minimally elevated uptake of FDG remained residually, whereas the lesions were not metrically measurable any more in the corresponding CT scan. In brain MRIs, minimal residual structures were interpreted as gliosis after total brain irradiation and immunotherapy. A definite distinction between inflammation or scar and minimal tumor residuals was not possible in PET-CT scans and MRIs.
+In February 2020, the patient suffered from herpes zoster as a complication, which was treated with brivudine for 7 days.
+The patient developed a mild facial palsy of the right side in March 2020, which can be considered as a side effect of the immunotherapy. In an examination of the cerebrospinal fluid, a slightly increased cell count of 9/nl could be detected but no signs of VZV encephalitis or meningeosis carcinomatosa, respectively.
+In March 2020, the patient developed an immunotherapy-related pneumonitis with clinically mild symptoms but clear correlations in CT scans of the lung and noticeably reduced diffusion capacity in a subsequent lung-function examination. Therefore, immunotherapy had to be discontinued, and nivolumab maintenance could not be started according to protocol.
+For treatment of pneumonitis, the patient received prednisolone with an initial dose of 50 mg per day (0.5 mg/kg). Because of decreasing signs of pneumonitis in control CT scans and an improving diffusion capacity in lung function, prednisolone could be quickly tapered to 7.5 mg, and re-exposure to nivolumab was feasible in June 2020. In the actual PET-CT scan and MRI of the brain, the patient still showed a profound remission of all tumor lesions, and there was no detectable sign of a relapse (, ). Currently, prednisolone is completely tapered, and the patient undergoes nivolumab maintenance (240mg) every 2 weeks. The performance state has further improved, and the patient is starting reintegration into work.
+outlines the patient’s history.

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+A 14-year-old girl was diagnosed with precursor B-cell acute lymphoblastic leukemia (B-ALL) at 7 years of age and treated per the protocol for the standard-risk group in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-B12 clinical trial at another hospital in February 2015. Molecular remission was achieved at the end of the consolidation therapy. Two years after treatment completion, she developed combined relapse in the bone marrow and central nervous system. Molecular remission was achieved with multi-agent and intrathecal chemotherapy, and umbilical cord blood transplantation (CBT) was performed 4 months after the diagnosis of relapse. The patient developed hemophagocytic lymphohistiocytosis (HLH) and exhibited delayed engraftment following CBT. Ten months after CBT, she developed autoimmune cytopenia with the production of anti-neutrophil antibodies, anti-erythrocyte antibodies, and platelet-associated IgG (PA-IgG), as well as pleural effusion and ascites. She was treated with prednisolone, cyclosporine, mycophenolate mofetil, and rituximab. Twenty-one months after CBT, she presented with dyspnea, dysuria, diarrhea, and disorders of consciousness and was diagnosed with combined second relapse in the bone marrow and central nervous system. The ferritin level was 10 606 ng/mL at the second relapse. She underwent multidrug chemotherapy, intrathecal chemotherapy, and whole-brain irradiation. Subsequently, she was referred to Keio University Hospital for CD19-targeted CAR-T cell therapy in September 2021, 1 month after diagnosis of the second relapse. CD19-targeted CAR-T cell therapy was performed, and 2.2 × 106/kg/dose of CAR-T cells were administered . Three to seven days after CAR-T cell therapy, the patient developed fever as grade 1 cytokine release syndrome. Pancytopenia requiring blood transfusion persisted for 2 months after CAR-T cell therapy. The patient remained in remission after the therapy and continued to receive TMP/SMX for PJP prophylaxis. The CD4+ T-cell counts remained above 200/μL from 3 months and above 500/μL from 6 months after CAR-T cell therapy. Phytohemagglutinin (PHA)-induced lymphocyte proliferation was normal. TMP/SMX therapy was discontinued 7 months after CAR-T cell therapy. CD19+ B-cell aplasia persisted, and IgG levels were maintained at 400–800 mg/dL with periodic immunoglobulin replacement therapy. Ten months after CAR-T cell therapy, she presented to our hospital with fever, cough, and dyspnea for 5 days. On admission, her body temperature was 38.0°C, and her O2 saturation was 91% on room air. Laboratory tests showed the following: white blood cell count, 8.0 × 109/L (normal range: 3.8–9.4 × 109/L) [band neutrophils, 4%; segmented neutrophils, 66%; lymphocytes, 21%; atypical lymphocytes, 2%; monocytes, 6%; eosinophils, 0%; basophils, 1%; CD4+ T-cell count, 771/μL; CD19+ B-cell count, 0/μL]; hemoglobin, 124 g/L (normal range: 118–149 g/L); hematocrit, 0.387 L/L (normal range: 0.350–0.436 L/L); mean corpuscular volume, 100 fL (normal range: 79.5–96.5 fL); platelet count, 92 × 109/L (normal range: 170–410 × 109/L); albumin, 3.3 g/dL (normal range: 3.8–4.8 g/dL); C-reactive protein, 1.24 mg/dL (normal range: 0–0.14 mg/dL); aspartate aminotransferase, 60 U/L (normal range: 13–28 U/L); alanine aminotransferase, 29 U/L (normal range: 9–29 U/L); lactate dehydrogenase, 535 U/L (normal range: 130–250 U/L); β-D glucan, 511 pg/mL (normal range: 0–11 pg/mL); KL-6, 643 U/mL (normal range: 0–500 U/mL); soluble IL-2R, 2494 U/mL (normal range: 121–613 U/mL); ferritin, 1163 ng/mL (normal range: 8–129 ng/mL); and IgG, 244 mg/dL (normal range: 861–1747 mg/dL). Chest radiography and computed tomography (CT) revealed diffuse ground-glass opacities in both lungs . Polymerase chain reaction (PCR) testing of the sputum showed positivity for Pj. PJP was diagnosed on the basis of the PCR test results, high β-D glucan and KL-6 levels, and characteristic CT findings. She was treated with immunoglobulin (250 mg/kg/day) for hypogammaglobulinemia and TMP/SMX (15 mg/kg/day of trimethoprim) and prednisolone (1.5 mg/kg/day) for PJP; this resulted in rapid amelioration of her symptoms. Immunoglobulin was administered only once. TMP/SMX was discontinued after 21 days, and prednisolone was tapered by 0.5 mg/kg/day every 5 days for 15 days. After treatment, the patient continued to receive TMP/SMX (4 mg/kg/day of trimethoprim) twice a week for PJP prophylaxis, along with periodic immunoglobulin replacement therapy to maintain her IgG levels above 600 mg/dL. Ten months after the treatment, there was no recurrence of PJP or any other complications.

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+A 71-year-old man was referred to our clinic for treatment of an iatrogenic total iridodialysis. Just before the referral, his iris had been totally torn out and jammed into the hinge of a prechopper during the removal of an instrument during cataract surgery. Examination revealed a visual acuity (VA) of hand-motion in the left eye. A complete iris defect with remaining lens cortex, a ruptured posterior lens capsule with radial tear of the capsule, and an intraocular lens (IOL) implanted in the sulcus were noted . The totally dialyzed iris was sent to our clinic preserved in sterile cold balanced salt solution, packed in a sterile biopsy bottle surrounded by a towel to prevent direct contact with ice cubes, and was transported in an icebox.
+We decided to perform surgery under general anesthesia considering the patient’s poor cooperation due to dementia. To minimize IOL decentration during scleral fixation, we used a toric axis marker and marked the fixation axis . After the scleral flaps were in two positions 180° apart, a 10–0 polypropylene suture was passed through the bed of half-thickness scleral flaps 2.0 mm posterior to the limbus . A sulcus positioned IOL (PC-60 AD, HOYA Corporation, Tokyo, Japan) was repositioned and fixed by ab externo scleral sutures . We conducted a pars plana vitrectomy to remove the remaining lens cortex material and vitreous fibre anterior to the equator to avoid trapping the vitreous during the iris-fixating suturing . The preserved iris was examined. It did not show any signs of necrosis but kept its own color and morphology soundly . We spread out the iris on the patient’s cornea to estimate the range of damage and locate a wider part of the iris inferiorly to minimize the glare after iridopexy . A 10–0 Prolene on a CIF4 needle (Ethicon, Somerville, New Jersey, USA) was consecutively passed through the iris and sclera 1.0 mm posterior to the limbus at the 6’ O/C position . Properly using both an iris spatula and ocular viscoelastic devices (OVDs), we inserted the iris into the anterior chamber completely and unfolded it to its proper position . The estimated cool-to-anterior chamber insertion time of the preserved iris was 8 h. Four more points of ab interno scleral sutures (4’, 1:30, 10:30 and 8’ O/C positions in sequence) were made . Then, the remaining vitreous, OVDs, and dispersed iris pigments were removed using a vitreous cutter .
+One week postoperatively, intraocular pressure (IOP) increased up to 30 mmHg because of hyphema from the torn root of the iris ; however, 3 weeks postoperatively, hyphema decreased with improved VA (20/200) and lowered IOP (15 mmHg) . At 4 weeks postoperatively, a much improved VA (20/100) and lowered IOP (14 mmHg) were detected . At 7 weeks postoperatively, VA was 20/63, IOP was 14 mmHg and there were no signs of inflammation in the anterior chamber . Until 6 months postoperatively, the engrafted iris did not have any signs of atrophic change, depigmentation, or inflammation; the patient complained of minimal glare, and the uncorrected VA was 20/25 with the IOP of 13 mmHg .

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+A 54-year-old female patient developed chest tightness and shortness of breath following activity 2 years ago and occasionally coughed, with yellow, sticky sputum that was difficult to expel. The patient did not demonstrate any fever or receive systemic treatment prior to hospitalization. Despite subsequent recurrence of the same symptoms, the patient did not receive any systematic treatment. Half a month prior to admission, the symptoms recurred, with no obvious trigger. Right chest pain occurred upon performing light activity but could be gradually relieved with rest. Chest CT in the local hospital showed the lower lobe of the right lung was occupied, and the upper lobe of the left lung had nodular high-density opacity. After considering the upper and middle lobes and left pneumonia of the right lung, the patient received symptomatic anti-infective drugs. She reported that her symptoms did not significantly improve; thus, she was treated at the Second Hospital of Jilin University for further diagnosis and treatment. Physical examination showed coarse breath sounds in both lungs, weak breath sounds in the right lower lung, and a small number of crackles at the base of the right lung. Laboratory tests demonstrated the following results: white blood cell count, 2.5 × 109/L; neutrophil count, 1.61 × 109/L; hemoglobin level, 91 g/L; and β2-microglobulin count, 6.15 mg/L. Blood gas analysis without oxygen revealed the following results: pH, 7.45; PCO2, 37 mm Hg; PO2, 53 mm Hg; SaO2, 89%; immunoglobulin G levels, 19.8 g/L; immunoglobulin A levels, 52.5 g/L; complement C3 levels, 53.5 mg/dL; complement C4 levels, 14.3 mg/dL; SS A antibody (WB) status, positive (+++); 52 kDa protein antibody (WB) antibody status, positive (+++); and ribosomal P protein antibody (WB) status, weakly positive (+–). Antinuclear antibody (ANA) screening (IIF) revealed a ratio of 1:320 and an ANA fluorescence model nuclear particle type. Lip gland (lower lip) biopsy revealed multifocal lymphocytes around the mucus gland of the lip gland, with each foci being >50 lymphocytes. Ultrasound-guided right lung mass aspiration biopsy was performed, and the pathology revealed diffuse proliferation of plasmoid cells. The cells had a plasma cell phenotype and light chain restricted expression, which combined with immunohistochemical staining results to support non-Hodgkin’s B-cell lymphoma and plasma cell differentiation, leading us to suspect MALT lymphoma. Immunohistochemistry results were as follows: CD10 part (+), CD79a (+), Bcl-2 (+), CD3, CD5, CD20, CD56, Bcl-6, and cyclin D1 (–), Kappa (light chain restrictive expression), and Lambdn (light chain restrictive expression) .
+Subsequent positron-emission tomography CT showed that the soft tissue density mass in the lower lobe of the right lung was flaky and had a slight high-density shadow of approximately 90 × 75 × 120 mm in size. The maximum standardized uptake value was 13.2, and the multiple flaky and slight high-density opacities in both lungs were consistent with lymphoma accompanied by intrapulmonary invasion. Accordingly, the tumor stage was considered to be stage IVB according to the Ann Arbor classification of lymphoma. After a clear diagnosis was reached, the patient received 3 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) treatment starting October 2021. After combining the patient’s blood M protein, IGM-Kappa type persisted, globulin levels were >40 g/L, and a second pathology biopsy still showed obvious plasma cell differentiation. Accordingly, the R-CHOP regimen was administered for 4 cycles. Repeat examination after 6 cycles of chemotherapy showed that the SPD of intrapulmonary lesions was reduced by ≥50% . The patient was considered to have undergone partial remission based on the evaluation criteria of the treatment effect on Lugano lymphoma.
+Ethical approval for this study was provided by the Ethics Committee of the Second Hospital of Jilin University, China, on May 18, 2023.

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+A 45-year-old male prisoner presented with necrosis on the penile shaft secondary to using a non-metallic penile constriction object. The patient reported a 5-day history of progressive penile pain, edema, and skin injury but no urinary symptoms. There was no notable medical background or history reported.
+Upon penile examination, the patient showed signs of malodor, purulent exudate, infected necrotic skin, and missing dermis on the dorsal and ventral aspects of the penile shaft . The distal penis was edematous and tender. The patient's vital signs were stable, and laboratory investigations were normal, with no fever present.
+Immediate treatment involved prescribing a combination of cephalosporin, gentamicin, and metronidazole, along with potent analgesia. Prompt operative management was then undertaken, which included urgent EUA, rigid cystoscopy, SPC insertion, and complete penile skin degloving. The procedure was performed under general anesthesia in the Lloyd Davis position, and a 16 Fr SPC was inserted under cystoscopy guidance. Complete skin degloving from the glans edge to the penile base and midline anterior scrotal skin was undertaken, along with circumcision. Buck's fascia was found to be intact . Following the procedure, a Jelonet dressing, blue gauze, and crepe bandage were applied.
+No early postoperative complications were reported, and the patient's laboratory investigations were normal. The patient remained afebrile and had stable vital signs. The patient was continued on the same antibiotics regimen.
+On the third- and seventh-day post-penile degloving, the patient had EUA, which revealed no necrotic tissue or infection. The penile tissue was healthy, and the wound was granulating. The penile wound was irrigated with peroxide, iodine, and saline and redressed. The microbiology team advised starting the patient on meropenem and clindamycin based on the penile skin microbiology results which showed the presence of Staphylococcus aureus and Beta-haemolytic streptococcus.
+On the eleventh day following penile degloving, a FTSG was performed from the groin area in a joint procedure involving the urology and plastic surgery teams. The wounds on the penile shaft and scrotum were found to be granulating and healthy. The wound edges and base were refreshed, and minimal excision of irregular benign subcutaneous tissue was performed. Hemostasis was achieved, and the wound was washed out with chlorhexidine and saline.
+Scrotal skin was mobilized with a sub-dartos layer to enable scrotal wound closure in layers. A urethral catheter was inserted to protect the urethra. The base of the penis was mobilized a few centimeters to enable penile fixation sutures at the base. The urethral and dorsal neurovascular bundle was identified and protected. The area of penile skin deficit was measured. Elliptical incisions were made in the bilateral groin creases to FTSG, which was then defatted. The FTSG was spirally inserted into the penile shaft, and Tisseel fibrin sealant (4 cc) was used. An Adaptic dressing and sponge gauze were applied and secured to the abdominal skin by prolene sutures. Groin closure was completed using staples.
+No early postoperative complications were reported, and the patient's vital signs and laboratory investigations were normal. The penile dressing was kept dry, and the penile glans were healthy with preserved sensation. The patient's hips were kept flexed to reduce tension in his groin wounds. Meropenem and clindamycin were continued.
+After a 20-day hospital admission, the patient was discharged back to the prison without antibiotics. The patient was clinically and vitally stable with clean wounds, which were healing . His laboratory investigations were normal, and a leg bag was attached to the SPC. The wound management plan was given to the prison medical team.

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+A 33-year-old Chinese woman was admitted to our medical institution on May 21, 2018, owing to progressive distension in the upper abdomen.
+Two weeks before admission, she was diagnosed with LC, portal hypertension and splenomegaly, based on an upper abdominal computed tomography (CT) scan at another hospital. Although she was taking prescribed medication that exerted effects such as anti-hepatic fibrosis, inhibition of gastric acid secretion, and protection of the stomach, her symptoms did not improve. She developed progressive distension in the upper abdomen with sour regurgitation. There was no nausea, vomiting, diarrhea, or abdominal pain.
+The patient had a history of thrombocytopenia going back more than 10 years and she had undergone surgery for an ovarian cyst on the left side in 2011.
+No special personal and family history.
+Physical examination revealed dark discoloration and mild tenderness in the left lower abdomen; other examinations were normal.
+Complete blood cell count showed a reduced white blood cell count 3.1 × 109/L (normal range 3.5-9.5 × 109/L) and platelet count 74 × 109/L (normal range 125-350 × 109/L). Liver and renal functions, coagulation, and tumor markers were normal. Serum electrolytes were within the normal range. The levels of protein C, protein S, immunoglobulin (Ig) G, IgA, and IgM were also within normal limits. Serology for hepatitis B surface antigen, hepatitis C antibody, anticardiolipin antibodies, and lupus anticoagulant was negative. No other obvious abnormalities were discovered.
+Gastroscopy showed mild esophageal varices. Magnetic resonance imaging (MRI) revealed caudate lobe hypertrophy, cirrhosis, and dilated lumbar and hemiazygos veins . Dilated azygos veins and narrowed IVC were present . Hypersplenotrophy and dilated veins in the lower esophagus and surrounding the hilus lienis were also observed.
+To confirm the diagnosis of BCS, liver biopsy was performed under CT guidance. Histochemical staining (hematoxylin-eosin and Masson trichrome) showed hepatocyte degeneration, bridging fibrosis, sinusoidal dilatation, and areas of fibrous tissue with substantial hyperplasia .

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+The female proband was born to a 33-year-old G2P2 mother at 37-weeks gestation by spontaneous vaginal delivery without complications. Pregnancy was unremarkable except for possible clubfoot noted on ultrasound scan. Birth weight was 2,440 g (20th centile), length 45.5 cm (10th centile), and head circumference 31 cm (10th centile). A hemangioma on the neck was diagnosed at one week after birth. A small patent foramen ovale (PFO, 3 mm x 4 mm) was found at 12 months of age and has been followed without surgical intervention. The proband was referred for clinical genetic evaluation at the age of 26 months for dysmorphic features, speech delay and mild growth delay. She walked at 15–16 months and her fine motor skills were age appropriate. She had four-five words at two years of age. When last reviewed at three years nine months of age, she was able to pronounce words with three syllables and had more than one hundred words. She understood multistep commands and exhibited age-appropriate behavior.
+She had mild to slight conductive hearing loss at 500–4000 Hz with a notch or normal hearing at 2000 Hz and she used bilateral hearing aids from age two years 11 months until three years two months, when her 10–15 dB loss had improved. Her teeth were late to erupt and she was missing three primary teeth.
+At thee years and nine months of age, height was 90 cm (4rd centile), weight was 13.34 kg (16th centile) and occipitofrontal circumference was 48 cm (19th centile). She showed mild dysmorphic features, including sparse frontal hair with a high anterior hairline, hypertelorism with an interpupillary distance (IPD) measuring 5.8 cm (>97th centile), synophrys, a preauricular pit on the left side, short philtrum with a short columella, downturned corners of the mouth, and small, widely spaced teeth . She had a resolving hemangioma on the neck that measured five cm, pectus excavatum and a small, reducible umbilical hernia. Her fingers were small with mild fifth finger clinodactyly, but measurements did not show brachydactyly. The second toe overlapped the third toe on right foot.
+The proband’s brother was delivered at 39-weeks gestation to the same mother (30 years old, G1P1) without complications. His birth weight, length, and head circumference were 3,650 g, 49.0 cm, and 35 cm, respectively, and all were within the normal range. At age of 5 years, his growth and development were appropriate for age. He had small epicanthic folds and mild clinodactyly of the fifth fingers and toes with mildly small fifth toes, but there were no other findings.
+The proband’s mother is a 35-year old and typically developed female. She had an embolic stroke at age of 26 years. Investigations with an echocardiogram showed a PFO with an atrial septal aneurysm and the PFO was closed using a transcatheter approach. Her hypercoagulability workup was negative. She had dyslipidemia with a slightly elevated lipoprotein level. Her family history was unremarkable for cardiac disease.
+The proband’s father is a normal healthy male.

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+An asymptomatic 41-year-old man underwent evaluation for employment health assessment and was accidentally discovered to have significant aortic dilatation. He reported a history of total repair of TOF with transannular patching at 2 years of age. Postoperatively, he underwent ambulatory follow-up for 21 years without any difficulty until he discontinued follow-up on his own because he was asymptomatic. Last transthoracic echocardiography (TTE) reports in his pediatric medical records at that time showed only trivial aortic regurgitation (AR) without any aortic root abnormality. On physical examination, he was 173 cm tall, weighed 65.6 kg, and his blood pressure was elevated to 165/60 mmHg; however, he had not received any medication. Contrast-enhanced computed tomography (CT) revealed significant aneurysmal aortic dilatation (maximum diameter of 88 mm at the sinus of Valsalva) . TTE revealed severe AR, without significant pulmonary regurgitation or residual VSD, and transesophageal echocardiography showed a slight shortening of the noncoronary cusp and poor coaptation of leaflets of the aortic valve at the central portion where a massive AR, which had 0.9 cm2 of regurgitant orifice area, could be seen. Cardiac magnetic resonance imaging revealed that significant pulmonary regurgitation flow and residual VSD could not be detected and that right ventricular (RV) ejection fraction was 37%, end-diastolic RV volume index was 201 ml/m2. He was referred to our department for surgical treatment of aortic root dilatation and AR.
+The procedure was performed through a midline sternotomy, after taping the left femoral artery and vein. Cardiopulmonary bypass was established after femoral arterial and bicaval cannulation. Left ventricular venting was initiated using a venting tube inserted through the right upper pulmonary vein. Exacerbation of AR and onset of ventricular fibrillation were observed after initiation of cooling, necessitating aortic clamping, and antegrade cardioplegic arrest. Inspection through the aortotomy revealed a dilatated aortic annulus (diameter 35 mm) and floppy aortic annulus and leaflets. All leaflets were thin and flail, and had irregular thickening which implied myxomatous degeneration. There was a stiff portion in the left ventricular outflow tract under the noncoronary and right coronary sinus, as a result of the VSD patch. Because we considered that valve-sparing aortic root replacement (VSARR) could be difficult, we performed the Bentall procedure using a 27-mm SJM Masters series Aortic Valved Graft (St. Jude Medical, Cardiology Division Inc., Minnesota), using felt strips in order to reinforce the aortic annulus. After cooling below 20 °C, we performed distal aortic anastomosis using a 28-mm J-Graft Shield Noe (27 mm ) (Japan Lifeline Co. Ltd., Japan) under deep hypothermic circulatory arrest with antegrade cerebral perfusion. After graft-to-graft anastomosis was performed, the patient was easily weaned from the bypass and showed an uneventful course except for the onset of ventricular fibrillation, which was controlled after short-termed assisted circulatory support.
+Histopathological examination of the ascending aorta specimens revealed cystic medial degeneration with some areas of mucopolysaccharides accumulation, collagen deposition, fragmentation, and loss of elastic lamellae across large areas of the media . The aortic valve showed mucoid degeneration with fragmentation of elastic fibers . The patient’s postoperative course was uneventful, and he was discharged on the 26th postoperative day.

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+The patient described herein, a 10-year-old girl, is the first child of healthy non-consanguineous parents, born after an uneventful pregnancy affected by ID, attention deficit, behavioral and speech delay, hypotonia, facial dysmorphisms, eye anomalies. She also showed congenital malformations such as cerebral anomaly and forward anus. Her birth weight was 3,450 g (50th centile), length was 50,7 cm (50th centile), and head circumference was 34 cm (25-50th centile). The Apgar score was 9/9. Since the birth, the child has been subjected to a series of medical tests that revealed a complex clinical picture, such as a brain ultrasound that showed the presence of a slightly wider left ventricle. Furthermore, the presence of further forward anus relative to the sphincter floor was observed, so she was subsequently subjected to electro stimulation and submitted to surgery for the removal of vegetation skin. At 30 days visit, a cranial ultrasound showed a slightly dilated left ventricle, while there were not cardiologic alterations or skeletal anomalies. A brain MRI (Magnetic Resonance Imaging) confirm the presence of a wider left ventricle. Standard karyotype was normal, as well as X-Fragile test. The neuropsychiatric evaluation performed at the age of 4.7 years showed an I.Q. of 89 (Stanfod Binet scale) and a mental age of 3 years and 10 months. At last clinical evaluation, performed when she was 10 years old, the patient showed facial dysmorphisms such as prominent mandible and enlarged nasal root , in association with mild hypotonia, a hint of curvature of the trunk; a comprehensive neuropsychiatric evaluation has also been performed. The girl showed mild ID, with a greater operating capacity of verbal thought than visual-motor thought. If properly stimulated, the patient offers the best overall performance; she showed also graphomotor delay, handling and grip difficulties. Regarding the affective and relational behavior, the child was introverted and showed attention deficit. About the communication and language area, the child showed speech delay (dyslexia). Finally, audiological tests showed normal hearing, and eye exams showed exotropia.

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+A 53-year-old Canadian Caucasian woman, who was a clerical worker, presented to her family doctor with a five week history of progressive pain and black discoloration of the distal right third finger. She was initiated on acetylsalicylic acid and warfarin and referred to a regional tertiary care hospital.
+Her past medical history included depression and a diagnosis of Wolfe Parkinson White (WPW) syndrome, treated since childhood with verapamil. She was taking no other medications. She has never smoked and denied a history of Raynaud's type changes in her digits. Her connective tissue disease review of systems was also otherwise unremarkable.
+On examination in the emergency room, there was obvious digital necrosis of the distal right third finger with an adjacent area of pale swollen tissue with ulceration . Allen's test was abnormal with poor refill bilaterally. Capillaroscopic examination of the periungal regions did not reveal dilated capillary loops. No peripheral bruits were audible. A teleangiectasia lesion was evident on the fifth digit. No other skin changes, specifically sclerodactyly, were present. She was admitted to hospital for further investigations and consultation with vascular specialists.
+An angiogram revealed evidence of a bilateral obliterative vasculopathic process . Radiographs of the hands did not reveal any bony abnormality. Further investigations revealed a positive antinuclear antibody with titer > 1280 and anticentromere specificity. ACA were confirmed by enzyme-linked immunosorbent assay (ELISA) at greater than 100 U/mL. Anti-double stranded DNA, anti-Sjogrens Syndrome A, anti-Sjogrens Syndrome B and anti-ribonucleoprotein antibodies (anti-SSA, anti-SSB, anti-RNP), anti-Sm, anti-Scl-70, antineutrophil cytoplasmic antibodies, anticardiolipin antibodies, cryoglobulins, C3, C4, C-reactive protein, complete blood count, electrolytes, creatinine, hepatic transaminases, alkaline phosphatase and urinalysis were all normal or negative. Associated underlying pathology including cardiopulmonary, gastrointestinal and renal involvement were excluded through cardiology consultation, chest radiograph, echocardiogram, pulmonary function testing, high-resolution computerized tomography (CT) of the chest, 24 hour urine for creatinine clearance, serum chemistry and urinalysis, barium swallow, and CT abdomen and pelvis.
+In hospital she was initiated on clopidogrel bisulfate, pentoxifylline, topical nitropaste, a two week trial of prednisone, a seven day course of clindamycin and morphine for pain control. Nifedipine was later initiated as an out-patient. Gradually over the next two months the necrosis resolved with minimal tissue loss at the digit tip. She continues to be followed in the rheumatology out-patient clinic with periodic evaluations for potential evolution of connective tissue disease and in cardiology clinic for follow-up of her WPW.

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+A 3.5-year-old girl, Caucasian, who was a product of a consanguineous marriage (first-degree cousins, Fig. (timeline of case presentation) and Fig. a) was registered in our department due to petechia and nose bleeding. She was born at 37 weeks and 5 days of normal vaginal delivery. Her birth weight, head circumference, and height were 2.8 kg, 32 cm, and 46 cm, respectively. Although her development was in the normal range, the growth chart revealed that her height and head circumference were below the third percentile line, and her weight was around the 5th percentile line. In addition, she took zinc supplements due to her short stature. On physical examination, short stature, poor weight gain, microcephaly (head circumference; 46 cm) and skin hyperpigmentation were detected. She had a history of two-time hospital admission due to pneumonia.
+Due to petechia, complete blood count was performed and the results identified anemia (Hb: 7.2 g/dL), leukopenia (WBC: 1.5 × 103/μL with an absolute neutrophil count of 455), and thrombocytopenia (Platelet count: 9 × 103/μL). Other laboratory and imaging findings, including C3, C4, ANA, dsDNA, CH50, Immunoglobulin level, TORCH study, metabolic panel, biochemistry studies, abdomen and pelvic sonography, brain MRI, lumbosacral and both hands X-ray, and echocardiography were normal. In addition, bone marrow aspiration and trephine biopsy revealed presented megakaryocyte and moderate to severe hypocellular bone marrow.
+The patient had been on irradiated packed cell and platelet transfusion approximately every one month. She was a candidate for allogeneic bone marrow transplantation, but she did not have the HLA-match donor. She was under regular follow-up and occasionally referred due to epistaxis or pallor, and received irradiated packed cell and platelet.
+Written informed consent was obtained from the parents. Whole blood samples were collected using EDTA tubes. Genomic DNA was prepared from peripheral leukocytes of the patient using the QIAamp DNA Blood Mini Kit (Qiagen, Germany) and then NanoDrop (ND1000, USA) was used to measure DNA concentration.
+NGS covering immunological and hematological disorders was carried out on Illumina NextSeq500 machine to the sequence close to 100 million reads. Bioinformatics analysis of the sequencing results was performed using BWA aligner , GATK and annovar as well as different databases and bioinformatics software such as REVEL, MCAP, ESP6500,1000G, Clinvar, CADD-Phred, SIFT, PolyPhen, GERP, PhastCons, LRT, Mutation Assessor, Mutation Taster, phyloP46way_placental, phyloP100way_vertebrate, SiPhy_29way, FATHMM_pred, RadialSVM, ExAC. Kaviar, GME, gnomAD.
+To confirm the novel identified mutation, we performed Sanger sequencing of the genomic DNA from the proband. For this test, PCR was carried out for the patient’s DNA using the following primers: F-FANCF: CGCTGGGAGATTGACATG and R-FANCF: GACCCCAGTCTGTTAGCA (PCR product: 978 bp) to amplify a mutated region of FANCF. Then, Sanger sequencing was used to sequence amplified DNA with both forward and reverse primers using ABI BigDye Terminator Cycle Sequencing Kit (Applied Biosystems®, USA). The analysis of Sanger sequencing data was performed with NCBI BLAST and Codon Code Aligner software. Multiple sequence alignment analysis was performed using the SIB BLAST+ Network Service From to compare the amino acid sequence of human FANCF proteins with other proteins across different Kingdoms. STRING (STRING: functional protein association networks, ), tool and KEGG database (, ) were also used to explain the FA pathway and its protein network.
+Owing to suspicion to inherited bone marrow failure, chromosomal study with MMC on the peripheral blood lymphocyte culture of the proband was requested. To evaluate the types and rates of breakages and rearrangements in the chromosomes of the cells in the proband, GTG banding and the chromosome breakage test were performed on the patient’s blood sample. The blood sample was then cultured and treated with different concentrations of MMC.
+NGS revealed a novel, private, homozygous, frame-shift deletion mutation in the FANCF gene (FANCF-201, ENST00000327470.4, NM_022725: exon1, c. 534delG, p. G178 fs, position 22,625,277 on chromosome 11). Using Sanger sequencing, the mutation was confirmed in the proband as homozygous . The identified mutation has not been reported yet in any database of genomic variants including ESP6500, 1000 Genome Project, ExAC, Kaviar, GME, gnomAD, and our internal database (Bayan Gene), confirming the novelty of mutation. This is the first report of FANCF mutation in Iranian patient affected with autosomal recessive FA, complementation group F.
+The comparative amino acid alignment of FANCF protein across most kingdoms was also carried out. As shown in Fig. , most of the residues were highly conserved during evolution, and any frame shift mutations could be deleterious.
+In the cytogenetic study, 100 metaphase spreads were studied from cultures prepared by adding MMC and compared to age-related control. The chromosomal breakage scoring was performed on 5 different slides (one untreated with MMC, one with 150 nM MMC concentration, one with 300 nM MMC concentration and one normal control sample treated with these 2 concentrations of MMC). 25 metaphases were evaluated on each slide for chromosomal aberration (gaps or breaks or radial formations). The results showed about 7–8 breaks/cell on average. In comparison to normal control sample which showed 0.3–0.5 breakages/cell. There was no radial formation in the normal control sample. The study showed 46, XX with multiple breaks and radial formation (quadri and triradial), compatible with Fanconi Anemia .

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+An 18-day-old female was admitted to the paediatric intensive care unit because of a heart murmur and weak femoral pulses. The patient was in a good clinical condition with spontaneous breathing on room air and normal vital signs, except for a blood pressure gradient of 30 mmHg between the upper and the lower extremities. A transthoracic two-dimensional echocardiography was performed and confirmed the suspected diagnosis of aortic coarctation, with a systolic pressure gradient of 30 mmHg and a closed arterial duct . In addition, a total retrograde perfusion of the left circumflex coronary artery (LCX) was found, without visible ostial blood flow at the left aortic sinus (, online, Video S1). The left ventricle had a normal ejection fraction without regional wall abnormalities or mitral valve regurgitation. Because of uncertainty regarding the anatomy, a coronary angiography was performed, showing no left main coronary artery, but a single right coronary artery (RCA) arising from the aorta. The LCX was perfused retrogradely via collaterals of a normal right posterior descending artery and it reached the lateral wall of the ascending aorta, not flowing into it but into the right pulmonary artery (RPA) (, online, Video S2). Arising from the LCX, small branches of a rudimentary left anterior descending artery were seen. The pulmonary artery pressure was normal.
+At 23 days of age, surgery was performed with resection of the aortic coarctation, end-to-end anastomosis, and reimplantation of the left coronary artery (LCA) into the posterior aortic sinus, using a button technique without stretching or torsion of the coronary artery (, online, Video S3). The RPA defect was closed with a xenopericardial patch. On post-operative Day 4, the patient exhibited recurrent episodes of supraventricular tachycardia, which were successfully treated with flecainide. After surgery, routine coronary angiography was performed, showing normal, antegrade flow into the LCA without stenosis . The girl recovered well from the operation and was discharged home soon with normal troponin values.

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+A 55-year-old Turkish man was admitted to our clinic with complaints of nasal obstruction and headache lasting for years. There was a nasal mass in front of his left middle turbinate extending nearly down to the inferior turbinate in anterior rhinoscopic examination which had an unclear origin. The endoscopic examination revealed a mass extending from his superior nasal cavity toward his inferior turbinate on the left side. The opposite nasal cavity was obstructed by the deviated septum. As shown in Figures and , paranasal sinus CT scans showed the overextension of his superior turbinate toward his inferior turbinate on the left side, a severe nasal septum deviation to the right with a spur formation and bilateral inflammatory mucosal thickening in maxillary sinuses. After giving information to the patient about the surgery, resection of the inferior part of the extensive left superior turbinate, minimal invasive endoscopic sinus surgery and septoplasty by endoscopic technique was performed under general anesthesia. He was discharged from the hospital 1 day after the operation. He had an uneventful follow-up period and complete resolution of his complaints. Histologic analysis after surgery revealed turbinate tissue.

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+The patient, a 43-year-old female was admitted to hospital due to a right upper lobe space occupying lesion. Nine months after lung surgery, she was treated again for painless gross hematuria.
+During physical examination, the patient was found to have space occupying lesions in the right lung, and was first admitted to hospital for right lung lesion resection. After 9 mo, there was no obvious inducement for painless hematuria for 5 d, thus she was admitted to hospital again.
+Her past history was unremarkable. No other operations were performed during this period.
+Her family history was unremarkable.
+Nine months after lung surgery, the patient was admitted to hospital again due to sudden, painless hematuria. A mass of 2.0 cm × 1.0 cm × 1.0 cm could be touched under the right chest wall, with fair activity, tough quality and a clear boundary.
+The results of a hemogram, ESR, and other tumor markers (alpha fetoprotein, carcinoembryonic antigen, CA-125, CA-199) were all within the normal range, tuberculin skin test (5 TU PPD) was negative.
+Computed tomography (CT) image showed an irregular dense soft tissue lesion in the posterior upper lobe of the right lung, approximately 3.8 cm × 3.3 cm × 4.0 cm in size, and calcification in the periphery of the tumor .
+The CT density of both kidneys was uneven, with patchy slightly high-density shadows in the upper and lower pole of the right kidney and the middle parenchyma of the left kidney, and an unclear boundary. Enhanced CT showed mild to moderate inhomogeneous enhancement, and the density decreased slightly in the delayed phase. The degree of enhancement was lower than that of the surrounding normal renal parenchyma. Filling defects were found in the bilateral renal veins, which showed mild enhancement. Magnetic resonance imaging (MRI) showed multiple long T1, short T2 and diffusion-weighted imaging high signals in both kidneys. Similar signal clusters were found in the left renal pelvis and upper ureter. Two dimensional ultrasonography images showed that the volume of both kidneys was increased, and several extremely low echo masses were seen in the parenchyma, with unclear and irregular boundaries, the bilateral renal veins were widened and hypoechoic filling was seen inside. Color Doppler flow imaging (CDFI) showed no obvious blood flow signals in both renal veins, and no obvious blood flow signal was found in the renal lesions. The following were seen on contrast-enhanced ultrasonography (CEUS, Figure ): Multiple solid space occupying lesions were found in both kidneys, the contrast medium filled the heart rapidly during the arterial phase, showing slightly high enhancement, and low enhancement when the contrast agent withdrew in 60 s. Metastasis of synovial sarcoma was considered based on the patient’s medical history and imaging findings.
+According to chest wall ultrasonography , a very low echo mass approximately 1.5 cm × 1.4 cm × 2.0 cm in size was seen in the superficial subcutaneous fascia layer, with a clear boundary, regular, aspect ratio > 1, and the echo of the surrounding fat layer was increased. On CDFI, a spot strip blood flow signal was seen inside. CEUS showed that the contrast medium filled the heart rapidly (9 s) during the arterial phase, showing overall high enhancement. After 39 s, the contrast medium quickly withdrew and showed low enhancement.
+Combined with the immunohistochemical results, postoperative pathology of pulmonary lesions indicated synovial sarcoma. Pathology of the chest wall mass and kidney mass showed that the nucleus was fusiform or ovoid in shape under the microscope with hyperchromasia, the nucleoli were not obvious, cytoplasm was sparse and unclear, and the mitotic count was rare. Pathological diagnosis was synovial sarcoma metastases .

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+A 77-year-old female with a history of chronic kidney disease and type II diabetes mellitus underwent workup for ongoing sinusitis, fatigue, malaise, and 20-pound weight loss. Patient quit smoking 30 years ago and denies any drug or alcohol use. She reports no significant family history including history of malignancy. MRI of the brain performed at an outside hospital to evaluate the extent of sinusitis revealed a posterior fossa lesion with surrounding edema causing compression on the fourth ventricle. The patient was transferred to our institution for neurosurgical evaluation. On presentation the patient was found to have mild cerebellar signs but an otherwise non-focal exam. Patient was surprised to learn of the cerebellar findings considering her lack of significant symptoms. MRI of the brain, including 3DT1, and T2 Flair showed an irregular enhancing lesion along the inferior & posterior surface of the right cerebellar hemisphere suggestive of an infiltrative malignancy . Based on these imaging findings, top differentials at the time included a metastatic disease process, an atypical meningioma, or a glioma. Upon retrospective review of this case and imaging findings, an additional differential was hypertrophic pachymeningitis. Contrast CT of the chest, abdomen, and pelvis was then performed and found to be negative for a primary malignancy. H1-MR-spectroscoy was not considered prior to resection. After discussion with the patient and her family, she elected to undergo open biopsy with or without further resection of the lesion. One week after her initial referral, she was taken to the operative theater and underwent a suboccipital craniotomy.
+An intraoperative frozen section biopsy was taken. Sections showed round or “whorled” structures, suggestive of meningioma. Additional tissue for permanent sections was requested. Permanent sections showed more of the well-circumscribed structures. Without frozen section artifact, the structures could be definitively characterized as necrotizing granulomas, involving both dura and cerebellum. The granulomas comprise central eosinophilic necrosis with surrounding epithelioid histiocytes and lymphocytes . No vasculitis was seen. Acid fast and Gomori methenamine silver (GMS) special stains were performed; they revealed no acid fast or fungal organisms.
+Given the frozen histology, imaging findings, and cerebellar symptoms further resection was completed to the point of gross total resection. cANCA and pANCA studies were sent and were found to be negative. The patient was discharged home on post-operative day 5 with a three-day steroid taper and referral to outpatient physical therapy. She returned for an office follow-up after 6 weeks and was informed that despite extensive work-up to explore the etiology of her granulomatous inflammation, no etiology was found. She had a follow-up MRI at this time which showed a non-enhancing fluid collection extending beyond the titanium mesh cranioplasty, differential to include seroma and pseudomeningocele. A follow up in 2 weeks was planned to monitor this fluid collection. At this appointment, it was found that the fluid collection under the incision was significantly decreased in size and continuing to resolve. Patient stated she was overall doing well. The current plan is to follow up in 1 year with an MRI. Patient stated she was happy with her recovery progress and plan of care moving forward.

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+A 74-year-old Caucasian woman (patient 1) with no significant medical history presented with constant rotational vertigo, progressive gait ataxia with a tendency to fall to the right side and vertical diplopia increasing in right gaze. All symptoms were characterized by subacute onset with moderate progression over 6 months. Her elder sister, a 76-year-old Caucasian woman (patient 2) likewise presented with a 6-year-history of rotational vertigo, continuous gait ataxia and marked vertical diplopia. Symptoms were reported to have presented subacutely at onset and had initially been misdiagnosed as brainstem infarction.
+In both patients, neurological examination revealed remarkably similar symptoms including gaze-evoked nystagmus and a slight abduction deficit of the right eye as well as ataxia and dysmetria in the upper and lower extremities with right-sided predominance. Because of the pronounced gait ataxia of both patients, they depended on a wheeled walker. Upon motor, reflex and sensory examination, no relevant findings were elicited, in particular no signs of dysarthria, peripheral neuropathy, spasticity, areflexia, vegetative symptoms or fasciculations that could have pointed to one of the hereditary ataxias, such as SCA1, 2, 3 and 6. Neuropsychological assessment did not reveal any substantial cognitive or memory deficits. Cerebral MRI findings showed mild generalized atrophy and multiple white matter lesions in both patients . Except for glycated hemoglobin (HbA1c) levels, which were expectably elevated due to the existing T1DM, all other routine laboratory examinations were within normal limits. Comprehensive workup with extended autoimmune laboratory examinations revealed remarkably high serum and CSF GAD-ab levels in both siblings . Other autoantibodies were negative, in particular antibodies against the NMDA, AMPA or GABA(B) receptor, LGI1, Caspr2, MAG, glycin receptor, or onconeuronal antibodies. Further CSF analysis showed slight pleocytosis in patient 1 and oligoclonal immunoglobulin bands in both patients.
+In addition, the medical history of patient 1 revealed Hashimoto's thyroiditis with elevated serum antithyroid peroxidase antibody levels and recently diagnosed T1DM, whereas patient 2 exhibited a 7-year-history of Grave's disease with high levels of thyroid-stimulating immunoglobulins and a 6-year-history of insulin-dependent T1DM . Their family history revealed a 73-year-old brother suffering from rheumatism and another 75-year-old brother without relevant diseases.
+The diagnosis of cerebellar ataxia with GAD-abs was established in both siblings based on the subacute onset, CSF inflammation in patient 1, the very high GAD-ab titers, the partial response to immunotherapy, the age at onset and the typical constellation of insulin-dependent diabetes. Because of these findings, no genetic testing was performed. Since the detection of GAD-abs can occasionally indicate a paraneoplastic etiology [, ], we undertook full-body computed tomography scans in both patients as well as whole-body and brain positron emission tomography in patient 1, all of which showed no pathological findings, suggesting the absence of any malignancy.
+Plasma separation by immunoadsorption was used to eliminate pathogenic antibodies from the serum compartment by binding to the extracorporeal columns. For this, patient 1 received 5 cycles every other day which led to subtle improvement of gait ataxia. Extended treatment with a further 10 cycles of immunoadsorption eventually resulted in remarkable improvement of gait which allowed the patient to walk without her walking frame. In patient 2, 7 cycles of plasmapheresis were administered every other day and resulted in subjective improvement of gait disability, and a slightly diminished degree of gaze-evoked nystagmus was seen on follow-up examination. However, relevant impairment persisted so that immunosuppressive therapy was escalated in both women to 1,000 mg rituximab intravenously according to common practice . Both patients gave their written informed consent for data analysis and the publication of this case report.

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+A 67-year-old Caucasian man presented to the emergency room because of a 4 days’ history of abdominal pain, with one episode of vomiting.
+The patient’s past medical history was significant for colonic diverticulosis and an episode of gastrointestinal bleeding one year before. The event had been investigated by two different gastroscopies, a colonoscopy and a MDCT, which produced inconclusive results. Ten months later he was newly admitted because of abdominal pain and fever at 38.0 C°, with valid urination and defecation. A CT of the abdomen was performed, which confirmed the colonic diverticulosis and revealed the presence of multiple diverticula of the small intestine, fat stranding, signs of inflammation as well as a small amount of free liquid in the abdomen. The patient was hence diagnosed with jejunal diverticulitis and managed conservatively with intra-venous antibiotics, with an apparent complete recovery.
+He re-presented to the emergency department two months later with acute abdominal pain. The pain was described as severe and constant, localized mainly in the lower abdomen with clinical signs of peritonitis. No change in bowel habits nor urinary symptoms were complained. His vital signs were stable, with a temperature of 37.2 C°; he appeared fully oriented and not in any acute distress. Laboratory examination reported a hemoglobin of 121 g/dL, a WBC count of 12.2 × 10E9/L and a CRP of 249 mg/L. Other laboratory data were within normal limit. An abdominal and pelvic contrast-enhanced computed tomography, with administration of oral contrast, was performed. Jejunum and ileum showed several diverticula as well as an inflammatory thick-walled mass involving different loops of the intestine. In addition, free fluid in the abdomen and a small amount of subdiaphragmatic air were reported (, ). On the basis of these findings, the diagnosis of perforated diverticulitis was hereby proposed.
+The patient underwent a diagnostic laparoscopy which revealed plenty of purulent yellowish liquid collected in the right abdomen and a conglomerate of intestinal inflamed loops. We hence decided to convert immediately the procedure to laparotomy. Large multiple diverticula were found covering a section of small intestine approximately 2.5 m long, without signs of obvious macro perforation. Among the middle distal tract of the jejunum and the middle distal tract of ileum, strong adhesions were identified . The involved segments of jejunum and ileum were connected by an intestinal loop free of signs of diverticulosis . There were no signs of bowel ischemia. Adhesiolisis was partially carried out, however, because of difficulties associated with the procedure, we opt to perform a double enterectomy, removing only those segments involved in the intestinal conglomerate and deeply affected by the pathology. Roughly 25 cm of ileum and 80 cm of jejunum were resected. Bowel continuity was restored with an ileo-ileal and a jejuno-jejunal anastomosis. Almost 700 cl of pus were drained and the peritoneal cavity was washed with 10 L of saline solution. The postoperative recovery was uneventful and the patient was discharged 8 days later. There were no signs of malignancy in the resected intestine.

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+A 6-year-old boy presented to the neuro-ophthalmic clinic with swelling over the lateral aspect of his left eye for 15 days. The swelling was not painful, but had been progressive and associated with lacrimation and drooping of the eyelid. Concurrently, an asymptomatic midline swelling was evident over the patient’s neck which had been present for 2 months. A history of occasional low-grade fever and a decrease in appetite were also reported. There was no history of bleeding tendency or similar swellings elsewhere, neither of cough or hemoptysis.
+On examination, visual acuity was 6/6 in the right eye and 6/24 (6/6 with pinhole) in the left. The left upper eyelid demonstrated fullness over its lateral aspect with erythema of the overlying skin. A minimally mobile, non-pulsatile, non-compressible, diffuse and firm mass with mild tenderness was palpable in the lateral upper lid. There was mild ptosis and the eyeball was displaced inferomedially. Both the palpebral and bulbar conjunctivae were congested. Anterior and posterior segments in both eyes were normal. The pupils were 4 mm in diameter, with brisk direct and consensual light reactions and no relative afferent defect. The neck swelling was soft, fluctuant, non-tender and moved on deglutition.
+Ultrasonography (US) of the orbital lesion showed low reflectivity, while contrast-enhanced computed tomography demonstrated a ring-enhancing, low density lesion in the lateral extraconal space with medial displacement of the globe and lateral rectus . The lacrimal gland could not be separately visualized. Sections obtained from the brain were normal.
+Laboratory investigations revealed hemoglobin level of 9.3 g/dL, leukocyte count of 15,000 cells/mm3, and erythrocyte sedimentation rate of 48 mm in the first hour. Thyroid function tests demonstrated high levels of thyroid stimulating hormone (TSH), 25.75 milliunits per liter (normal, 0.3 to 5.0 mU/L), with T3 and T4 within standard limits. US of the neck revealed a cystic swelling measuring 3 × 2 cm in the left lobe of the thyroid gland. A technetium-99 scan was performed which revealed a hypofunctioning nodule involving the lower third of the left lobe, extending to the isthmus.
+US-guided fine needle aspiration of the orbital lesion was performed and the specimen underwent microscopic examination, and culture for bacteria, mycobacteria and fungi. Cytology demonstrated lymphocytes and a few giant cells, but no micro-organisms. Cultures remained sterile after 2 weeks. Fine needle aspiration from the neck mass revealed acid-fast bacilli, together with lymphocytes, and epitheloid and giant cells . Mycobacteria grew on the culture media incubated with the thyroid specimen. Chest X-ray and abdominal US were normal.
+Eventually, a diagnosis of thyroid gland TB with coexisting tuberculous orbital abscess was made and the patient received a 3-drug antitubercular regimen. The orbital and neck swelling resolved after 6 months of therapy and the child remained asymptomatic up to one year .

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+A 10-year-old Kurdish boy presented with bone pain and fever associated with night sweats, shortness of breath, weight loss (5kg/month), purple purpuric spots over the skin and bleeding from the nose. The patient’s history dated back to 1 month before admission. On examination, we observed pallor, cachexia, dyspnea, fever, tachycardia, tachypnea, multiple petechiae and ecchymoses all over the skin, dilated tortuous veins over the chest, pulse rate 120bpm, respiratory rate 23cycles/minute, temperature 39°C and blood pressure 90/45mmHg. Moreover, we found multiple small cervical lymphadenopathies and mild splenomegaly 3cm below the left costal margin. The boy’s liver was tender 7cm below the right costal margin, and he had gross abdominal distention. The initial blood counts were hemoglobin 64g/L, white blood cell count 34 × 109/L, platelets 25 × 109/L and blasts 38% (Figure
+A). The blasts were homogeneous with a high nuclear to cytoplasmic ratio, inconspicuous nucleoli and open chromatin, and some of the blasts were vacuolated. Platelets were markedly reduced (Figure
+B). There was mediastinal widening visualized on a chest X-ray (Figure
+). MRI showed lumbosacral vertebrae with diffuse infiltration of the axial bone marrow of the lower dorsal and lumbar vertebrae, suggestive of bony metastases predominantly osteolytic in nature (Figure
+A–
+C). Bone marrow aspiration (BMA) showed no fragments but few areas of necrosis. Bone marrow biopsy showed marked BMN (Figure
+A and
+B). The first immunophenotyping was not conclusive, but the second was positive for CD3 and terminal deoxynucleotidyl transferase and negative for CD20, CD79a and CD10.
+After admission, the patient’s condition deteriorated and features of frank superior vena cava syndrome developed. The patient was treated with chemotherapy according to the ALL protocol, and complete remission was achieved on day 28. At the 24th week of chemotherapy, his condition relapsed on treatment. He returned to our hospital with fever, chest infection and 60% blasts observed on peripheral blood film, and the complete blood count revealed severe pancytopenia. The BMA was a dry tap, but the biopsy showed hypercellular marrow with extensive infiltration by mononuclear cells and disappearance of necrosis (Figure
+C and
+D). Treatment was reinitiated according to the ALL protocol (bone marrow relapsed protocol), after which he developed severe mucositis, uncontrolled septicemia and electrolyte imbalance. Eventually, that led to death.
+The BMA at the time of diagnosis was diluted, and the slides appeared to show artefact with a few necrotic cells. The biopsy was a 1.6cm piece of tissue that consisted of a fragment of trabecular bone showing marked BMN, as shown in the image in Figure
+A (before treatment). The result of immunohistochemistry was not interpretable for the first specimen, but for the second the diagnosis was definitive as precursor T-cell ALL.
+During admission, we gave the patient intravenous fluid 3000ml/m2/day, allopurinol tablets 100mg/m2/dose and antibiotics. The patient’s condition subsequently deteriorated, and he developed progressive dyspnea, chest tightness, abdominal distention and fever. The patient was near to developing frank features of superior vena cava syndrome, but later he developed bilateral lower-limb weakness. The straight leg raising test was observed to be positive bilaterally. MRI of the dorsolumbosacral spine showed diffuse focal infiltration of the axial bone marrow of the lower dorsal and lumbar vertebrae causing altered hypointense T1-weighted signal intensity (Figure
+A and
+B). The image was suggestive of bony metastasis that was predominantly osteolytic in nature (Figure
+A and
+B). Incidental hepatosplenomegaly and bilateral renal enlargement were also observed (Figure
+C), but there was no pressure on the spinal cord.
+We started dexamethasone intravenous infusion at 6mg/m2. Seven days after the patient’s admission, we started induction therapy with vincristine 1.5mg/m2 intravenous bolus on days 7, 14, 21 and 28. Dexamethasone 6mg/m2 was administered daily, and daunorubicin 25mg/m2 was given on the days 1 and 7.
+Upon starting induction, the patient developed attacks of tonic-clonic contractions. We found computed tomography of the brain without contrast to be negative. Electrolyte measurements showed severe hypocalcemia, and we induced correction, which stabilized the convulsions. On day 28, BMA indicated a few fragments and megakaryocytes were seen. Erythroid and myeloid series were present with all stages of maturation. The data also indicated predominant neutrophils and histiocytes, but the cellular elements could not confirm an excess of blast cells. The bone marrow biopsy report showed 95% cellularity, which was composed predominantly of early-stage granulocytes and normal maturation stages of hematopoietic cells. The blasts constituted about 2% of total marrow nucleated cells. The myeloid to erythroid cell ratio was 8:1.
+After a 4-week induction period, complete remission was observed and we continued giving the early consolidation chemotherapy. Unfortunately, at the 24th week of treatment, the patient returned with fever, chest infection, neutropenia and thrombocytopenia, and we found the presence of a few blasts in the peripheral blood film. The patient was not responding to supportive treatment that included antibiotics and antipyretics. The follow-up analysis of BMA showed excessive bone marrow infiltration by mononuclear cells with multiple inconspicuous nucleoli. Both erythroid and megakaryocytic precursors were suppressed in BMA, whereas in relapsed biopsy no necrosis was observed (Figure
+C and
+D).
+On the reinduction therapy date, we followed a bone marrow relapsed protocol. On the 14th day of treatment reinduction, the patient developed severe anemia, thrombocytopenia and neutropenia. In addition, he developed grade IV mucositis with hypokalemia. The patient could not tolerate the complications, and he developed septicemia followed by sepsis. The patient’s death was an inevitable outcome. The overall survival period was 26 weeks after first diagnosis.

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+The proband was a 22-year-old Iranian woman (south of Iran, Fars province) with DHP deficiency whose parents are a first-degree cousins. There was not any symptoms in the proband until 20 years of age, when during her first pregnancy, elevated liver enzymes was detected during her routine laboratory evaluations (ALT of 147 U/L, reference range: < 31 U/L, AST of 108 U/L, reference range: < 31 U/L and Alk-P of 350 U/L, reference range: 64–306 U/L). She also had increased level of serum iron of 227 μg/dL, reference range: 50–170 μg/Dl and PT of 14.5 s, reference range: 10.5–11.5 s. A spontaneous abortion happened to her during the first trimester of pregnancy. She was evaluated and tested for autoimmune antibodies in which the negative results excluded autoimmune hepatitis as a disease leading to liver dysfunction. Thereafter, she was presented with bloody vomiting, diarrhea, jaundice, weight loss and bilateral mild mid frequency sensorineural hearing loss. Abdominal and pelvic ultrasonography was in favor of cirrhosis and in liver biopsy cryptogenic cirrhosis was confirmed. The patient was initially diagnosed as having glycogen storage disease by considering the clinical evaluation, and referred to genetic counseling where whole-exome sequencing was conducted to discover the underlying etiology. According to NGS results, for confirming the genotype-phenotype correlation, the patient was referred to evaluate the levels of dihydrothymine and dihydrouracil by HPLC tandem-mass spectrometry in which elevated levels of both were identified in the patient’s urine in comparison with the mean concentration observed in control group’s urine (dihydrothymine (μmol/mmol creatinine): patient = 148, controls = 1.4 ± 1.1 (n = 106), dihydrouracil (μmol/mmol creatinine): patient = 254, controls = 4.9 ± 3.2 (n = 106)). There was no history of such condition in other family members.
+All exons of protein coding regions and flanking introns belonged to the extracted DNA from the proband were captured and enriched by Whole Exome Sequencing method (Agilent sure select v5 exome capture kit). Next Generation Sequencing (NGS) method was conducted using illumina sequencing platform to sequence the libraries with mean > 80-100X coverage. The human reference genome (GRCH37/hg19) was downloaded in order to perform the alignment to Sequence reads using BWA program [, ]. Picard and GATK version 3.6 were used to identify the relevant variants [, ]. The VEP program was used to annotate the variants . In order to perform further annotation a set of related disease databases including OMIM, HGMD, GWAS, SwissVar and Clinvar as well as published variants were used. Filtering of common variants was done according to allele frequency in ExAC, 1000 Genome phase3, dbSNP147 and EVS. Some bioinformatics online softwares such as SIFT, polyphen2, LRT, mutation assessor and mutation taster2 were also used to discover the disease causing variants.
+In order to segregate the mutation, Sanger sequencing was conducted using ABI BigDye Terminator Cycle Sequencing Kit (Applied Biosystems®, USA) on extracted DNA (QIAamp DNA minikit, Qiagen, Germany) belonged to the patient and her family members (parents, sister and brother). Epoch Microplate Spectrophotometer (Bio Tek Instruments, USA) was utilized to calculate the quality of extracted DNA. Desired genomic region was amplified using following oligonucleotide PCR primer pairs: DPYS-E9-F: 5′-CACAAAAAGTGGGACAATCC-3′, DPYS-E9-R: 5′-GTGAAGCCTCTGACCTTGAT-3′. The obtained sequences were analyzed using Finch TV software and NCBI Blast.
+Liver biopsy specimens underwent RNA (total RNA) extraction via Invitrogen TRIzol Reagent (Thermo Fisher Scientific, USA) based on the company protocol. Quality of RNA was evaluated by Epoch Microplate Spectrophotometer (Bio Tek Instruments, USA). Normalized RNA samples were used to synthesis cDNA by Fermentas cDNA synthesis kit (Thermo Fisher Scientific, USA) per manufacturer’s instructions. In order to assess the DPYS gene expression SYBR Green Master Mix (Invitrogen) was used to perform the Real Time PCR in Rotor-Gene Q (QIAGEN, Germany) Real Time PCR cycler. The experiment was conducted in triplicate. In the current study, GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) was used as an internal control gene. The following intron-spanning primer pairs were utilized in our study: DPYS-F: 5′-ACCCGACTTCCTCATGAATCT-3′, DPYS-R: 5′-CATCCGATCTTCAACACCATTCA-3′, for the gene of interest and GAPDH-F: 5′-ACAACTTTGGTATCGTGGAAGG-3′, GAPDH-R: 5′-GCCATCACGCCACAGTTTC-3′ for the reference gene (GAPDH PrimerBank ID: 378404907c2, ). Comparative threshold cycle method (2-∆∆CT) was used to compare the relative expression of DPYS gene between the patient’s liver tissue and her sister’s liver tissue who genetically confirmed to be unaffected (the liver biopsy was performed in her sister due to the increased levels of ALT, AST, Alk phosphatase and she was suspected to be affected with Autoimmune hepatitis due to a positive test for ANA and ASMA (titers ≥1:160)).

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+The present case is a 12-year-old boy who was admitted to the orthopedic department of our medical center due to chronic and severe pain in his left knee. He was not a professional athlete, and his activity level was typical for an adolescent. The parents stated a blunt traumatic injury to the affected knee about two years ago that triggered the knee pain in the patient. He had undergone conservative treatments, including non-steroidal anti-inflammatory drugs (NSAIDs) for the past six months and also a single dose of lidocaine and corticosteroid intra-articular injection three months ago that did not result in significant persistent improvements but temporarily relieved the pain.
+During the physical examination of the lower limbs at the time of admission, normal skin was observed without signs of injuries. There was a regional pain in the supra-lateral site of the patella in the 90° flexion position during ROM examination that was relieved with more flexion or extension. Moreover, point tenderness was felt in the lateral side of the patella directly on the condyle in the knee 90° flexion position. The patient's pain was not related to the activities. During the knee range of motion (ROM) examination, a mild click was also found when going from full extension to flexion at 100°. Knee ROM was 0–130°.
+The hyperflexion and hyperextension of the knee were associated with no pain. Knee stability was preserved in the valgus stress test and varus stress test. The extensor mechanism was normal, no mal-alignment was observed, and the patient's gait was intact. Other examinations, including pivot, McMurray, and Lachman tests, were normal. Neuromuscular examinations of lower limbs were normal. The patient's knee clinical appearance is shown in .
+The X-ray of the affected knee indicated no pathologies , but the left knee MRI showed significant hypertrophy of the synovial membrane .
+The patient underwent knee arthroscopy with suspicion of hypertrophic plica. A hypertrophic synovial plica in the lateral side of the left knee was observed. A complete resection of hypertrophic plica was performed. The surgery details are as follows: A systematic examination of the knee joint was performed. The patellofemoral, medial, and lateral compartments were evaluated for any signs of pathology. Cartilage surfaces, menisci, ligaments, and synovium were inspected thoroughly. Attention was directed towards the lateral compartment, specifically the lateral plica. The lateral plica was identified and assessed for any abnormalities, including thickening, fraying, or impingement. Subsequently, arthroscopic shavers and scissors were used carefully to resect the affected portion of the plica. Great care was taken to preserve surrounding structures and minimize trauma to the synovium. After resection, the knee joint was thoroughly irrigated with saline solution to remove debris. The arthroscope was used to confirm the successful resection of the lateral plica and to ensure the absence of any residual pathology.
+Moreover, an accidental finding of the knee arthroscopy was angiogenesis in the femoral condyle beneath the hypertrophic plica . Angiogenesis is commonly found in pathologic plica, caused by inflammation due to friction, with increased inflammatory cells and hyalinization .
+The patient's follow-up immediately and after six months showed complete remission without further knee pain. No ROM restrictions or complications are reported during flexion from 0° to 140°. Moreover, in the recent follow-up visit of this patient, 1.5 years after surgical resection, he did not suffer from any pain in the rest and physical activity. He also had a full knee range of motion without any limitation or lag. shows the follow-up MRI.

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+A 63-year-old man was diagnosed with schizophrenia at age 49 and had been treated at the outpatient department of Songde Branch of Taipei City Hospital since the diagnosis. His symptoms included delusional jealousy, persecutory delusion, irritability, self-destructive behaviour and self-talk. Sulpiride 600 mg/day was prescribed but he quit the outpatient follow-up 2 months later. From age 50, he had an average daily consumption of four standard drinks of alcohol. Drinking worsened his impulse control and caused him to get into conflicts with his neighbours. He had been admitted to the acute psychiatric ward of Songde Branch of Taipei City Hospital three times since age 55. Brain computed tomography was performed that showed mild bilateral frontal lobe atrophy, but no other significant abnormal findings were identified. Benzodiazepine and thiamine were given whenever he was admitted for the prevention of Wernicke’s encephalopathy and alcohol withdrawal symptoms. Neither acute confusion state nor obvious amnesia was noted during admission.
+Risperidone 4 mg/day was used at first during admission for about 1 month with significant improvement in his psychotic symptoms. Unfortunately, the side effect dysphasia occurred and the patient developed aspiration pneumonia. Therefore, risperidone treatment was ceased and quetiapine was prescribed with gradual increase in dosage to about 550 mg/day. However, the treatment efficacy was not satisfactory in this patient.
+At age 62, amisulpride at a dosage of 400 mg/day was prescribed instead in the outpatient department. After 6 months, obvious akathisia was noted, and he was transferred to Bali psychiatric centre for further treatment. The amisulpride dosage was tapered to 200 mg/day. His psychotic symptoms remained stable, but the side effects persisted, and amisulpride was further reduced to 50 mg/day gradually. His akathisia showed improvement, but he began to suffer from other forms of abnormal involuntary movements comprising dyskinesia mixed with dystonia and akathisia. The involuntary movements involved his trunk, head and neck, and four limbs. He kept twisting his body and head around or back and forth (Additional file : Video 1), which may be the dyskinesia symptoms mixed with the cervical dystonia. Further, the feeling of inner restlessness and a compelling need to be in constant motion meant that akathisia played a role in his abnormal involuntary movements. Meanwhile, the stepping movement could also be observed when he was made to sit (Additional file : Video 1). According to the patient and his family’s report, the abnormal involuntary movements, which were subsequent to the dosage reduction of amisulpride, never occurred previously.
+The symptoms persisted for 2 weeks until amisulpride was increased to 100 mg/day. He still had slightly involuntary movement of his head and body but with much declined severity (Additional file : Video 2). Besides the adjustment of antipsychotic dosage, we used propranolol 10 mg twice a day for treatment of his akathisia and biperiden 0.5 mg twice a day for some dystonia-like symptoms. Further, lorazepam (0.5 mg twice a day) was prescribed for supplementary treatment of akathisia and dyskinesia for about 2 weeks. After discharge, the patient got relapsed about 1 year later with poor treatment adherence. The abnormal involuntary movements were still noted, although very mild, even though he did not take any psychotropic medications for about 3 months.

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+A 52-year-old man was admitted in our institutional emergency department for chest pain, sweating, and vomiting. The patient had no medical history or known cardiovascular risk factors and denied any other symptoms. Blood pressure was 85/50 mmHg and heart rate 54 b.p.m. Intravenous fluid administration was started to manage hypotension. Twelve-lead electrocardiogram showed sinus rhythm with only non-specific ST-segment changes . Trans-thoracic echocardiogram showed normal global and regional left and right ventricular function and normal size of left and right chambers. In particular, left ventricular ejection fraction was 60%, left ventricular end-diastolic diameter was 45 mm, and right ventricular end-diastolic diameter was 38 mm. Troponin T levels were mildly elevated (3.0 and 5.0 ng/L at 0 and 3 h, respectively).
+The clinical presentation was consistent with non-ST-segment elevation acute coronary syndrome (ACS). Aspirin was administered and patient underwent coronary angiography, which revealed a patent large left anterior descending coronary artery providing collaterals to a large dominant right coronary artery draining into the pulmonary artery . Non-obstructive coronary artery disease was found. Right and left cardiac catheterization was concomitantly performed, showing a normal pulmonary artery pressure (24/10 mmHg, average 12 mmHg) and a non-significant left-to-right shunt (pulmonary venous oxygen saturation 95%; pulmonary artery oxygen saturation 80%; mixed venous oxygen saturation 76%; QP/QS: 1.3). Then, the patient was transferred to our Cardiac Care Unit for monitoring.
+After 2 days, a cardiac computed tomography (CT) angiography was performed to better define the coronary anatomy. CT angiography confirmed ARCAPA, excluded any other coronary anomalies and showed normal calibre of pulmonary arterial vessels (diameter of pulmonary trunk: 26 mm; ). Finally, a 99mTechnetium-gated single-photon emission computerized tomography (SPECT) with bicycle exercise test and then a 201Thallium-gated SPECT with dipyridamole were performed to assess the functional implication of the coronary anomaly , showing a reversible mild inferior perfusion defect without any significant difference between the two tests. Stress test was maximal: it lasted 9 min and the patient attained 154 b.p.m. (91% of target heart rate), 6.8 estimated metabolic equivalents and 180/85 mmHg as peak blood pressure. The patient experiences a subsequent event-free hospital stay, and was discharged on aspirin 100 mg and bisoprolol 2.5 mg. The patient was educated on actions to prevent future vaso-vagal episodes, including keeping adequate fluid intake (2 L/day), recognizing prodromes and lying down and performing counter manoeuvres in case of vaso-vagal symptoms. Also, in order to minimize gastrointestinal triggers the patient was visited by a gastroenterologist and diet recommendations were made.
+At 2-year follow up, the patient was asymptomatic and repeated myocardial scintigraphy with dipyridamole stress test was performed after beta-blocker washout. The test confirmed the reversible mild inferior perfusion defect, previously observed. Bisoprolol dosage was up-titrated to 3.75 mg daily and aspirin was maintained.

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1221_en.txt

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+A 36-year-old Caucasian woman, gravida 3, para 2, presented to our antenatal outpatient clinic in the 10th week of gestation complaining of uterine prolapse and amenorrhea. Five years earlier, at the age of 31 years, she had her first spontaneous vaginal delivery, after 39 weeks of clinically unremarkable gestation and after a seven-hour labor. A living male baby weighing 2950 g, with Apgar scores of 10/10, was delivered. After that, a total uterine prolapse (POP-Q IV) was observed and, therefore, a pelvic reconstruction operation was scheduled. However, she missed the appointment and she was lost to follow-up.
+Four years later, at the age of 35 years, the patient had her first pregnancy in a prolapsed uterus and the delivery was performed by an elective caesarean section after 38 weeks of gestation. During this second pregnancy follow-up she experienced symptoms of heaviness, but no pelvic pain or urinary incontinence. Pelvic examination showed that the uterus persisted in the pelvis because of increased volume. The cervical os was closed, while the entire cervix was lying outside the vulva during the first three months and after week 18 it appeared completely inside. When the cervix was outside the vulva, it appeared enlarged and edematous with marked ectropion but it was not ulcerated. A live male baby weighing 3150 g, with Apgar scores of 10/10, was delivered with elective caesarian section. After that, a total uterine prolapse persisted but she refused any procedure for pelvic reconstruction; neither was a vaginal pessary used.
+One year later, at the age of 36 years, she presented again in our clinic with a 10-week pregnancy in a prolapsed uterus. A vaginal pessary was applied to keep the uterus inside the pelvis after manual reposition. The pessary was removed at the 24th week. The gravid uterus persisted in the abdominal cavity because it was increased in volume . She did not show any symptoms of heaviness or urinary incontinence. The cervix was lying at the os of the vulva (POP-Q II) without signs of dessication or ulceration. It was enlarged and edematous but showed no evidence of cervical incompetence.
+Serial transabdominal ultrasonograpic examinations showed a normally developing fetus in longitudinal position in the uterine cavity. Elective caesarean section was performed at the 38th week. A living, healthy female baby weighing 3030 g, with Apgar scores of 10/10, was delivered.
+The postnatal period was uneventful and she was discharged home four days later in good health. Normal postpartum uterine involution was observed. After that, a total uterine prolapse (POP-Q IV) was still observed .
+She is scheduled for follow-up examination and pelvic reconstruction surgery.

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1236_en.txt

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+A total laryngectomized 72-year-old male was admitted with a complaint of difficulty in swallowing the foods and intractable liquid leakage from the valve of the tracheoesophageal prosthesis. The examination revealed a prosthesis covered with crust and dry mucus. Patient history was obtained from medical records and it was revealed that he had been using the same voice prosthesis smoothly for 17 years without changing. In fact, he had no significant complication in this period. However, he had been experiencing some difficulties in swallowing and leakage around the valve for a year. In addition, he had a serious iatrophobia and refused the change of prosthesis for several times.
+He was questioned for his daily habits which might help to preserve the prosthesis for a long time Tracheoesophageal fistula construction was performed after total laryngectomy for voice and speech restoration. Furthermore, flexible fiber optic esophagoscopy was performed to evaluate the fistula in case of a lesion; however, no lesion was detected on the esophageal mucosa . The patient was referred to a psychologist to make him convinced regarding the prosthesis change. After the removal of the old prosthesis , a new voice prosthesis (20-F,16 mm) was inserted and no complication occurred.

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1246_en.txt

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+A 46-year-old man with a history of hypertension, smoking, and alcohol use experienced a stroke on waking up with left limb weakness (4/5) and slurring speech on August 30, 2020. He was diagnosed to have a right internal carotid artery (ICA) territory infarct based on non-contrast computed tomography (NCCT) at local hospital. Despite antiplatelet therapy with aspirin 100 mg/d and clopidogrel 75 mg/d, over the next 3 days, left limb weakness progressively worsened (2/5), accompanied by somnolence (GCS 3 + 5 + 6). Therefore, he was transferred to our hospital on September 2, 2020. The Glasgow Coma Scale (GCS) score was 13/15. The head NCCT revealed new infarcts in the right internal watershed area and CT perfusion (CTP) showed a 100.3 mL mismatch of bilateral cerebral hemispheres, indicating that a considerable penumbral region was present in the supply area of each internal carotid artery (ICA) . Emergent EVT was performed under general anesthesia. The patient received IV heparin (50 U/Kg) before the surgical procedure. Preprocedural angiogram showed a double-lumen sign in the ascending segment of the right ICA with severe stenosis of the true lumen and linear stenosis in the ascending segment of the left ICA, suggesting dissections . The anterior communicating artery (ACom A) and the right posterior communicating artery (PCom A) were not open, and the left posterior cerebral artery (PCA) mildly compensated the left middle cerebral artery (MCA) through ipsilateral PCom A . Because we judged that the right ICA was the main vessel responsible for stroke, and worried about the risk of hyperperfusion-related bleeding in the simultaneous treatment of bilateral ICAs, we decided to treat right ICA first. An 8F Envoy guide catheter (Johnson & Johnson Co. Ltd., New Brunswick, NJ, USA) and 5F MPA catheter were introduced into the distal common carotid artery (CCA) by applying a coaxial technique. After traversing the true lumen with a Trevo Pro 18 microcatheter over a Synchro-2 microwire (Stryker Corp., Fremont, CA, USA), a Solitaire FR 6 × 30 mm stent-retriever (Medtronic Inc., Wexford, PA, USA) was temporarily deployed at the key flow-limiting site . An angiogram showed an image of a patent true lumen with a significantly reduced false lumen. After observation of 30 min, blood flow was maintained well, and ipsilateral anterior cerebral artery (ACA) compensated left ACA through ACom A. Thus, the Solitaire stent was detached . After recovery from anesthesia, the muscle strength of left limb was improved from grade 2/5 to grade 3/5, but the somnolence was not improved with a 13/15 GCS. Repeated CTP revealed that the perfusion of the right anterior circulation recovered, but a large area of hypoperfusion in the left anterior circulation was still seen . Due to concerns about clopidogrel resistance, the dual antiplatelet regimen was adjusted to aspirin 100 mg/d and ticagrelor 90 mg twice daily. On the 6th day after the procedure, the patient suffered from a generalized seizure and became stupor with a 9/15 GCS. Further, the muscle strength of right limb was decreased to grade 2/5. But no new lesions were found on the emergent head NCCT. Nevertheless, head CTP showed a new core infarction of 18.2 mL in the left frontal lobe with a penumbra of 100.4 mL in the left anterior circulation . Then, an emergent EVT was performed again. The angiogram revealed that the right ICA was patent with an inadequate compensation to the left anterior circulation via ACom A, and left ICA was occluded . A triaxial assembly including an 8F Mach1 guide catheter (Boston Scientific, Marlborough, MA, USA), AXS Catalyst 6 (Stryker Corp.), and a Trevo Pro 18 microcatheter over a Synchro-2 microwire were navigated through the left dissected segment . Subsequently, the Catalyst 6 and guide catheter were successively withdrawn to the beginning of the ICA under continuous negative pressure application, namely the simple catheter-passing (SCP) technique. Several dark red emboli were captured by Catalyst 6. A repeated angiogram showed that the left ICA was successfully recanalized and the structure of the dissection was fully revealed . After traversing the true lumen with the Pro 18 microcatheter over a Synchro-2 microwire, a Solitaire FR 6 × 30 mm stent-retriever was temporarily deployed at the key flow-limiting site . A subsequent angiogram showed that the antegrade blood flow was significantly improved and the dissecting aneurysm disappeared. After observation of 30 min, the Solitaire stent was detached. After recovery from anesthesia, the patient's consciousness became clear with a 15/15 GCS, the tracheal intubation was removed on the following day, and the muscle strength of four limbs was significantly improved to grade 4/5. A repeated head NCCT showed infarction in the left frontal lobe, but repeated head CTP showed that the cerebral perfusion of bilateral anterior circulations was recovered .
+After 3 months of dual antiplatelet therapy, another 3 months of aspirin single antiplatelet therapy was followed. The modified Rankins Scale score (mRS) was 1 at the 90-day follow-up. Follow-up neck CTA at three months showed no residual lesion in both ICAs. No relapse of cerebral ischemic events during the 15-month follow-up occurred. A recent neck CTA showed that both ICAs remained patent without relapse of dissection .

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1254_en.txt

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+A 63-year-old man having received a heart transplant due to dilated cardiomyopathy (May 2012) was hospitalized at the Department of Internal Medicine in Ilava hospital, Slovakia (December 2012). The patient had dyspnoea, left-sided bronchopneumonia and fevers. He was treated with amoxicillin/clavulanate and ciprofloxacin. The left-sided hemiparesis becoming hemiplegia evolved during the hospitalization. The CT (computed tomography) of the brain revealed numerous focal changes in the brain parenchyma, and suspected infra- and supratentorial metastatic lesions.
+The patient was transferred to the ICU (Intensive Care Unit) of the Clinic of Infectology and Geographic Medicine (January 2013). His pulse was 75 BPM and blood pressure was 125/70 mm mercury. The patient had a headache, cough and he was afebrile, with hemiparesis on the left lower limb. Anti-oedemotous and switched antibiotic therapy by third-generation cephalosporin and metronidazole was initiated. The investigations were complemented by MRI (magnetic resonance imaging) of the brain, which did not prove metastases and showed numerous abscesses with a strong oedema supra- and infratentorially in the posterior cranial fossa. In the quest for the brain abscess etiology, biological materials were collected for serological and microbiological tests. Blood culture was sterile. The cerebrospinal fluid was negative for any bacteria and bacterial antigens (Neisseria meningitidis serotypes a, b, c, y, w135; Streptococcus group B; Haemophilus influenzae serotype b; Streptococcus pneumoniae; Escherichia coli K1). The mycological serology, antigens of Cryptococcus neoformans, Aspergillus spp. and Candida spp., was negative as well. The pus from the skin lesion was examined by the Gram staining technique, showing the presence of Gram-positive hyphae. Native preparation and Lactophenol Cotton Blue staining of the material from the skin biopsy revealed the same observation – numerous darkly pigmented fungal elements with septa. As a bacteriological examination was negative, the samples were further cultured on Sabouraud dextrose agar (SDA) (HPL SERVIS Ltd. Nesvady, Slovak Republic) or Sabouraud dextrose broth (SDB) (HPL SERVIS Ltd. Nesvady, Slovak Republic) with antibiotics. The SDA and SDB were incubated at both 25 °C and 37 °C. The growth rate was moderate and it took about 4–5 days of incubation. After that time, velvety, olivaceous, grey colonies with olivaceous, black reverse could be observed . Colonies did not produce any diffusible pigment. The slide culture of the mould was incubated at 25 °C and after 5–7 days showed dark-walled, septate hyphae with poor branching. The one-celled oval conidia (7.5–11 µm×2.5–4 µm) were smooth-walled and pale brown without pigmented hila. They formed long, coherent, sessile, lateral or terminal chains on undifferentiated hyphae . The fungus grew on SDA and malt agar at 42 °C, with the optimal growth temperature between 35 and 37 °C. The mould was urease positive, growth on 10% NaCl agar was negative and colonies could grow on media containing cycloheximide. Based on these results, the isolate was identified in our laboratory as C. bantiana. To confirm this observation, we performed DNA sequencing-based identification. DNA was extracted using a Qiagen kit according to the manufacturer’s protocol and used for PCR with a specific set of primers for the internal transcribed spacer (ITS) regions of the fungal rRNA gene ITS1 (5′-TCCGTAGGTGAACCTGCG-3′) and ITS4 (5′-TCCTCCGCTTATTGATATGC-3′) (Invitrogen) according to . The PCR products were sequenced twice in both directions and the consensus sequence (596 nt) was used for subsequent blastn analysis against the nucleotide database with standard blast settings. The consensus obtained was aligned with the sequence of the ITS1 and ITS2 region of C. bantiana strain 1394 (sequence ID GQ258793), which had the highest score (1037 bits). Over 578 nt of the alignment, 99% identity, 2 gaps and 8 mismatching nucleotides were observed. Other C. bantiana strain ITS sequences represented all 13 highest-scoring blast matches. Finally, the isolate was identified as C. bantiana based on morphological and physiological features, and on the DNA sequence analysis. The sequence obtained was registered in the genetic sequence database GenBank under accession number KM525668.
+Susceptibility testing to selected antimycotics was performed on RPMI medium by quantitative assay for determining the MIC (MIC Test Strip; Liofilchem). After 48–72 h of cultivation at 30 °C, the MICs of 0.006 mg posaconazole l−1, 0.125 mg voriconazole l−1, 0.016 mg itraconazole l−1 and 0.75 mg amphotericin B l−1, were evaluated. There are no standard guidelines for antifungal therapy and until now, it has not been confirmed that therapy alone can improve survival . The current recommendation for eradication of disease associated with dematiaceous fungi is a combination of total surgical excision followed by systemic antifungal therapy . Our patient received an intravenous administration of amphotericin B and intense anti-oedematous therapy. The status of the patient was not improved, retrograded neurological complications and accelerated respiratory insufficiency resulted in the patient’s death one month later (February 2013). As the death of the patient was classified as being due to systemic fungal infection, a pathological-anatomic autopsy was recommended. Finally, C. bantiana was isolated from autopsy material taken from the lung, brain and skin.

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1269_en.txt

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+A 16-year-old girl was diagnosed with TOF, secundum, and sinus venosus atrial septal defect (ASD) at birth. Additionally, she had Turner syndrome [46, X, del(X)(p11.2)] and a horseshoe kidney. She underwent total correction of TOF and ASD closure at the age of 14-months, including patch closure of the subarterial ventricular septal defect, direct closure of the ASD, resection of the infundibular muscle, and transannular patch extending to the main pulmonary artery. However, the diagnosis of PAPVR was missed. She was doing well at her annual outpatient clinic follow-up. At the age of 16, she developed dyspnea on exercise. Echocardiography demonstrated severe pulmonary regurgitation, mild tricuspid regurgitation, and D-shaped left ventricle (LV) with paradoxical septal motion along with RIV and sinus venous ASD. Computed tomography also confirmed RIV and PAPVR . The right upper pulmonary vein (RUPV) drained into the SVC and the right middle pulmonary vein (RMPV) showed dual drainage into the SVC and LA. Surgical repair of PAPVR, sinus venous ASD, and pulmonary regurgitation was planned.
+Redo-median sternotomy and bicaval venous cannulation were performed. SVC cannulation was performed with a 20 Fr angle catheter at the utmost distal SVC above the anomalous PV and RIV. Under mild hypothermia cardiopulmonary bypass and after pharmacological cardiac arrest, the lateral wall of the SVC was incised from just above the junction of the anomalous RUPV to just below the junction of anomalous RMPV . Systemic and pulmonary venous blood pathways were separated by bovine pericardial patch. Consequently, dual pulmonary venous blood flow was created; RUPV and RMPV drained directly or through the intra-atrial tunnel and sinus venous ASD into the LA . Pulmonary valve replacement was performed with a 25 mm Trifecta aortic bioprosthesis valve (St. Jude Medical, Inc., USA). The duration of bypass and aortic cross-clamp was 125 and 96 min, respectively. After an uneventful postoperative course, patient was discharged on postoperative day 6. Postoperative echocardiography demonstrated improvement of D-shaped LV and laminar flow through the SVC and PVs. Postoperative computed tomography showed a well-reconstructed SVC and pulmonary venous pathway without stenosis .

data/test_raw_data/en_test/multiclinsum_test_en/fulltext/multiclinsum_test_1273_en.txt

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+An 86-year-old New Zealand European white man was diagnosed as having smoldering myeloma of IgA lambda subtype in June 2008. His diagnostic bone marrow aspirate showed 38% plasma cells. His paraprotein at diagnosis was 9 g/L and gradually increased to 46 g/L by mid-2016 without any evidence of end organ damage .
+His other medical history includes L2–3, L5–S1 spondylosis and early stage prostate adenocarcinoma, T2A Nx M0, Gleason grade 6, which was successfully eradicated with radical radiotherapy in 2000. He takes cholecalciferol 1.25 mg once monthly, cilazapril 2.5 mg daily, amitriptyline 10 mg daily, and paracetamol 1 g twice daily and is intolerant of Augmentin (amoxicillin-potassium clavulanate; diarrhea). He lives with his wife and is fully independent with all his activities of daily living. He does not smoke tobacco and he consumes two units of alcohol per day.
+In June 2016, he developed mild normochromic anemia of 104 g/L and 6 weeks later he was hospitalized with melena in the context of recent non-steroidal anti-inflammatory drug (NSAID) use for low back pain. No bleeding source was identified on upper and lower endoscopies. The ibuprofen was stopped and he was started on omeprazole. He was also found to be mildly vitamin B12 deficient with a raised methylmalonic acid, and was commenced on vitamin B12 treatment. His hemoglobin fell to a nadir of 72 g/L during the NSAID-induced gastrointestinal bleed, but quickly recovered to its new baseline of 92–97 g/L and remained unchanged for the next 12 months. With regards to his back pain, a computed tomography (CT) skeletal survey and subsequent magnetic resonance imaging (MRI) of his lumbar spine showed mild osteoporotic compression fractures of L1–4 without any evidence of lytic disease. A follow-up bone density scan confirmed osteoporosis with a T-score of −2.7 in the left neck of his femur. He was treated with a single dose of zoledronic acid in August 2016 and a weaning course of analgesia. Concordant with his hemoglobin, his paraprotein remained stable at 45–50 g/L over the subsequent 12 months. Given the absence of other myeloma-defining events and unclear etiology of the anemia, he continued with watchful observation.
+In August 2017, he was prescribed a 10-day course of roxithromycin 150 mg twice daily for a clinically diagnosed community-acquired pneumonia. He had presented to his general practitioner with a 10-day history of productive cough, malaise, and anorexia. His temperature was 37.4 °C, blood pressure 140/70 mmHg, heart rate 70 beats per minute, and O2 saturations 98% on room air. Focal crepitations were heard at his left base and the rest of his physical examination was unremarkable. On review 4 days later, he had clinically deteriorated with a temperature of 39.0 °C, blood pressure 140/70 mmHg, heart rate 100 beats per minute, and O2 saturations 97% on room air but his physical examination findings were otherwise unchanged. Cephalexin 500 mg twice daily for 1 week was added to his treatment regime. He completed full courses of both antibiotics with eventual complete recovery. No blood test or sputum sample was submitted to the laboratory, and a chest X-ray was not performed. He did not receive any corticosteroids or herbal remedies with his chest infection.
+At his next routine hematology follow-up a week later, his paraprotein level (quantified by capillary electrophoresis) had decreased by 57% from 46 to 20 g/L. Over the next 4 months, while off all treatment, it slowly increased to 23, 26 then 28 g/L. Quantitative IgA levels demonstrated a similar pattern, falling from 54 to 22 g/L, before increasing to 27, 31 then 33 g/L. His hemoglobin increased from a pre-treatment average of 97 to 123, 126 then 132 g/L over the next 4 months. The rest of his laboratory parameters remained stable; his creatinine was 102 mmol/L, adjusted calcium 2.3 mmol/L, and albumin 32 g/L. Serum free light chains were not measured. When reviewed 4 months after the course of roxithromycin, he was asymptomatic apart from his chronic intermittent low back pain, which was improving.
+His International Staging System was calculated as II in August 2016. Clearly, his myeloma had a favorable slow progressive phenotype, as evidenced by the prolonged latent phase (8 years) from diagnosis and the stability of symptoms and paraprotein despite being untreated.

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+A 73-year-old woman presented to our institution with a 17-mo history of a mass originating in the right submandibular gland and a one-year history of excision of the right submandibular gland tumor.
+She found a 3 cm × 3 cm hard, fixed mass in her right submandibular region with local pain 17 mo prior. There was no restriction in mouth opening or facial nerve dysfunction. The nature of the mass was unclear until the surgery. Radiotherapy was recommended as an adjuvant therapy, so the patient accepted intensity modulated radiation therapy at a dose of CTV1 (right mandibular gland) 2.0 Gy/F; CTV2 1.8-2.0 Gy/F; and CTV1n 1.64 Gy/F. Regular follow-up was performed after radiotherapy. Local recurrence and metastasis were not observed until positron emission tomography-computed tomography (PET-CT) suggested bilateral lung metastasis a half month later.
+She accepted surgery to remove the right submandibular gland and mass 5 months later; after the surgery, she received radiotherapy (66 Gy/33 fractions/45 d).
+She denied smoking and had no personal or family history of the related disease.
+Physical examination revealed old surgical scars about 6 cm in length on the right submandibular angle with no superficial lymphadenopathy or other signs. There was no local pain or facial nerve dysfunction.
+Pathological analysis revealed the tumor type to be Ca ex PA. The main components of this malignant tumor were poorly differentiated carcinomas, including myoepithelial carcinoma and spindle cell carcinoma, while the sarcoma was classified as osteosarcoma. Immunohistochemical (IHC) analysis showed that the tumor cells were positive for PCK, S-100 protein, CK14, P63, calponin, CK5/6, and desmin; the proliferative activity of Ki-67 was 20% .
+After the second and fourth cycles of chemotherapy, head and neck enhanced magnetic resonance imaging (MRI), chest enhanced CT , and abdominal ultrasound were reviewed, which showed that the lung metastasis was controlled.

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+A 25-year-old gentleman presented to our clinic with a complaint of recurrent pain and swelling on his right cheek of three-month duration. He visited a general practitioner each time, and the condition was resolved with analgesic and antibiotics. However, his symptoms got worse and he attended our Oral Surgery Clinic for consultation.
+The patient is a fit and healthy young man with no relevant medical history and no known history of allergy. Past surgical history revealed that he had underwent bimaxillary orthognathic surgery one and half year earlier in a local hospital. Although the postoperative period was uneventful, the surgical team informed him that there was a dislodged orthodontic appliance in his right cheek that must have occurred during the operation. The team explained to the patient that this accident was realized later on the next day after the surgery when the molar tube from the right maxillary second molar was found missing, and its presence was confirmed high up in the right maxillary-zygomatic buttress area shown in the postoperative X-ray image taken on the next day following the surgery. A series of further postoperative radiographs confirmed its location, lying outside the right maxillary antrum. Due to the pronounced postoperative facial oedema at that time, no attempt was made to remove the appliance. The absence of sign and symptoms during further follow-up sessions confirmed the decision to leave it in-situ with continuous clinical observation.
+On examination, there was no extraoral swelling noted. The mandible and maxilla seemed firm indicating good healing following previous mandibular saggital split and maxillary Le Fort I osteotomy sites and a stable class I dental occlusion. Intraorally, there was a sinus with slight pus discharge on the upper right buccal sulcus region adjacent to the upper right first premolar. All teeth in that quadrant were firm and vital. Tenderness was elicited upon palpation on the upper right vestibular region. We suspected the sinus track may originate from the dislodged appliance embedded in the cheek soft tissue. A periapical view was then taken with gutta-percha inserted into the sinus for foreign body localization purpose. The radiograph revealed the gutta-percha pointed towards the site of titanium plate and screws placed used for rigid fixation, and with the molar orthodontic tube appliance in its vicinity . A cone beam CT was performed to provide a 3D detailed location of the appliance and confirmed it to be located outside the maxillary antrum.
+The presence of the molar orthodontic tube foreign body reaction was suspected as the most probable cause of the recurrent right cheek pain and swelling associated with an intraoral discharging sinus. Exploration of the site was performed through the sulcular incision under general anesthesia. The dislodged molar tube was identified lying on the zygomatic bone just beneath the raised flap. It was removed by dividing some surrounding fibrous tissue strands. Just below it, one titanium straight bone plate with four screws used for fixing the previous Le Fort I osteotomy site was inspected and found to be rigidly embedded in normal bone. However, a decision was made to remove them based on the fact that they are present in an infected area. . The Le Fort I osteotomy site showed good healing with new bone formation. Patient had an uneventful recovery thereafter, and the orthognathic surgical team who attended him previously was informed of his progress.

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+A 19-year old Caucasian male presented to the University Hospital of Muenster emergency department after being unresponsive for 5 h. After consuming liquid methadone intravenously the night before, the patient awoke and immediately complained of partial bilateral hearing loss, walking impairment and numbness of both inner thighs.
+According to third-party history obtained from two accompanying friends (the patient was amnestic regarding the night before) the patient had consumed 3 × 2.5 mL of liquid methadone (produced for substitution therapy) intravenously. They reported observing unconsciousness, urinary incontinence, and a twist of his eyes. The patient and accompanying friends admitted to occasionally orally using illegally obtained methadone and cannabis but credibly denied consuming these substances or other opiods and illegal drugs in the days before. This was the first event of intravenous methadone abuse. The medical history of the patient was otherwise unremarkable.
+In the neurological examination the patient presented fluctuating consciousness, severe psychomotor and cognitive slowing (slowed speech, increased response latency, concentration deficits), mild paraparesis of the lower limbs, clonus when testing the left patellar reflex and symmetrical bilateral hypoesthesia of the inner thigh. Medical examination showed a heart rate of 76 beats per minute, blood pressure 121/73 mmHg, peripheral oxygen saturation of 97% and temperature of 36.8 °C. An electrocardiogram (ECG) showed only unspecific change of the ST-segment in V2 and V3. FAST-ultrasound did not reveal any abnormalities.
+Blood tests revealed a slightly elevated c-reactive protein (5.2 mg/dl; reference < .5 mg/dl), an elevated GOP (400 U /l; reference: < 30 U/l), GPT (118 U/l; reference < 40 U /l) and an increased creatin-kinase (7104 U/l; reference: < 174 U/l) and lactatdehydrogenase (563 U/l; reference 117–217 U/l). Sodium and potassium levels were within normal range. Intoxication screening of the urine was positive for methadone (2.55 mg/l) and cannabinoids (THC-COOH: 29 μg/l) but was negative for other drugs including non-methadone opioids and barbiturates, benzodiazepines, tricyclic antidepressive drugs, methamphetamines, cocaine, phencyclidine and paracetamol. An initial magnetic resonance imaging (MRI) showed multifocal, bilateral edema of the basal ganglia , of both cerebellar hemispheres as well as the capsula interna with diffusion restriction and apparent diffusion coefficient (ADC) signal reductions and fluid attenuated inversion recovery (FLAIR) imaging revealed hyperintense alterations in those areas. In addition, DWI and FLAIR imaging presented mild, confluent white matter abnormalities above the lateral ventricle (Supplementary figure A, B). A time-of-flight (TOF)-angiography was normal. An initial spinal tap and subsequent cerebrospinal fluid analysis revealed a disturbance of the blood-brain barrier but normal total protein (542 mg/l) and normal lymphocyte counts (4/μL) and no intrathecal antibody synthesis. An electroencephalogram (EEG) revealed intermittent deceleration without epileptic discharges.
+After admission, the patient was continuously awake and responsive and did not require intensive care treatment. Initially, walking was impaired without a need for a walking aid.
+A transesophageal echocardiography revealed no cardiac abnormalities and especially no endocarditis. Repeated blood cultures were negative. Ear-nose-throat consultation revealed an injury of the inner ear with a diminished ability to hear below 55 dB. We performed treatment with prednisolone for 3 days (days 7–9) at 1 mg per kilogram body weight, which did not cause any immediate conceivable improvement of hearing but the hearing ability improved continuously. The unsteady gait improved to an almost normal level between days 9–11 of inpatient treatment. In contrast, cognitive deficits remained unchanged with increased response latency, slowed speech and concentration deficits. Additionally, the hypoesthesia of the inner thigh remained unchanged.
+An additional MRI after 11 days revealed the known FLAIR-hyperintense lesions of basal ganglia, capsula interna and subtle abnormalities above the lateral ventricles (Supplementary figure C, D) as well as the cerebellar hemispheres , which were now ADC increased. Interestingly, new lesions were found in the crura cerebri bilaterally . Another spinal tap revealed an increase of lymphocytes (11/μl), but otherwise no pathological findings with a normal blood-brain barrier. Flow cytometry analysis of cerebrospinal fluid (CSF) cells revealed a shift in monocyte subtypes with a significant increase of the non-classical CD14 + CD16+ monocyte-fraction and decrease of the CD56bright natural killer cell-fraction in the lymphocyte subset in the CSF . Reference values had been previously collected from 29 patients (female: 58%, mean age: 24.1y + − 5.0 standard deviation (SD)) with psychsosomatic disorder (exclusion of inflammatory CNS disorder; CSF: less than 5 cells/μl, normal protein, no intrathecal antibody synthesis).
+With improved walking and hearing but considerable neurocognitive impairment we discharged the patient after 13 days to subsequent rehabilitation.
+A neuropsychological assessment on day 18 revealed mild-to-moderate overall cognitive impairments when compared with normative data stratified for age and education . Particularly tests assessing cognitive processing speed (e.g., TAP, SDMT, TMT, Time to copy a complex figure) showed consistent alterations from the norm. Learning efficiency of both verbal (RAVLT) and visual material (BVMT-R) was also impaired whereas recall from memory was only reduced for verbal but preserved for complex visual material. Interestingly, the patient showed preserved performance in tests for complex attention and higher executive functions such as planning abilities (D-KEFS Tower Test).

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+A four-month-old previously well Sri Lankan male infant from an urban area presented with high grade fever of 102-103 °F of 2 days duration. He had conjunctival redness, bilateral pedal oedema, a scaly rash in the cheeks, and a sand-paper like papular erythematous rash on the trunk and bilateral upper and lower limbs. Both liver and spleen were palpable 2 cm below the costal margin. There was no redness in the tongue and no cervical lymphadenopathy. Other system examinations were normal, except for high blood pressure measured by both manual and electronic methods, which was above the 99th percentile.
+The initial full blood count showed a total white cell count (WBC) of 18,000/uL with a neutrophil leukocytosis of 53%, a platelet count of 552,000/uL and a haemoglobin of 12 g/dL. C-reactive protein (CRP) was 130 mg/dL and the erythrocyte sedimentation rate (ESR) was 10 mm in the 1st hour. Serum sodium was 134 mmol/L and potassium 5.4 mmol/L. Renal and liver function tests were normal. Covid-19 rapid antigen and PCR tests were negative.
+He was empirically initiated on intravenous cefotaxime and flucloxacillin based on the local sensitivity patterns, suspecting either a streptococcal or staphylococcal septicaemia. However, blood culture was sterile and high fever spikes continued despite continuous antibiotics. Ultrasound scan abdomen on day four was normal and 2D echocardiogram did not show any coronary artery dilatations. Atypical Kawasaki disease was suspected and intravenous immunoglobulin (IVIG) 2 g/kg was administered on day six, followed by aspirin 80 mg/kg/day in four divided doses. As the response was poor, investigations were repeated. CRP and ESR had risen to 143 mg/dL and 130 mm/1st hour respectively. Cerebrospinal fluid (CSF) showed polymorphs 10/mm3, lymphocytes 43/mm3, red cells 23/mm3 and protein 136 mg/dL. Antibiotics were escalated to intravenous meropenam and vancomycin. CSF culture showed no growth.
+Fever spikes continued on day ten and the child developed periungual desquamation in fingers and toes. 2D echocardiogram was repeated which showed dilated coronary arteries (left main coronary artery 5.3 mm, left anterior descending artery 6.5 mm, right coronary artery 5 mm) and a thin pericardial effusion suggestive of KD. A second dose of IVIG 2 g/kg was given and Aspirin dose increased to 100 mg/kg/day. Intravenous Methylprednisolone 30 mg/kg pulse therapy was given for 3 days followed by oral prednisolone. Fever settled for 72 hours, only to recur again. Repeat 2D echocardiogram on day fifteen showed progressive worsening of the coronary dilatation (LMCA 5.7 mm, LAD 9 mm, RCA 6 mm). Electrocardiogram (ECG) showed ST elevations in inferior leads which were persistent on serial ECGs. Cardiac Troponin I levels and Creatine-kinase levels were normal. Clopidogrel and warfarin were added while Aspirin was continued. Oral prazosin and furosemide were added to control the hypertension. His serum electrolytes, renal functions and ultrasound abdomen and kidney-ureter-bladder and renal artery doppler were normal. Extensive investigations in view of aetiology for hypertension such as renal angiogram, urinary and plasma metanephrines, renin-aldosterone levels were not performed as the preliminary investigations were normal and due to limitation of resources in the local setting. His 2D-Echocardiogram did not reveal left ventricular hypertrophy and ophthalmic assessment did not reveal hypertensive retinopathy which confirmed the acute onset of hypertension with the current illness.
+On day sixteen he developed a vesiculo-papular rash involving face, trunk and distal upper and lower limbs including the periungual regions and the perineum . It progressively evolved into bullous lesions. Biopsy of the rash revealed parakeratosis and neutrophils in the epidermis with broad papillae suggestive of guttate psoriasis . It did not show small or medium vessel vasculitis.
+Intravenous infliximab 5 mg/kg was administered on the 28th day of illness after screening for and excluding tuberculosis, followed by two more doses on the 2nd and 6th week after the initial dose. Fever responded to infliximab within 24 hours and the skin lesions showed gradual improvement. He developed a small joint arthritis involving proximal and middle inter-phalangeal joints of hands and feet on day 40 which showed a diurnal worsening . Oral Methotrexate was added. Repeat 2D echocardiogram on day 60 showed a reduction in the coronary artery diameters, finally indicating a therapeutic response (LMCA 5.3 mm, LAD 6.9 mm, RCA 5 mm). The infant was discharged on day 61 of illness on aspirin, warfarin and prazosin. Oral prednisolone, clopidogrel and methotrexate were gradually tailed off after discharge. Oral prednisolone 2 mg/kg dose was given for 6 weeks followed by gradual taper over a period of 3 months.
+On follow up, his arthritis and skin rash resolved completely. The hypertension which was present from the beginning of illness settled completely four and a half months from disease onset, enabling discontinuation of anti-hypertensive medications.

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+A 59-year-old woman was diagnosed with IgG kappa MM in May 2002, when she presented with Durie-Salmon stage III A disease with lytic destruction of the pelvis. Fluorescence in situ hybridization (FISH) performed on a bone marrow aspirate in 2006 did not reveal any high-risk cytogenetic abnormalities. Induction therapy with vincristine/doxo-rubicin/dexamethasone was followed by double autologous stem cell transplantation after conditioning with high-dose melphalan (200 mg/m2), resulting in a PR that lasted for 2 years. At first relapse, 4 cycles of bortezomib and subsequent bortezomib maintenance were administered and led to a PR for further 3 years. Third-line treatment with lenalidomide, bendamustine and dexamethasone produced only a short-lived response. Therapeutic attempts with the Hsp-90 inhibitor AUY-922 (phase I-Ib/II study) and bortezomib/dexa-methasone resulted in disease progression. Salvage treatment using multidrug combinations of two novel agents (bortezomib plus lenalidomide), alkylating agents (cyclophosphamide or melphalan) and dexamethasone also failed to induce a durable response. With high-grade plasma cell infiltration of the bone marrow , increasingly severe pancytopenia developed, causing chronic fatigue and impaired quality of life and eventually led to treatment discontinuation.
+In August 2010, at the age of 68 and 8 years after primary diagnosis , we started treatment with pomalidomide (4 mg days 1–21 of a 28-day cycle) and low-dose dexamethasone (40 mg weekly) in combination with doxorubicin (4 mg days 1–4 by continuous infusion). Due to grade 3 thrombocytopenia, the pomalidomide dose was reduced to 2 mg from cycle 2 onwards, resulting in improved tolerability, serological PR and hematological improvement. However, myeloma therapy had to be stopped after six cycles due to the reactivation of a hepatitis B virus (HBV) infection (11.7 × 106 copies/ml), which the patient supposedly acquired in 1945 and which had never emerged during therapy before. Antiviral treatment with entecavir was initiated, which led to a sufficient drop in viral load (9.7 × 102 copies/ml).
+Five months after the interruption of antimyeloma treatment, the patient suffered from serological disease progression and a pathological humeral fracture requiring surgical treatment . To prevent further disease progression, one more cycle of pomalidomide/doxorubicin/dexamethasone was administered. For the subsequent cycles, doxorubicin was replaced by bendamustine (40 mg/m2 days 1–2) in light of the published data reporting an increased risk of HBV reactivation in patients receiving anthracyclines. However, two cycles of the new combination regimen resulted in transfusion-dependent anemia and grade 3 neutropenia, and only stable disease was observed.
+Since the patient was not eligible for treatment within one of the active clinical trials at our institution, individualized therapy was initiated, whereby pomalidomide (2 mg on days 1–21 of a 28-day cycle) was combined with bortezomib (1.3 mg/m2 day 1, 4), cyclophosphamide (250 mg days 1–3) and dexamethasone (10 mg days 1–3, weekly thereafter). As ninth-line therapy, this individualized combination regimen inhibited the progression of the bone lesions, and the patient continued to experience a good quality of life. When the symptoms of sensory polyneuropathy worsened after 18 cycles, bortezomib was reduced to 1.0 mg/m2 and the cycle length was extended to 43 days. Neuropathy improved gradually; however, we observed a steady rise in serologic disease activity. For the subsequent cycles, the pomalidomide dose was increased to 3 mg days 1–21 and the cycles were repeated on day 29, resulting in sustained PR. Due to an extended treatment-free interval after 34 cycles of pomalidomide + VCD (bortezomib/cyclophosphamide/dexamethasone), we observed an increase of serologic markers. More than 12 years after primary diagnosis and 4 years and 4 months after the first treatment with pomalidomide, regrettably, our patient succumbed to a fulminant pneumogenic septicemia in grade 1 neutropenia.

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+A 67-year-old woman underwent PBSCT for therapy-related acute myeloid leukaemia and received azacitidine, busulfan and fludarabine therapy. Before PBSCT, she had been diagnosed with resolved HBV infection; HBsAg, negative; hepatitis B core antibody (HBcAb), positive (180.6 C.O.I.); and hepatitis B surface antibody (HBsAb), positive (36.9 mIU/mL). She had no history of HBV vaccination, but she experienced acute hepatitis B caused by blood transfusion for her child birth before PBSCT. Changes in HBsAb and HBcrAg during the course are presented in Fig. , as well as other liver function and viral status, alanine aminotransferase (ALT), HBsAg, HBcAb, HBeAg, hepatitis B e antibody (HBeAb) and HBV-DNA levels. Serum HBcrAg levels were determined via chemiluminescent enzyme immunoassay (LUMIPULSE®, Fujirebio Inc., Tokyo, Japan).
+She received rituximab for post-transplant lymphoproliferative disorder 26 months after PBSCT, her HBsAb decreased (8.6 mIU/mL) and HBV-DNA increased slightly to detectable though the levels of < 1.3 logIU/mL. Since she tested positive for HBV-DNA (1.4 logIU/mL) 103 days after the first rituximab therapy (day 0, Fig. H), the scheduled rituximab administration was skipped and the first entecavir treatment was started according to the Japanese guideline for HBV reactivation . Immediately after the first entecavir treatment, the HBV-DNA test became negative (day 63, Fig. H). Since her liver function (ALT levels) had been normal and both HBsAg and HBV-DNA remained negative during NA treatment , entecavir was terminated on day 376. According to the retrospective measurements, HBcrAg remained positive (3.6–3.9 logU/mL) while the HBV-DNA level was undetectable under the first entecavir treatment (day 63–455, Fig. D). One hundred forty-one days after entecavir cessation, the HBV-DNA test turned positive again (1.8 logIU/mL), suggesting HBV rebound (day 517). Her HBV-DNA level reached 5.2 logIU/mL (day 601, Fig. H), her liver function deteriorated and HBV infection worsened; ALT, HBsAg, HBcrAg, HBcAb and HBeAg were elevated to high levels at 280 U/L, 1101.8 IU/mL, 7.0 logU/mL (above the detection range), 727.3 C.O.I. and 1060 S/CO, respectively (day 658, Fig. A, B, D, E and F), even though entecavir treatment was resumed on day 615. The HBsAb level, which had been negative before the HBV rebound, further decreased (0.3 mIU/mL) when the HBV rebound was detected . ALT peaked at 455 U/L on day 685 when the levels for HBsAg, HBcrAg, HBeAg and HBV-DNA peaked out and declined . On the contrary, HBsAb and HBeAb levels increased to 292.8–1631.6 mIU/mL and 99.2–99.5%, respectively , after the rebound, resulting in HBsAg seroconversion with HBcrAg and HBV-DNA levels undetectable. The second entecavir treatment was terminated on day 986. HBV reactivation has not been detected 392 days after the second entecavir cessation, and both HBcrAg and HBV-DNA levels remained undetectable. No difference in medication adherence and renal function was observed between first and second entecavir treatment. Daily dose of entecavir was 0.5 mg for both first and second treatment.

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+A 19-year-old unmarried Chinese woman presented to the anorectal surgery clinic with a complaint of congenital anal atresia from birth.
+Abdominal pain and distension appeared again 6 d prior and could not be relieved.
+The patient had a history of abdominal distension caused by constipation, and unformed loose stools were produced during defecation. At the age of 1 year, she was diagnosed but was not treated. Four months before admission, the patient was found to have abnormal bowel habits for 2-4 d a month, and the symptoms of abdominal pain and distension were relieved after resolving a large amount of loose stool. Computed tomography (CT) examination revealed intestinal obstruction, colon and rectum dilation with a large amount of contents, intestinal wall edema and thickening.
+The patient denied any family history of intestinal diseases.
+Physical examination on admission: There were no abnormalities in the general examination of skin and mucosa; however, the physical examination of the perineum showed that there was no anus in the normal anal position, but there was an anal incisure, and a red and swollen defecation fistula measuring 10 mm in diameter in the rectovestibular, and no abnormalities in the location or appearance of the labia majora, labia minora, vagina or urethra opening .
+No abnormality was found in routine blood and urine analyses.
+Auxiliary examination: (1) Abdominal CT: Rectal dilation with intestinal wall thickening, with a maximum diameter of approximately 10 cm ; (2) X-ray imaging: The distal end of the rectum was the blind end and located approximately 6 cm away from the anal notch ; (3) pelvic MRI: A gap was visible in the upper section of the transverse anal canal , the thickness of the internal sphincter of the anus was approximately 1 mm in the coronal position, some of the internal sphincter was discontinuous, the thickness of the external sphincter was approximately 2 mm in the sagittal position , the positions of the rectum, vagina and fistula were visible in the sagittal position, and the fistula was adjacent to the posterior wall of the vagina .

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+One year before his current presentation, a 38-year-old Sri Lankan man who had previously been well went to the local hospital with intermittent severe epigastric pain radiating to his back, in addition to vomiting. At this initial presentation, acute pancreatitis with high amylase levels was diagnosed. He had been consuming around 12 units of alcohol per week for a 12-year period. He did not have diabetes, hypertension, cholelithiasis, thromboembolic disease, or any other medical disease. He had no family history of significant medical illness. Following this presentation, he had intermittent episodes of epigastric pain, which subsided spontaneously without any medical treatment. At his current presentation, he had a 1-month history of steatorrhea and abdominal pain. His abdominal pain was intermittent and was associated with vomiting. He did not have fever. His initial serum amylase level was high. He was not immobilized. On the third day of admission, he developed progressive abdominal distention with bilateral ankle edema and normal urine output. He was not breathless.
+His physical examination revealed that his body mass index was 21.6 kg/m2. He was afebrile and pale and had ankle edema. He had a pulse rate of 80 beats per minute, and his blood pressure was 130/80 mmHg. His jugular venous pressure was elevated (8 cm). He was not tachypneic, and both lower zones of his lungs were dull to percussion. His breath sounds were reduced without any added sounds. His abdomen was tensely distended and tender, with gross ascites.
+The patient’s amylase level was rising. On day 1 of admission (1 month after symptoms started), his amylase level was 1331 U/L; on day 2, it was 1780 U/L; and on day 3, it was 3570 U/L. His amylase level remained elevated for 3 weeks. His white blood cell count (WBC) was 11.04 × 103 /μL with 70 % neutrophils. His hemoglobin level was 6.7 g/dl, with a hematocrit of 24.9 % on admission (normal 37–54 %). On day 2 of admission, his hematocrit was 25.6 %. His platelet count was 243 × 109/L. Hypochromic microcytic red blood cells (RBC) with a few pencil-shaped cells and macrocytes as well as hypersegmented neutrophils were visualized by mircroscopy. The patient’s reticulocyte index was normal, and the result of his Coombs test was negative. His serum ferritin level was 37.0 μg/L (normal 25–240 μg/L), his serum iron level was 13.4 μg/dl (normal 37–148 μg/dl), his total iron-binding capacity was 296 μg/dl (normal 274–385 μg/dl), and his iron saturation was 4.5 % (normal 15–50 %).
+The patient’s liver function tests were within normal range, except for a marginally low albumin level (aspartate aminotransferase 14 U/L, alanine transaminase 10 U/L, alkaline phosphatase 125 U/L, total bilirubin 18 μmol/L, total protein 48 g/L, albumin 32 g/L, globulin 16 g/L, international normalized ratio [INR] 1.23). His erythrocyte sedimentation rate was 56 mm/h in the first hour, and his C-reactive protein (CRP) levels were 35 mg/L on admission and 24 mg/L (normal 0–5 mg/L) after 48 hours. His serum ionized calcium on day 2 of admission was 0.91 mmol/L (normal 1.09–1.3 mmol/L), and it was 1.14 mmol/L with replacement of calcium on day 5. His serum creatinine concentration was within normal range throughout (75, 88, and 78 μmol/L; normal 60–120 μmol/L : on days 1,2 and 5 respectively), and his blood urea nitrogen level was normal (2.6 mmol/L, normal 2.9–8.2 mmol/L). His serum sodium level was 133 mmol/L, and his serum potassium concentration was 3.3 mmol/L. His random blood sugar level on admission was 126 mg/dl. Arterial blood gas analysis showed a pH of 7.5 with partial pressure of carbon dioxide of 31.4 mmHg, bicarbonate of 30.0 mmol/L, base excess of +8.0, lactate of 1.0 mmol/L (normal 1.0–2.5 mmol/L), oxygen saturation of 95.8 %, and partial pressure of oxygen of 73.4 mmHg. His fasting blood sugar level was 5.6 mmol/L (normal <5.6 mmol/L). His lipid profile was normal, with a normal triglyceride level of 120 mg/dl. His thyroid-stimulating hormone level was 0.97 mIU/L (normal 0.55–4.78 mIU/L), and his free thyroxine was 1.54 (normal 0.89–1.76).
+An ultrasound scan of the abdomen showed gross ascites with a normal liver and kidneys. Contrast-enhanced computed tomography (CECT) of the abdomen revealed two pancreatic pseudocysts, measuring 4.5 cm × 3.5 cm and 4.2 cm × 5 cm, respectively, in relation to the pancreatic head . The pancreatic duct and the rest of the pancreas were normal, without evidence of necrosis or changes of chronic pancreatitis. Gross ascites was visualized on both an ultrasound scan of the abdomen and a CECT scan. The patient’s bowel appeared normal. His peritoneal fluid was an exudate with 4.3 g/dl protein and a serum-to-ascites albumin gradient of −1.1 g/dl (<1.1 g/dl), a lactic acid dehydrogenase level of 527 U/L, WBC of 73 cells/mm3 with 90 % lymphocytes, and RBC of 1.6 × 109/mm3. His ascitic fluid amylase level was high at 3618 IU/L. No malignant cells were seen, and the patient’s Gram stain and acid-fast bacilli smear results were negative, with the culture remaining sterile. His adenosine deaminase level was normal (12 IU/L).
+One of the pseudocysts in the head of the pancreas was compressing the inferior vena cava (IVC), as shown in the CECT scans in Figs. , and . There were filling defects in the left common and internal iliac veins and both proximal external iliac veins, suggesting DVT . The patient’s IVC was patent. Multiple filling defects were seen in the right lower lobe pulmonary artery and in segmental branches of the left pulmonary artery, compatible with pulmonary embolism . The patient’s liver, gallbladder, spleen, kidneys, and adrenal glands were normal. He had bilateral atelectasis of the lung bases with minimal pleural effusions.
+Venous Doppler sonography of the patient’s lower limbs did not reveal DVT in the femoral and popliteal veins. The patient’s D-dimer level was 1.43 mg/L. His left ventricular ejection fraction was 55 %, with diastolic dysfunction visualized on a two-dimensional echocardiogram. His main pulmonary artery was normal, with a pressure gradient of 23 mmHg, and his right ventricular function was good.
+His antinuclear antibody and anticardiolipin antibody test results were negative. He had no nocturnal hematuria, and the findings in three consecutive early morning samples were negative for hemosiderin. The results of genetic testing for prothrombin gene mutation, factor V Leiden, and MTHFR gene mutation were negative. The results of the patient’s Ham test and the thrombophilia screen for antithrombin III as well as protein C and protein S deficiency were negative. His test result for dengue antibodies was negative. The results of his monospot test for Epstein-Barr virus, hepatitis B surface antigen, and hepatitis C antibodies were negative. His test result for HIV was also negative, and his VDRL was nonreactive. His upper gastrointestinal endoscopy was normal initially. His carcinoembryonic antigen level was 0.9 μg/L (normal <5 μg/L).
+After the diagnosis of DVT and pulmonary embolism was made, the patient was started on subcutaneous enoxaparin 1 mg/kg twice daily and warfarin to achieve a target INR of 2–3. Initially, he was kept nil orally; later, gradual enteral feeding was introduced. Calcium was replaced orally. Later, he developed bleeding into the peritoneal cavity with a high INR, and 6 U of blood were transfused. He was managed in the intensive care unit (ICU) during this period, and total parenteral nutrition was given. His bleeding settled spontaneously with INR correction. His ascitic fluid and large pseudocyst were drained using a pigtail catheter. The pigtail catheter was kept in place until the drainage stopped, and then it was removed. After 10 days in the ICU, the patient recovered and was discharged on oral warfarin to achieve a target INR of 2–3. He was planned to be treated with anticoagulation for 6 months because he did not have any other acquired or congenital risk factors for thromboembolism.

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+A 62-year-old female with MFS was presented to the hospital for an emergency after being diagnosed with cerebral thromboembolism due to atrial fibrillation (AF). Apart from the acute endovascular thrombectomy, the patient was treated for congestive heart failure associated with aortic valve regurgitation with tachycardic AF. Echocardiography revealed severe regurgitation with reduced left ventricular ejection function (32%) and massive left ventricular diastolic dimension (88 mm). Aortic valve was tricuspid, and the eccentric regurgitation jet revealed prolapse of right coronary cusp. The aortic root was moderately dilated (42 mm). After 2 months of treatment, the patient was referred to our hospital for the surgical treatment of aortic valve regurgitation. The patient was free from the sequela of brain stroke, but complained of general fatigue consistent with a New York Heart Association class III condition with weakened leg muscle strength due to disuse syndrome. N-terminal pro-brain natriuretic peptide (NT-proBNP) level at admission was 3964 pg/mL. Sinus rhythm had been maintained after initiating oral amiodarone. The diameter of the aortic root in this patient was below the size required for indicating surgical treatment for MFS . In addition, the dimension and systolic function of the left ventricle suggested the progression of ventricular remodeling. Therefore, aortic valve replacement was selected primarily for the prevention of heart failure. In contrast, there were various options for the management of AF in the present case. Left atrial appendage closure was thought to be an appropriate treatment option to prevent recurrence of cerebral thromboembolism because AF had been effectively controlled by antiarrhythmics and the patient would receive coumadin following mechanical valve implantation. Thus, combined surgery involving aortic valve replacement and left atrial appendage (LAA) closure was planned in order to achieve early rehabilitation and return to daily life. Her chest XP revealed severe scoliosis . Spirometry showed normal lung function. A computed tomography was performed to determine the optimal intercostal space to access both the aortic valve and LAA . Three-dimensional reconstruction imaging showed that right lower hemisternotomy in a reverse “L” fashion was the optimal approach for clamping and incising the aorta with the ectopic origin of the right coronary artery arising from anteromedial surface of ascending aorta .
+The patient was intubated using a double-lumen tube and laterally positioned at approximately 30 degrees right-side up. A skin incision was made from the second intercostal space down to the xiphoid process, after which the chest was opened via right lower hemisternotomy. The surgical field was secured using a Kent retractor (Takasago medical Inc., Tokyo, Japan) and sternal retractor with the costal arch folded back. Cardiopulmonary bypass was established with femoral arterial and cavoatrial cannulation. The ascending aorta was cross-clamped using flexible aortic clamp . Cardiac arrest was obtained using bidirectional cardioplegia. An oblique aortotomy was created 10 mm medial to the ostium of the right coronary artery. The aortic valve cusp was then resected, and a 25-mm mechanical valve was implanted in the intra-annular position. After closing the aortotomy, the 40-mm AtriClip (Atricure Inc, Westchester, OH, USA) was applied to the stump of the LAA before releasing the aortic cross-clamp. The patient was carefully weaned from cardiopulmonary bypass, which required an intraaortic balloon pump for the treatment of perioperative low-output syndrome due to reduced left ventricular function. The extracorporeal circulation time and aortic cross-clamp time were 165 and 87 min, respectively. The total operative time was 303 min. Transfusion of 4 units of red blood cells and 6 units of fresh frozen plasma was required during the surgery.
+The patient was extubated on postoperative day 2, and the intraaortic balloon pump was removed 2 days after the extubation. Further, she was then transferred to the rehabilitation center for the management of her disuse syndrome on postoperative day 21; thereafter, she has been living independently without any cardiac and cerebrovascular event.

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+A 38-year-old female nursing technician presented a prior history of three episodes of anaphylaxis within one year, all in the workplace. She had a personal history of mild intermittent allergic rhinitis from childhood, for which antihistamines and nasal corticosteroid had been used only during exacerbated episodes. She had a family history of atopy and presented a positive prick test for aeroallergens (Dermatophagoides pteronyssinus and Blomia tropicalis). She tested negative for serum-specific immunoglobulin E (IgE) for latex.
+Because of her recurrent pattern of anaphylaxis and risk factor for latex allergy, a latex prick test using a standard commercial extract (500 mcg/ml; ALK Abelló, Spain) was performed. Five minutes after the puncturing, the patient developed a generalized rash, itchy skin, hoarseness, dyspnea, dry cough and a sensation of a foreign body in the oropharynx. Her vital signs were: blood pressure of 134 x 84 mmHg, heart rate of 130 bpm and peripheral oxygen saturation of 94%. The patient was placed in dorsal decubitus, with elevation of the lower limbs and 0.5 mg of adrenaline was applied intramuscularly in the upper third of the vastus lateralis muscle of the thigh, in addition to 200 mg of hydrocortisone and 50 mg of diphenhydramine intravenously, and inhalation of short-acting ß2-agonist. The patient presented progressive improvement of the condition without presentation of the late-phase reaction.
+The patient was evaluated in the context of another major study that was ongoing, and signed a free and informed consent statement for that study, which had been approved by the institution’s ethics committee, under the number 0538/10 on September 22, 2010.

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+A 42-year-old woman had a medical history of melanoma excised in 2002. Following the surgery, she was placed on active surveillance. In 2021, she developed a left inguinal lymph node and liver nodules, which were confirmed to be metastatic melanoma positive for the BRAF V600E mutation through biopsy. Initially, she received a combination of immune checkpoint inhibitors (ICI), specifically anti-PD-1 and anti-CTLA-4, for nearly three months, with the only side effect being hypothyroidism. Due to disease progression under ICI treatment, she was switched to encorafenib/binimetinib (E/B). On the fourth day of E/B treatment, she developed serous retinopathy, which resolved after a brief temporary discontinuation of the targeted therapy. This allowed the resumption of the E/B regimen at a reduced dose. One week later, she experienced severe acute pain in her left shoulder, scoring 8 on the Visual Analog Scale, without any traumatic context. During the medical examination, she displayed no motor deficits, no movement limitations, and her deep tendon reflexes remained intact. Both X-ray and ultrasound examinations of the shoulder were normal, but a C5-C6 discopathy was noted on cervical spine X-ray. The patient received treatment with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), which led to the resolution of pain within one month. However, this was followed by muscle weakness, prompting further investigations. An MRI of the cervical spine confirmed degeneration at the C5-C6 and C6-C7 levels, but without cervical radiculopathy. A lumbar puncture revealed no signs of inflammation, and serology testing for Lyme disease came back negative. Serum inflammatory markers remained within normal ranges, and the search for various autoantibodies, including antiganglioside antibodies, also yielded negative results. An electromyogram (EMG) was performed, revealing severe axonal denervation of the suprascapular nerve that did not respond to stimulation . The clinical presentation and EMG data led to the diagnosis of Parsonage-Turner syndrome. Given the temporal relationship with the oncological treatment and the absence of alternative triggers such as infection, vaccination, or mechanical events, the causality of the sequential use of ICI-targeted therapy was established. However, the E/B regimen was continued in the absence of an alternative treatment for her metastatic melanoma. The patient recovered and regained function in her arm through physical rehabilitation. No specific treatment was introduced, and corticoids were not administered because the diagnosis was made at a stage where the muscles were already atrophied, and the goal was to prevent the development of additional steroid-induced myopathy.
+Regular clinical evaluations and EMG assessments were conducted. At present, the patient is still undergoing treatment with E/B, with her oncological disease remaining stable. She is in good clinical condition, and there has been complete recovery of the suprascapular nerve.

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+A 76-year-old woman had an 8-year history of atrial fibrillation (AF) and severe TR. Her history included mild hypothyroidism and right upper lobectomy for lung carcinoma 11 years previously. For 2 years, she had complained of shortness of breath when lying in the left lateral decubitus position. She had felt dyspnea after mild exercise for 9 months. Recently, she had a sense of abdominal fullness. Although administration of diuretics was started, her symptoms did not completely improve, and she was referred to our department for surgical treatment. The follow-up chest X-ray showed a gradually protruding right-side shadow of the cardiac silhouette, and the cardiothoracic ratio on the chest X-ray reached 88% . The electrocardiogram showed AF with low fibrillatory wave amplitude. Echocardiography showed an enlarged right ventricular (RV) cavity and mild paradoxical motion of the ventricular septum. The tricuspid valve had no findings of an organic and constructive abnormality, with no severe tethering. The annular size of the tricuspid valve was 50 mm, and the tricuspid annular plane systolic excursion was 21 mm . Repeated preoperative cardiac catheterization showed slightly elevated wedge pressure with mild pulmonary hypertension, although LV function was preserved with a cardiac index of 4.0 . There was no L-R shunt disease. Computed tomography (CT) findings showed that the maximum size of the RA reached 121 mm . The change in dimension of the RA by CT showed that the size of the RA increased with time . Blood tests showed no liver dysfunction.
+Surgery was performed via median sternotomy. The pericardium was extremely thin on the RA side without any defect. There was no adherence in the pericardial cavity. Cardiopulmonary bypass was established by ascending aorta cannulation with bicaval drainage. The RA was extremely thin and the tricuspid valve annulus was enlarged, with a diameter of 55 mm, but there was no tricuspid structural abnormality. Tricuspid annuloplasty was performed on the beating heart using a 28-mm Carpentier-Edwards Physio tricuspid annuloplasty ring (Edwards Lifesciences, Irvine, CA, USA). Plication of the enlarged RA was performed, mainly at the interatrial septum, the free RA wall, including the appendage, and the space between the inferior vena cava and the tricuspid ring, in addition to the free RA wall, including the appendage . Additionally, closure of the left atrial appendage from the outside was performed to prevent left atrial thrombus formation. All procedures were performed on the beating heart. The postoperative course was uneventful. The pathological findings of the RA wall demonstrated thinning of the myocardium, inflammatory cell infiltrate, and few cardiomyocytes . Postoperative X-ray and CT showed reduced cardiac silhouette and RA volume . Postoperative echocardiography showed an ejection fraction of 58% and mild TR with a pressure gradient of 29 mmHg . The postoperative value of tricuspid annular plane systolic excursion (TAPSE) decreased after the operation. However, the patient’s symptoms were completely resolved, and she was discharged 3 weeks after surgery. The patient is doing well 2 years after surgery.

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+A 81-year-old man with an adenocarcinoma of the prostate diagnosed one year earlier presented with a five month history of gradually progressive complaints of dyspnea. At the time of diagnosis of the prostate cancer, there had been no signs of metastases and since it was an asymptomatic grade 2 prostate cancer in a man of advanced age, a watchful waiting policy was followed. The medical history revealed hypertension and a transurethral resection of the prostate six years before presentation. The patient complained of dyspnea, progressive peripheral edema, orthopnea, and painful knees and thighs which made walking extremely difficult. There had been weight loss of ten kilograms over six months, with associated loss of appetite. No thoracic pain, hemoptysis or other pulmonary or cardiac complaints were present. The patient had been a heavy smoker for fifty years.
+On admission his blood pressure was 150/80 mmHg with an irregular pulse of 96 per minute, temperature 36.2°C, and he had a normal central venous pressure. The heart sounds were normal. Percussion and auscultation of the left lower lung revealed dullness with diminished breath sounds. These signs were indicative of pleural effusion. The liver was not enlarged. There was pitting edema especially at the lower extremities, but also of both hands, which were also noted to be remarkably large. Percussion of, and axial pressure on, the vertebrae was not painful. The patient refused rectal examination because of painful earlier experiences.
+Laboratory examination revealed the following data: ESR 35 mm in the first hour (normal: <7), CRP 134 mg/l (normal <10), hemoglobin 6.3 mmol/l (normal: 8.9–10.7) with a MCV of 82 fl (normal: 80–100), leukocytes 8.6 × 109/l (normal: 4.5–10.0) with 90% neutrophilic granulocytes (normal 40–70), normal blood platelets, electrolytes and liver enzymes. Creatinine was 77 μmol/l (normal: 64–108), alkaline phosphatase was elevated at 285 U/l (normal: 40–120), calcium was 1.95 mmol/l (normal: 2.15–2.68) with an albumin of 23.9 g/l (normal: 35–50 g/l) and a normal phosphate. Blood gas analysis showed a chronic compensated respiratory acidosis with an oxygen saturation of 80%.
+Electrocardiography showed atrial fibrillation with a left bundle branch block, similar to earlier ECGs. Chest X-ray revealed a large amount of pleural fluid on the left side and an enlarged heart without signs of vascular redistribution. There were no signs of tumor or pulmonary metastasis on chest X-ray.
+Analysis of the pleural fluid was performed. A total amount of 4.5 liters was evacuated. Cytological and biochemical analysis showed only lymphocytosis with no signs of malignancy or bacterial infection. Auramin and Löwenstein cultures were negative. An echocardiography showed good left ventricular function. Ultrasound investigation of the abdomen showed a dilated inferior caval vein without other abnormalities. The entire presentation was compatible with right-sided heart failure in a patient with probable pulmonary hypertension. On Computed Tomography Angiography (CTA) there were no pulmonary embolisms visible but a large amount of pleural fluid was seen in the left pleural cavity.
+Because of the elevated alkaline phosphatase, the bone pains and the previously diagnosed prostate cancer, skeletal scintigraphy was performed. It showed a 'super scan', meaning there was diffuse uptake throughout the entire skeleton. This was judged as fitting diffuse skeletal metastasis of the prostate cancer [Figure ]. However the prostate specific antigen was within the normal range at 1.4 μg/l (normal < 4.4)
+With the remarkably large hands in mind, additional investigations were carried out [Figure ]. A bone marrow examination showed no marrow disease nor malignancy. X-ray of the hands, humeri, femora and pelvis revealed extensive subperiosteal bone appositions compatible with generalized hypertrophic osteoarthropathy [Figure ]. Repeat of the earlier performed CTA indeed now showed a fluid-containing cavity in the lower left lobe surrounded by a large amount of pleural fluid at that side suggestive of a lung cancer. Bronchoscopy confirmed this diagnosis. The left main bronchus was stenotic with tumor totally occluding the left lower lobe and almost occluding the left upper lobe. Histological examination was not possible due to technical difficulties during the procedure. The diagnosis of incurable bronchial carcinoma with hypertrophic osteoarthropathy was made with the prostate cancer as an "innocent" bystander. Since the patient was rapidly deteriorating palliative care was given. The patient died several weeks after admission. Post mortum examination confirmed the clinical diagnosis. There was a large undifferentiated non-small cell lung carcinoma with a diameter of 10 cm and extension in the adventitia of the esophagus and lymphatic metastasis in the hili and mediastinum. Three liters of tumor-positive pleural fluid and extensive hypertrophic osteoarthropathy was seen without distant metastasis.

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+A 39-year-old woman demanded the resection of her primary renal carcinoma after receiving 6-mo target therapy.
+The patient was diagnosed with renal clear cell carcinoma with bone metastasis half a year ago. After receiving 6-mo target therapy, manifestations of bone lesions disappeared while the size of the renal mass increased. A partial nephrectomy was recommended for the treatment of her primary renal tumor.
+The patient had been on hormone for lupus nephritis treatment for 17 years.
+The patient had no markable personal and family history.
+On arrival at the urosurgery ward, the patient’s blood pressure (BP) was 128/76 mmHg, and her pulse rate was 77 beats per minute (bpm). No percussion pain was detected alongside her urinary system.
+Nothing abnormal was shown in the laboratory examinations.
+A mass with mixing density was found on her left kidney on the enhanced computed tomography (CT). Its size was about 5.6 × 4.4 × 4.8 cm.

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+A 25-year-old Sri Lankan woman presented with several episodes of central abdominal pain, abdominal fullness, and non-projectile vomiting for 1-week duration. The vomitus was non-bilious, with undigested food particles and was noted particularly 1 to 2 hours after meals. Episodes of vomiting were accompanied with colicky central abdominal pain but these symptoms were only mild and between attacks she was completely asymptomatic. As she had had at least five similar episodes over the last 3 years, she sought medical advice. Most of those episodes were self-limiting, but she had a couple of hospital admissions during which she was managed conservatively. During one episode, she had noticed pruritus and darkening of urine as well, which again resolved spontaneously. She had undergone an upper GI endoscopy 1 year earlier which did not provide a positive finding. She had a past history of rectal polypectomy, at the age of 16 years, when she was investigated for painless per rectal bleeding, the histology of which was consistent with a tubular adenoma. Follow-up colonoscopies had not detected any further polyps.
+On examination, she had a body mass index of 20.3 kg/m2. She had a few scratch marks on her trunk and upper limbs confirming pruritus. She was not icteric or febrile. An abdominal examination was unremarkable and her gall bladder was not palpable. Succussion splash was not elicited. There was no mucocutaneous pigmentation.
+There was biochemical evidence of biliary obstruction with alkaline phosphatase (ALP) of 896 IU/L, a total bilirubin of 2.6 mg/dl and direct bilirubin of 2.2 mg/dL. An ultrasound scan of her abdomen detected intrahepatic and extrahepatic duct dilatation with a dilated common bile duct (CBD) of 11.5 mm without evidence of gallstones or CBD stones. She was found positive for fecal occult blood and was subjected to upper GI endoscopy and colonoscopy both of which were negative. Plain radiographies of her chest and abdomen were unremarkable. She was further investigated with a computed tomography (CT) enterogram and a magnetic resonance cholangiopancreatogram (MRCP). The CT enterogram revealed a large soft tissue mass causing duodenal intussusception into her proximal jejunum. Her CBD was found to be stretched to the left of the midline resulting in its dilatation of up to 12 mm at the lower end. MRCP also confirmed the absence of gall stones and other filling defects in her CBD . Based on these findings she underwent a small bowel enteroscopy which demonstrated a large duodenal polyp, originating from the second part of her duodenum and intussuscepting into the proximal jejunum beyond the duodenojejunal junction. The major duodenal papilla appeared stretched and elongated along the long axis of her duodenum. The rest of the enteroscopy study was normal. A biopsy was not taken because of the presence of intussusception.
+Even though it was possible to negotiate the scope beyond the polyp it was decided to go ahead with open surgery after two multidisciplinary team meetings because of the large size of the polyp, its critical location, and the presence of the intussusception. An intraoperative upper GI endoscopy was performed to localize the polyp because the polyp was not readily palpable through her duodenal wall. An oblique duodenotomy was done and a large polyp with a broad and long stalk was found. The origin of the stalk was at the second part of her duodenum, 1 cm below the ampulla. A polypectomy was done and the intussusception was reduced and the duodenum was closed transversely with 5/0 polydioxanone sutures . She had an uncomplicated recovery and was discharged on sixth postoperative day.
+On macroscopic examination the specimen was a polyp of 50 × 45 × 30 mm in size with a broad, 20 mm long stalk . On microscopic examination it was composed of a branching villous structure of small intestinal mucosa containing a core of smooth muscle. The overlapping mucosa was histologically normal. Thus, microscopically this was a hamartomatous polyp consistent with a Peutz–Jeghers polyp .
+Our patient became completely asymptomatic following surgery. She is followed up in general surgical clinic and is scheduled for routine upper GI endoscopy surveillance every 3 years.

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+A 62-year-old Chinese female was admitted to The First Hospital of Hebei Medical University with a two-day history of abdominal pain, especially in the subxiphoid region, as well as dyspnea, sweating, headache, and dizziness. She had received regular treatment for nine years for a coronary stent and had a nine-year hypertension history.
+The initial physical examination returned the following results: temperature = 36.2°C, heart rate = 90 beats per minute, respiratory rate = 18 breaths per minute, and blood pressure = 90/51mmHg. She was week and apathic. She had clammy skin, abdominal distension, and percussion sound on the abdomen. No obvious abnormalities were found in terms of auscultation and palpation of the lung and abdomen or in terms of the nervous system.
+The initial laboratory examinations revealed an increased neutrophil percentage (90%) and a decreased platelet count (PLT) . The serum biomarkers of glucose, urea, creatinine, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase, total protein, albumin, and globulin returned values of 7.80 mmol/L (reference range: 3.90–6.10 mmol/L), 12.39 mmol/L (2.60–7.50 mmol/L), 194 μmol/L (41.0–73.0 μmol/L), 78.6 U/L (7.0–40.0 U/L), 111.3 U/L (13.0–35.0 U/L), 159 U/L (7–45 U/L), 354 U/L (50–135 U/L), 44.5 g/L (65.0–85.0 g/L), 29.1 g/L (40.0–55.0 g/L), and 15.4 g/L (20.0–40.0 g/L), respectively. The coagulation tests indicated a prolonged prothrombin time (21.6 s) (reference range: 9.4–12.5 s), an activated partial thromboplastin time (42.1 s) (25.1–36.5 s), and an extremely elevated D-dimer (43.49 mg/L) (0–0.55 mg/L), while the patient’s fibrinogen (3.50 g/L) (2.38–4.98 g/L) and thrombin time (14.9 s) (10.3–16.6 s) were normal. Among the heart biomarkers, the serum N-terminal pro-B type natriuretic peptide (NT-proBNP) level was markedly higher, while the patient returned a mildly high troponin I result and a normal creatine kinase–MB result. The arterial blood gas analysis indicated compensatory metabolic acidosis with a pH of 7.36 (reference range: 7.35–7.45), a partial pressure of carbon dioxide of 33.4 mmHg (35–45 mmHg), and a partial pressure of oxygen of 61.6 mmHg (80–100 mmHg). The routine urine tests indicated increased red blood cell (RBC) count (134 cells/μL) (reference range: 0–17), white blood cell (WBC) count (1264 cells/μL) (0–28 cells/μL), purulent cell count (32 cells/μL) (0–2 cells/μL), bacteria (325/μL) (0–340 cells/μL), fungi (0 cells/μL) (0–1 cells/μL), urine protein (2+) (negative), and occult blood (3+) (negative), with negative nitrite (negative). Hepatitis virus series, human immunodeficiency virus (HIV), and syphilis antibodies were negative. Pneumoclide IgM test showed that the antibodies of Legionella pneumophila type 1, mycoplasma pneumoniae, rickettsia Q, chlamydia pneumoniae, adenovirus, respiratory syncytial virus, influenza A virus, influenza B virus, and parainfluenza virus type 1, 2 and 3 were all negative. All other autoantibodies were negative.
+The computed tomography (CT) and CT angiography (CTA) examinations revealed a TAA rupture and no abnormality on both lungs, while the electrocardiogram (ECG) examination indicated a prolonged corrected QT interval. Finally, the cardiac ultrasound examination indicated left ventricular enlargement, thickening of the basal segment of the ventricular septum, and left ventricular diastolic dysfunction.
+Based on the general manifestations and the ECG, cardiac ultrasound, CT, CTA, and BNP results, the patient was diagnosed with a TAA complicated with heart failure, while a urinary tract infection was also considered. Other laboratory examinations, including serum procalcitonin (PCT), interleukin (IL)-6, and lymphocyte subset examinations, were also performed to identify the infection and immune function, along with a bacterial culture of blood and urine . Meanwhile, the cefazolin antibiotic was empirically administered as an anti-bacterial agent. An aortography operation, stent implantation involving the aortic branch, and an exploration of the right femoral artery and left brachial artery were performed immediately to target the TAA rupture and to determine the etiology of chest pain. The aortography procedure revealed a TAA 12 cm in diameter, while the bilateral renal arteries and bilateral iliac arteries were observed to be well developed. The surrounding tissue showed no inflammatory findings and no pus was discharged from the aortic aneurysm wall incision. During the operation, 10 units of cryoprecipitate and 200 mL of fresh frozen plasma were transfused. The operation was successful and resulted in a better recovery of blood flow . There were no clear differences in complete blood count, serum biomarkers, coagulation tests, and heart biomarkers, but the NT-proBNP level increased after the repair operation. During the whole procedure, the patient’s blood pressure continuously dropped, and they experienced acidosis aggravation and shock. The patient died 8 h after the operation. On the second day after death, both serum fungitec G test and serum glactomannan test were negative while both the blood and the urine cultures for bacteria and fungi showed positive for Pseudomonas aeruginosa.
+All procedures were performed in accordance with both the ethical standards of the institutional and/or national research committee(s) and the Helsinki Declaration (as revised in 2013). Written informed consent for publication was obtained from the patient’s legal husband.

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+A 32-year-old woman was admitted to the ward with a two-month history of headaches, occasionally accompanied by nausea, vomiting, and vertigo. She had a chronic daily headache, starting in the morning and becoming worse in the upright position. The headaches manifested as a dull ache with moderate to severe intensity, which was constant during the day in the frontal and occipital regions bilaterally. Her headache got better when lying down. She also had a negative history of lumbar puncture, trauma, or manipulation. There was no fever, chills, dizziness, unsteady gait, blurred vision, diplopia, or photophobia. In her past medical history, previous headaches, Ehlers-Danlos, Marfan syndrome, polycystic kidney disease, and spontaneous retinal detachment were not detected; all these conditions are related to intra-cranial hypotension. In drug history, the use of oral contraceptive pills was positive, but she did not use any other drugs. On physical examination, her vital signs were normal, with blood pressure: 12080, pulse rate: 88/minutes, respiratory rate: 16/minutes, temperature: 37.2ºC orally. General physical examination indicated that the head, neck, abdomen, extremities, and skin were normal. In addition, in neurological examination, the patient was awake, obeyed requests, and was oriented to time, place, and person. Her speech was fluent, and all cranial nerves were intact. An ophthalmologic exam showed normal eye movement and reactive pupils, and normal fundoscopic exam was detected. In the motor system, there was no atrophy, and the muscle power was 5/5. The plantar reflex was bilaterally downward and deep tendon reflexes were all 2/2. Sensory and cerebellar tests were normal, and meningeal signs were absent. She had no family history of these diseases, nor any past history of any other diseases. She was a teacher and did not have any psychiatric disorders. The patient had normal complete blood count (CBC). Brain computed tomography (CT) and magnetic resonance venography (MRV) were normal. Brain MRI, with and without gadolinium, was performed; the MRI without gadolinium was completely normal, but in the MRI with gadolinium, meningeal enhancement was clearly seen ( and ).
+A lumbar puncture was conducted, revealing an opening pressure of 2 - 3 cm H2O with no leukocytes or erythrocytes, and with normal protein and glucose levels and regular lactate dehydrogenase (LDH) . The lumbar puncture clearly worsened her positional headache. Her CT myelography from the cerebrum end to the spine revealed a normal condition, without any leakage of CSF or abnormality. Therefore, we tried to increase the intracranial pressure (ICP) of the patient with hydration, using dextrose water serum and a high caffeine diet, including drinking tea, and reducing daily activity. After two days, a significant improvement was seen in her headache.

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+A 29-year-old man visited our urology clinic for a premarital medical examination, with complaints of occasional scrotal pain.
+For the previous month, the patient had experienced occasional minor pain in the testicles.
+The patient had no notable previous medical history.
+He denied any family history and had no specific past history.
+His height was 167 cm, and his weight was 57.9 kg. After physical examination, we found that he had no dysmorphisms and had a normal distribution of pubic hair and body hair. His external urethral meatus was in a normal position, and his penis had a normal appearance and size (5.7 cm, non-erectile).
+The results of the patient's serum test revealed that the luteinizing hormone (LH) concentration was elevated at 15.73 IU/L (normal range: 1.7-8.6 IU/L), and the follicle-stimulating hormone (FSH) concentration was elevated at 14.13 IU/L (normal range: 1.5-12.4 IU/L). However, the serum testosterone hormone concentration was 3.22 μg/L, which was in the normal range for adult males of 2.49-8.36 μg/L. Azoospermia was determined after repeated seminal analysis. Chromosomal analysis was performed twice on samples collected at different times, and 100 metaphases were analyzed in each analysis. Two different cell lines with the karyotype 45,X[93%] /46,X,+mar(Y)[7%] were observed by GTG banding. Fluorescence in situ hybridization analysis with screening of metaphase and interphase lymphocytes was carried out to confirm the result of the karyotype analysis. Two cell lines, one with one green signal for Xcen (182/200) and the other with one green signal and one red signal for Xcen and Ycen (18/200), respectively, were observed according to fluorescence in situ hybridization . All the metaphase and interphase lymphocytes showed one signal for Xcen but no SRY signal, except for cell lines containing SRY . Polymerase chain reaction amplification of 16 Y-STS gene loci (SRY, ZFY, sY86, sY84, CDY2, SMCY, sY127, sY134, sY1161, sY1191, sY254, sY255, DAZ, sY157, CDY1, ZFX, SMCX, DAZL) using a Y-chromosome microdeletion detection kit (Microread Gene; Beijing, China) demonstrated the presence of Y chromosome-derived sequences. The SRY and ZFY genes were not amplified in the AZF region . The negative amplification of SRY further confirmed the partial absence of the Y-chromosome sequence.
+Ultrasound scanning of the scrotum showed that both testicles were located in the scrotum, but the volumes (6.6 mL and 6.8 mL, respectively) were significantly smaller than the normal adult male testicle size (range: 15-23 mL). In addition, a normal-sized prostate and seminal vesicles were observed by internal genitalia ultrasound analysis.

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+A 13-year-old boy was referred to Taleghani Children's Hospital with a complaint of swelling and pain in his Right lower quadrant and right testicle, erythema, and warmth on the scrotum without any Past medical history, drug history, and surgical history who had fallen to the ground three days ago. Ultrasound results revealed that the right testicular appendix is prominent, but it also has a hypoechoic structure that resembles the testicular parenchyma. This structure is above the right testicle and the medial part of the right epididymis, is wholly attached to the testicle, and has 17 × 12 mm dimensions. Furthermore, in color Doppler, the coloration is sharply increased .
+The above findings suggest extreme Epididymo-orchitis on the right and maybe a type A3 polyorchidism with adjacent extra testis or a bilobed testis.
+After treatment of the Epididymo-orchitis, Magnetic resonance imaging (MRI) was performed one month later. In axial and coronal T2 FISP images, a Hemi-testicular structure of similar signal intensity to that of the adjacent normal testis is noted on the right side, albeit with significantly decreased size due to the resolution of the inflammatory phase .

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+A 43-year-old man with a tumor in his left leg was referred to our institute. The diagnosis was myxoid liposarcoma based upon biopsy findings. Radiation and chemotherapy were administered. Consequent wide resection with the surrounding normal tissue was performed. Two years after the initial surgery, when the patient was 45 years of age, metastasis appeared in the right neck region and the retroperitoneum, and resection of these lesions was performed. Seven years after the initial surgery, when the patient was 50 years of age, lung metastasis was found and resection was performed. Eight years after the initial surgery, when the patient was 51 years of age, recurrence was found in the thigh and involved the major vessels. Amputation at the thigh was carried out. Histological diagnosis of myxoid liposarcoma was confirmed in each of the resected materials. Chemotherapy was performed after every resection of metastatic and recurrent lesions. Ten years after the initial operation, at 53 years of age, the patient experienced back pain. Plain radiographs showed a compression type fracture in the second lumbar vertebra. MRI of all the vertebrae showed abnormally high signal intensity on T2-imaging with fat suppression in eight vertebrae: the fifth cervical vertebra (C5), the seventh, tenth, eleventh and twelfth thoracic vertebrae (T7, T10, T11 and T12), the second and fourth lumbar vertebrae (L2 and L4), and the second sacral vertebra (S2). High signal intensity on the MRI was seen throughout the entire vertebral body in L2 accompanied by deformity, suggestive of a pathological fracture. Extraskeletal extension of the lesion was seen in the T12, L2 and S2 vertebrae (Figure ). Bone scans showed negative findings except for the L2 fracture. FDG-PET was negative for all of the vertebrae, including the fractured L2 vertebra (Figure ). These examinations of bone scans and FDG-PET were performed within one month after the MRI examination. With a diagnosis of vertebral metastasis arising from myxoid liposarcoma, radiation and chemotherapy were administered. The patient was informed that data from his case would be submitted for publication, and his consent was obtained.