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Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor–arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the ‘hibernation–ageing hypothesis’ whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7–8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation–ageing hypothesis and may explain the enhanced longevity in hibernators.

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

Background: Patients hospitalized due to gross hematuria frequently complete evaluation in the outpatient setting. The use of office flexible cystoscopy during hospitalization may lead to prompt diagnosis and treatment but can be limited due to low visualization and artifacts that can hamper diagnostic ability. Objective: The objective of this study was to assess flexible cystoscopy findings and yield performed in patients hospitalized due to gross hematuria. Methods: Medical records of patients who underwent flexible cystoscopy while hospitalized during September 2018–December 2019 were reviewed. Cystoscopic findings were categorized into (1) suspicious mass in the bladder or prostate, (2) nonsuspicious changes in the bladder, and (3) nondiagnostic exam. Descriptive statistics were used to report the clinical characteristics of the study cohort and the findings of cystoscopy. Univariate logistic regression analyses were used to identify predictors of malignant findings. Results: The study cohort consisted of 69 patients (median age of 76 years). Initial cystoscopy findings were suspicious for malignancy in 26/69 patients (38%), nonsuspicious for malignancy in 34/69 patients (49%), and nondiagnostic in 9/69 patients (13%). The median follow-up time was 9 months (range 4–14 months). Twenty patients (29%) were diagnosed with malignancy (sensitivity of 75% and specificity of 78%). The procedure led to either diagnosis or treatment of 39 patients (57%). However, in 30 patients (43%), the initial cystoscopy did not aid in the diagnosis, led to misdiagnoses, or required a follow-up cystoscopy. On univariate analyses, none of the precystoscopy variables were predictive of bladder malignancy. Conclusion: Flexible cystoscopy in the setting of acute hematuria requiring hospitalization did not lead to diagnosis or treatment in over 40% of cases. In this setting, consideration should be given to performing an upfront cystoscopy under anesthesia.

Blood loss during and following elective total hip arthroplasty (THA) can be substantial and may require allogeneic blood transfusions which carries significant risks and morbidity for patients. Intraoperative use of tranexamic acid (TXA) has been proven to reduce the need for allogeneic blood transfusion in elective THA patients. Data regarding TXA efficacy in reducing blood loss in trauma patients undergoing non-elective primary THA is sparse, and its routine use is not well established.This is a retrospective analysis of a consecutive cohort of patients who underwent non-elective primary THA in a tertiary medical center between January 1st 2011- December 31st 2019. The cohort was divided into two groups; one received perioperative TXA treatment while the other did not. Blood loss, blood product administration, peri and postoperative complications, readmissions and 1-year mortality were compared between groups.A total of 419 patients (146 males, 273 females) who underwent THA were included in this study. The "TXA" group consisted 315 patients compared to 104 patients in the "no TXA" group. TXA use reduced postoperative bleeding, as indicated by changes in hemoglobin levels before and after surgery (ΔHb= -2.75 gr/dL vs. ΔHb= -3.34 gr/dL, p0.001) and by administration of allogeneic blood transfusions (7.0% vs. 16.3%, p = 0.004).Similar to the known effect of TXA in elective THA patients, the use of TXA treatment in patients undergoing non-elective THA led to a significant reduction in postoperative blood loss and in the proportion of patients requiring allogeneic blood transfusions.

The development of a vaccine for COVID-19 presented hope for a way out of the global crisis caused by the virus. However, a potential barrier may be vaccine hesitancy, and identifying the factors that affect it is critical, especially concerning a new vaccine technology. The purpose of this research is to identify the factors that effects vaccine hesitancy by using a holistic view. The data were collected from 504 people in December 2020, 3 days before the vaccine operation started in Israel. The analysis included three categories of determinants: (1) contextual influences; (2) health records; and (3) perceived health attitudes. The results indicate that different sets of variables affect willingness to accept the vaccine among the whole spectrum of the vaccine-hesitant and the undecided subsample. In the full sample, gender, age, income, influenza vaccine, perceived trust, perceived susceptibility, perceived benefits, and perceived barriers affected vaccine acceptance. The perceived level of suffering from COVID-19 was associated with willingness to vaccinate, and when religious beliefs increased, the intention to vaccinate decreased. For the undecided subsample, the factors included gender, influenza vaccine, trust in the vaccine company, and perceived vaccine benefits and barriers. The results suggest that efforts of governments and health institutions should focus on women and highlight the vaccine as an opportunity to "go back to normal" without worries. Those results will help implement vaccine strategy in the following cases: if infant vaccination is pursued and if emergency vaccines or new vaccine technologies emerge for another pandemic as well.

GOAL The aim was to assess proactive specialized inflammatory bowel diseases (IBD) emergency department (ED) consultation and multidisciplinary IBD team (IBD-MDT) intervention on IBD-related patient outcomes after discharge. BACKGROUND Despite advances in patient care, IBD-related ED visits have increased and substantially contribute to the IBD burden. METHODS Consecutive patients with IBD (below 50 y) who visited the ED during November 2017 to April 2018 (intervention group) were compared with patients with IBD that visited the same ED during 2014 to 2017 (standard-care group). The primary outcomes were hospitalization and ED revisits at 30, 90, and 180 days. RESULTS The intervention group (45 patients, mean age 32.43±8.6 y, 57.8% male) and the standard-care group (237 patients) had comparable baseline characteristics, including age, sex, and IBD type, and similar rates of hospital admissions from the ED (46.7% vs. 38.8%, P=0.32). The intervention group more frequently underwent computed tomography (40% vs. 8%, P

Identifying patients with hypertrophic cardiomyopathy (HCM) who warrant a primary prevention implantable cardioverter-defibrillator (ICD) is crucial. ICDs are effective in terminating life-threatening arrhythmias; however, ICDs carry risks of complications.The purpose of this study was to assess the incidence and predictors of appropriate ICD therapies, inappropriate shocks, and device-related complications in patients with HCM and primary prevention ICDs.All patients with HCM who underwent primary prevention ICD implantation at Toronto General Hospital between September 2000 and December 2017 were identified. Therapies (shocks or antitachycardia pacing) for ventricular tachycardia180 beats/min or ventricular fibrillation were considered appropriate.Three hundred two patients were followed for a mean 6.1 ± 4.3 years (1801 patient-years of follow-up). Thirty-eight patients (12.6%) received at least 1 appropriate ICD therapy (2.3%/y); the 5-year cumulative probability of receiving appropriate ICD therapy was 9.6%. None of the conventional risk factors nor the European Society of Cardiology risk score was associated with appropriate ICD therapy. In multivariable analysis, age40 years at implantation and atrial fibrillation were independent predictors of appropriate ICD therapy. In a subgroup of patients who had undergone cardiac magnetic resonance imaging before ICD implantation, severe late gadolinium enhancement was the strongest predictor of appropriate ICD therapies. ICD-related complications or inappropriate shocks occurred in 87 patients (28.8%), with an inappropriate shock rate of 2.1%/y; the 5-year cumulative probability was 10.7%.The incidence of appropriate ICD therapies in patients with HCM and primary prevention ICDs is lower than previously reported; a high proportion of patients suffer from an ICD-related complication. Traditional risk factors have low predictive utility. Severe late gadolinium enhancement, atrial fibrillation, and young age are important predictors of ventricular tachyarrhythmias in HCM.

Platypnea-Orthodeoxia syndrome (POS) is a rare clinical syndrome characterized by shortness of breath in the upright position that is relieved with supine positioning. We present a rare case of persistent left superior vena cava (PLSVC) draining into the left atrium causing a right-to-left shunt and subsequent POS. A 30-year-old female with a past medical history of hypertrophic cardiomyopathy, congenital Long QT syndrome and a left-sided dual chamber implantable cardioverter-defibrillator (ICD) presented with dyspnea and lightheadedness. Prior to presentation, the patient underwent a left-sided ICD extraction due to ICD lead infection and re-implantation from the right side through the cephalic vein. After further investigation, it was concluded that the PLSVC resulted in a physiological right-to-left shunting causing POS, with resolution of her symptoms after surgical ligation. To our knowledge, this is the first case report of PLSVC presenting with POS without anatomical intracardiac shunts following iatrogenic right superior vena cava (RSVC) obstruction.

In adults, both immature and mature ovarian teratomas show frequent genetic homozygosity consistent with tumorigenesis involving germ cells after meiosis I. Investigation into genetic zygosity of various teratomas in children has been limited. Thirteen sacrococcygeal, 12 ovarian, and 3 testicular teratomas in children 18 years or younger were retrieved from our departmental archives and histologically reviewed. Tumor and paired normal tissues were microdissected and subjected to short tandem repeat (STR) genotyping. DNA genotyping was informative in 12 sacrococcygeal teratomas, 8 ovarian teratomas, and 3 testicular teratomas. Sacrococcygeal teratomas included seven mature teratomas, four immature teratomas, and one mixed germ cell tumor with patient age ranging from 0 days to 3 years. All but two patients were female. Ovarian teratomas included five mature and three immature teratomas with patient age ranging from 2 to 18 years. Testicular teratomas included two mature teratomas and one immature teratoma with patient age ranging from 3 months to 3 years. All sacrococcygeal, testicular, and ovarian teratomas in patients younger than 4 years showed no evidence of genetic homozygosity by STR genotyping. In contrast, all four ovarian teratomas in patients older than 9 years showed either partial or complete homozygosity. In conclusion, unlike adolescent and adult ovarian teratomas, prepubertal sacrococcygeal and gonadal teratomas lack genetic homozygosity, supporting the hypothesis that teratomas before puberty develop at an early stage of germ cell development different from that of teratomas in adolescents and adults.

Acetylsalicylic acid (aspirin) is a commonly prescribed medication, especially in the age group of individuals who undergo elective total hip arthroplasty (THA). Preoperative discontinuation of aspirin is believed to reduce intraoperative bleeding and other complications, but it may increase the risk of perioperative cardiovascular events. In this study we have sought to evaluate the safety of continuous aspirin treatment in patients undergoing elective THA. This is a retrospective analysis of a consecutive cohort who underwent elective THA in a tertiary medical center between 2011 and 2018. The cohort was divided into two groups—one that received continuous preoperative aspirin treatment and one that did not. Blood loss, peri- and postoperative complications, readmissions, and short- and long-term mortality were compared between groups. Out of 757 consecutive patients (293 males, 464 females) who underwent elective primary THA, 552 were in the “non-aspirin” group and 205 were in the “aspirin” group and were not treated preoperative with other medication affecting hemostasis. Perioperative continuation of aspirin treatment did not significantly increase perioperative bleeding, as indicated by changes in hemoglobin levels (P = 0.72). There were no significant differences in short- and long-term mortality (P = 0.47 and P = 0.4, respectively) or other perioperative complications, such as readmission (P = 0.78), deep or superficial infection (P = 1 and P = 0.47, respectively), and cardiovascular events (none in both groups). Peri-operative continuation of aspirin treatment in patients undergoing elective primary THA did not increase perioperative complications or mortality compared to the non-aspirin-treated patients. The protective effects of aspirin from postoperative thrombotic and cardiovascular events are well documented. The current findings dispute the need to preoperatively withhold aspirin treatment in patients undergoing elective primary THA.

A recent phase II clinical trial showed increased progression-free survival in patients with HER2-positive endometrial serous carcinoma receiving trastuzumab in addition to carboplatin-paclitaxel chemotherapy. Similar to endometrial serous carcinomas, carcinosarcomas of the female genital tract have a dismal prognosis and could potentially benefit from new targeted therapeutic approaches. We aimed to systematically evaluate the characteristics of HER2 expression/amplification in gynecologic carcinosarcomas using standardized staining methods and scoring criteria. Tumors from 80 patients (65 uterine, 15 tubo-ovarian) were included, containing a serous (60%), endometrioid (10%), clear cell (3%), undifferentiated (3%), neuroendocrine (1%), or mixed (24%) carcinoma, and either a homologous (46%), or a heterologous (54%) sarcoma component. HER2 scores were assigned to both components per the 2007 and 2013 ASCO/CAP breast scoring criteria. A total of 13 cases (12 uterine, 1 ovarian, 16%) were HER2 positive (either by immunohistochemistry or FISH) using the 2013 criteria, while only 10 cases (9 uterine, 1 ovarian, 13%) were HER2 positive per the 2007 criteria. Nine cases showed a change in their HER2 immunohistochemical score between the two scoring systems, including two cases with a change in the overall HER2 status from negative (2007) to positive (2013). Heterogeneity of HER2 protein expression was observed in 38% of HER2-positive tumors, and a lateral/basolateral membranous staining pattern was common. The sarcoma component showed 2+, equivocal HER2 expression in five cases, one of which also demonstrated HER2 amplification by FISH. All HER2-positive carcinosarcomas had either a serous or a mixed carcinoma component, and all but one HER2-positive tumors were of uterine primaries. Our study demonstrates that gynecologic carcinosarcomas share similarities in their HER2 expression/amplification profiles to endometrial serous carcinomas, which should be taken into account when assessing their HER2 status to ensure appropriate patient selection for potential targeted HER2-based therapies in the future.

IMPORTANCE: Trastuzumab deruxtecan (T-DXd) has shown efficacy in patients with breast cancer with ERBB2 immunohistochemistry (IHC) scores of 1+ or 2+ but not 0 as read in central pathology laboratories. The drug is currently being tested in large randomized clinical trials with registration intent for this patient population. OBJECTIVE: To determine the suitability of the current standard ERBB2 IHC assays to select patients with low ERBB2 positivity for treatment with T-DXd. DESIGN AND SETTING: Assessment of data from College of American Pathologists surveys and assessment of analytic data from a Yale University–based study of concordance of 18 pathologists reading 170 breast cancer biopsies. RESULTS: The total survey data set included scores over 2 years from 1391 to 1452 laboratories of 40 ERBB2 cores from each laboratory (20 cores twice a year for a total of 80). College of American Pathologists surveys show that 19% of cases read by the laboratories generate results with less than or equal to 70% concordance for IHC ERBB2 score 0 vs 1+. When 18 pathologists read the scanned slides from a selected set of breast cancer biopsies using a 4-point scale, there was only 26% concordance between 0 and 1+ compared with 58% concordance between 2+ and 3+. CONCLUSIONS AND RELEVANCE: In this study using a current standard ERBB2 IHC assay, the scoring accuracy for ERBB2 IHC in the low range (0 and 1+) was poor. This inaccuracy in the real world could lead to misassignment of many patients for treatment with T-DXd.

Background Endoscopic-post-operative-recurrence [ePOR] in Crohn’s disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting. Methods A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] ≥ i2 or colonic-segmental-SES-CD ≥ 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents. Results The study included 297 patients (53.9% males, age at diagnosis 24 years [19–32], age at ICR 34 years [26–43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01–2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25–1.19], OR = 1.86 [95% CI: 0.79–4.38]), respectively. Conclusion Prevention of ePOR within 1 year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

Summary The AJCC Cancer Staging Manual 8th edition included tumor grade in the pathologic prognostic stage for breast carcinomas. Due to the known subjectivity of tumor grading, we aimed to assess the degree of interobserver agreement for invasive carcinoma grade among pathologists and determine its effect on pathologic prognostic stage. One hundred consecutive cases of invasive stage II carcinomas were independently graded twice, with an 4-week intervening wash-out period, by 6 breast pathologists utilizing established Nottingham grading criteria. Inter- and intra-observer variability was determined for overall grade and for each of the 3 scoring components. Interobserver variability was good to very good (κ range = 0.582–0.850) with even better intra-observer variability (mean κ = 0.766). Tubule score was the most reproducible element (κ = 0.588). Complete concordance was reached in 54 cases and 58 cases in rounds 1 and 2 respectively. In round 1 this resulted in different pathologic prognostic stage in only 25 of discordant cases, 18 of which were stage IA versus IB. In conclusion, grading agreement between pathologists was good to very good and discordant grades resulted in small changes to pathologic prognostic stage.

We sought to define the effectiveness and safety of tofacitinib in a real-world (RW) cohort of Israeli patients with moderate to severe ulcerative colitis (UC).This was a multi-center retrospective observational cohort study (2019-2020) to assess the effectiveness and safety of tofacitinib induction and maintenance therapy up to 26 weeks. Clinical response and remission were defined as a reduction in Simple Clinical Colitis Activity Index (SCCAI) or partial Mayo score (PMS) of ≥3 points, and SCCAI ≤2 or a PMS ≤1, respectively.We included 73 patients, 47% male; median age 26 years [IQR: 19.5-39.5], disease duration 7 years [IQR: 2.5-14.5], follow-up 7.1 months [IQR: 3-12], 91% biologics-experienced, and 74% ≥ 2-biologics. Half of patients used concomitant corticosteroids (CS). Overall, 56.1% discontinued therapy due to either lack of response and/or adverse events (AEs), median time to discontinuation - 9.7 months [IQR 3.4-16]. Overall, response, remission, and CS-free-remission were achieved in 47.6%, 20.6%, and 17.5% of patients, respectively. At early maintenance (week 26), response, remission, and CS-free-remission were achieved in 65%, 22.5%, and 20% of patients, respectively. At week 26, tofacitinib 10 mg BID was still used in 43%. Seventeen patients (23.2%) had an adverse event including herpes zoster- 2.7%, hospitalization- 12.3%, and colectomy- 2.7%.Tofacitinib was effective in achieving CS-free-remission in about 1/5 of highly biologics -experienced patients with UC. Despite a considerable proportion of patients maintained on tofacitinib 10 mg bid, it was well tolerated and safe. Earlier positioning of tofacitinib in the therapeutic algorithm may result in improved outcomes.

To evaluate whether meatal stenosis treated concomitantly with urethral fistula repair alters the results of fistula closure.A retrospective cohort study, included were all children who underwent local fistula closure following hypospadias repair between 2006 and 2017. Patients who underwent reoperative urethroplasty were excluded. Data were extracted from electronic records, and missing data were supplied by telephone interviews. Characteristics of patients and fistulas were compared between children who underwent fistula closure only and those who underwent meatoplasty for meatal stenosis during the same surgery. The primary endpoint was fistula recurrence.In total, 106 local repairs of urethrocutaneous fistulas were performed during the study period, and 25 of them included concomitant meatoplasty for meatal stenosis. There was no difference in terms of location, size, and number of fistulas or the number of recurrent fistulas between the 81 patients who underwent fistula closure only and the 25 who underwent concomitant meatoplasty. The fistula recurrence rate was 17 per 81 (21%) for the fistula only group and 5 per 25 (20%) for the fistula and meatoplasty group after a median follow-up of 7 and 8 years, respectively. Meatoplasty was required in a subsequent procedure in 5 of 81 in the former group vs 3 of 25 patients in the latter group.The presence and repair of meatal stenosis does not alter the recurrence rate of urethrocutaneous fistulas repaired concomitantly following hypospadias repair.

Flexible flatfoot (FF) is a common foot deformity that can often consist of foot pain. Surgical treatment is designed to lengthen the lateral column.To resolve whether radiographic standing feet measurements of normo-plantigrade feet and FF, symptomatic or not, differ and to determine whether the lateral column is shorter.The study comprised 72 patients (127 feet) consecutive patients, 18 years of age and older, who were divided into three groups: normal feet (56), asymptomatic FF (29), and symptomatic FF (42). All patients had a standing anterior posterior (AP) and lateral radiographs. AP images were used for the measurement of the talocalcaneal angle, talar-1st metatarsal angle, and talonavicular coverage. Lateral X-rays were used to estimate the talocalcaneal angle, talar-1st metatarsal angle, calcaneal pitch, naviculocuboid overlap, and column ratio.All three of the AP radiograph measurements differed among groups, and higher values were measured in the symptomatic FF group. Post hoc analysis found that the talonavicular coverage and the talocalcaneal angles also differed between symptomatic and asymptomatic FF patients. While some lateral measurements differed within groups, only the lateral talar-1st metatarsal angle distinguished between asymptomatic and symptomatic patients. The lateral column length was not found to be shorter among FF patients, weather symptomatic or not.Only the talonavicular coverage, the AP talocalcaneal, and the lateral talar-1st metatarsal angles were found to differ between asymptomatic and symptomatic FF patients. The lateral column was not found to be shorter.

Purpose Some recent studies have suggested a relationship between cardiac dose and mortality in non-small cell lung cancer (NSCLC), but others have reported conflicting data. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between cardiac dose and mortality in these patients. Methods and Materials A systematic review of MEDLINE (PubMed) and Embase databases (inception to January 2018) was performed according to PRISMA guidelines. Studies that evaluated cardiac dosimetric factors in patients with NSCLC and included outcomes of cardiac events, cardiac mortality, and/or overall survival were identified. Results From 5614 patients across 22 studies, a total of 214 cardiac dosimetric parameters (94 unique) were assessed as possible predictors of cardiac toxicity or death. Assessed predictors included general (eg, mean heart dose [MHD]), threshold-based (eg, heart V5), and anatomic-based (eg, atria, ventricles) dosimetric factors. The most commonly analyzed parameters were MHD, heart V5, and V30. Most studies did not make corrections for multiplicity of testing. For overall survival, V5 was found to be significant on multivariable analysis (MVA) in 1 of 11 studies and V30 in 2 of 12 studies; MHD was not significant in any of 8 studies. For cardiac events, V5 was found to be significant on multivariable analysis in 1 of 2 studies, V30 in 1 of 3 studies, and MHD in 2 of 4 studies. A meta-analysis of the data could not be performed because most negative studies did not report effect estimates. Conclusions Consistent heart dose-volume parameters associated with overall survival of patients with NSCLC were not identified. Multiplicity of testing is a major issue and likely inflates the overall risk of type I errors in the literature. Future studies should specify predictors a priori, correct for multiplicity of testing, and report effect estimates for nonsignificant variables.

The aim of this study was to investigate the predictive value of early changes in depression levels during inpatient treatment of adolescent anorexia nervosa (AN). Fifty-six adolescents (88% girls) aged 10–18 years (M = 15.35, SD = 2.23) diagnosed with AN were assessed at admission and 1 month following admission to an inpatient setting. Depression levels and eating disorder symptoms were reported at both assessments. Re-hospitalization within 12 months of discharge was documented using official national records. Whereas depression levels at baseline were found equivalent between subsequently re-hospitalized and non-re-hospitalized patients, at 1 month after admission patients who were later re-hospitalized had higher levels of depression compared to those who were not re-hospitalized. These differences remained significant after controlling for weight gain and anti-depressant medication intake. We additionally found that the proportion of boys in the non-re-hospitalized group was substantially larger than their proportion in the re-hospitalized group. Our results suggest that depression at the point of hospital admission may not be a reliable predictor of treatment outcomes, and highlight the risk of relapse in AN patients whose depression levels do not alleviate after a month of inpatient treatment. Clinicians should consider providing more adjusted and intensive attention to such patients in their efforts to facilitate remission. Well-designed cohort study.

Background Advancements in the management of human immunodeficiency virus (HIV) now permit HIV-positive patients to have longer life spans, increasing their cumulative risk of developing an advanced degenerative joint disease, necessitating total hip arthroplasty (THA). The purpose of this study was to provide an extended follow-up on a previously published study on a cohort of HIV-positive THA recipients in an effort to confirm the safety and longevity of THA in this population. Methods This study is a follow-up on a previous study comprised of 41 hips in 31 HIV-positive THA recipients. At this follow-up, 5 patients from the original cohort required contralateral THA. Postoperative complications were recorded up to the patient’s last follow-up date. A survivorship analysis was performed using the Kaplan-Meier method with revision THA as the end point. Results Since the last report, 2 additional hips were revised (one for aseptic loosening and one for a periprosthetic fracture), and 5 patients underwent contralateral THA. This resulted in a total of 5 (13.8%) hips requiring revision THA at the latest follow-up. The mean follow-up interval for the original cohort and for the contralateral 5 hips was 78.9 ± 50.2 months and 54.6 ± 45.3 months, respectively. Kaplan-Meier survivorship analysis with revision THA for any reason as the end point demonstrated survivorship of 93% (2 years), 90% (5 years), and 81% (10 and 14 years) after primary THA, respectively. Conclusion Our study suggests that it is possible to achieve a low incidence of postoperative infection in HIV-positive THA recipients. In addition, our study demonstrates that non-hemophiliac HIV-positive patients have comparable revision rates to previously published reports on HIV-negative patients of similar age, underscoring the clinical efficacy of highly active antiretroviral therapy.

OBJECTIVES To examine the relationship between late gadolinium enhancement (LGE) extent and nonsustained ventricular tachycardia (NSVT) characteristics in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND NSVT has been shown to be independently associated with sudden cardiac death (SCD) in HCM. Previous studies have found LGE on cardiac magnetic resonance (CMR) to be independently associated with NSVT. METHODS Seventy-three patients who had 14-day Holter monitoring for either risk stratification for SCD (n = 62) or evaluation of atrial fibrillation (n = 11) on a CMR study were included. Areas of LGE in left ventricle (LV) were visually identified and analyzed quantitatively for both high (≥6 SD above the mean signal intensity of normal myocardium) and intermediate (≥4 but

BACKGROUND Septal myectomy relieves left ventricular outflow obstruction (LVOTO) and is associated with excellent long-term outcomes. LVOTO is associated with diastolic dysfunction and increased left atrial (LA) size. We sought to investigate the changes in LA volumes and function postmyectomy and the association between these changes with clinical outcomes postmyectomy. METHODS Sixty-six hypertrophic cardiomyopathy patients undergoing myectomy were retrospectively studied. Preprocedural and 6- to 18-month postmyectomy follow-up transthoracic echocardiographic images were obtained. LA volumes and strain were assessed by two-dimensional speckle-tracking echocardiography. RESULTS Left atrial volumes, that is, indexed maximal, minimal, and pre-A volumes reduced postmyectomy, yet remained increased compared to controls (105.6 ± 34.5 mL vs 84.9 ± 26.7 mL, 45.2 ± 25.7 mL vs 35.4 ± 22.6 mL, 70.1 ± 31.4 mL vs 35.4 ± 22.6 mL, respectively, P

The clinical picture of BRCA1-associated protein required for ATM activation-1 (BRAT1) comprises retractable early-onset epileptic encephalopathy, progressive microcephaly, and early demise. Both, inter- and intrafamilial variations of features of BRAT1-associated disease have been described. Here, the familial case of a brother and sister with homozygous pathogenic variants in BRAT1 is presented with special emphasis on differences in seizure type/onset and central nervous system lesions. The neuropathology is extensively discussed and hypotheses put forward that may shed light on etiology of brain symptomatology within the context of BRAT1 mutations.

Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor-arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the 'hibernation-ageing hypothesis' whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7-8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation-ageing hypothesis and may explain the enhanced longevity in hibernators.

Sub-capital femoral fractures (SCFF) are impacted or non-displaced in Garden types 1 and 2, respectively. Non-surgical treatment is protected weight-bearing combined with physiotherapy and radiographic follow-up in selected patients. Traditionally, in situ pinning is the surgical treatment of choice. The aim of this study was to estimate whether the valgus deformity in Garden types 1 and 2 (AO classification 31B1.1 and 31B1.2) SCFF is a virtual perception of a posterior tilt deformity and if addressing this deformity improves patients’ outcomes. The records of 96 patients with Garden Types 1 and 2 SCFF treated in tertiary medical center between 1/2014 and 9/2017 were retrospectively reviewed. They all had preoperative hip joint anteroposterior and lateral radiographic views. 75 patients had additional computed tomography (CT) scans. Femoral head displacement was measured on an anteroposterior and axial radiograph projections and were performed before and after surgery. Preoperative 3D reconstructions were performed for a better fracture characterization, and assessment of the imaging was performed by the first author. The average age of the study cohort was 73 years (range 28–96, 68% females). There were 58 right-sided and 38 left-sided fractures. Ninety patients had Type 1 and six patients had Type 2 fractures. The average preoperative posterior tilt was 15 degrees and the average valgus displacement was 10 degrees on plain radiographs compared to 28 degrees and 11 degrees, respectively, on CT scans. Posterior tilt was found with a virtual perception as valgus-impacted fractures. The postoperative posterior tilt was corrected to an average of 3 degrees and the valgus displacement to 5 degrees. CT provides an accurate modality for measuring femoral head displacement and fracture extent. The posterior tilt displacement should be addressed during surgery to lower failure risk and the need for additional procedures. TLV-0292-15. IV.

Obesity has been considered a relative contraindication to performing a direct anterior approach total hip arthroplasty (DAA-THA) since it is hypothesized to lead to component malpositioning and poor outcomes. Fluoroscopy-assisted DAA-THA has been reported to diminish variability in acetabular component positioning. However, fluoroscopy-assisted DAA-THA in the obese patients has not been well described. We report on a single surgeon consecutive series of fluoroscopy-assisted primary DAA-THA's examining the radiographic and perioperative outcomes in obese patients.A retrospective review was conducted of 509 consecutive unilateral fluoroscopy-assisted DAA-THAs on a specialized orthopaedic table performed by a single surgeon. All patients were divided into three cohorts according to their body mass index (BMI): Group I (30 kg/ m2 ), Group II (≥ 30 to35 kg/m2 ), and Group III (≥ 35 kg/ m2 ). Perioperative parameters, outcome scores (EuroQol 5 Dimension and hip disability and osteoarthritis outcome scores), and radiographs were comparatively assessed. Cup position was determined using Widmer's method.A total of 492 DAA-THAs (minimum follow-up: 2.1 years) with appropriate radiographs were analyzed. Of which 356 (72.2%) were in Group I (average: 25.1 kg/m2 ), 105 (21.3%) in Group II (average: 32 kg/m2 ), and 31 (6.5%) in Group III (average: 38.6 kg/m2 ). There were no differences in any parameters between Group II and III. Group I differed in average age and included more female patients than Groups II and III. There was a statistically significant difference in cup anteversion between all groups with average measurements of 20.8°, 19.5°, and 17.6°, respectively. No other differences were identified in radiographic parameters or postoperative outcomes.There were no clinically relevant differences in component positioning or perioperative parameters between obese and non-obese patients. We do not consider a BMI ≥ 30 kg/m2 to be a contraindication for fluoroscopyassisted DAA-THA when performed by a surgeon experienced in the technique.

A Randomized Controlled Trial was conducted to evaluate the effectiveness of the Hebrew adaptation of the Program for the Education and Enrichment of Relational Skills (PEERS®), a parent-assisted i...

PIGT is one of over 29 glycosylphosphatidylinositol biosynthesis defect genes. Mutations cause genetically determined disorders characterized mainly by epilepsy with fever-sensitivity, central hypotonia, psychomotor delay and congenital malformations. The disease is known as multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) or glycosylphosphatidylinositol biosynthesis defect-7. Twenty-eight cases have been reported until today. We present seven novel Polish patients, all harboring 1582G>A variant in a homozygous or compound heterozygous state which seems to cause a milder phenotype of the disease.

Intraoperative use of tranexamic acid (TXA) has been proven to reduce the administration of allogenic blood transfusion in total joint arthroplasty (TJA) patients. Data on TXA efficacy in reducing blood loss in trauma patients undergoing hip hemiarthroplasty are sparse, and its use is not yet well-established. The purpose of this study was to assess the efficacy and safety of intraoperative TXA use in patients undergoing hip hemiarthroplasty as treatment for intracapsular femoral neck fracture.This is a historical cohort of patients who underwent hip hemiarthroplasty in a tertiary medical center between 2011 and 2019, with minimum follow-up of one year. The cohort was divided into one group of patients who received intraoperative TXA treatment and another group that did not. Blood loss, peri‑ and postoperative complications, readmissions, and short- and long-term mortality were compared between groups.Of the 1722 consecutive patients (601 males and 1121 females) who underwent hip hemiarthroplasty who were included in this study, 504 were in the "TXA" group and 1218 were in the "non-TXA" group. TXA use significantly reduced 30-day mortality (4.6% vs 7.3%, respectively, p0.046) and perioperative blood loss, as indicated by changes in hemoglobin levels before and after surgery (Δ-1.38 gr/dL vs Δ-1.76 gr/dL, p0.001), and by administration of allogenic blood transfusions (17.5% vs 44.4%, p0.001).Similar to the known effect of TXA in TJA patients, the use of TXA treatment in patients undergoing hip hemiarthroplasty led to a significant reduction in 30-day mortality, in postoperative blood loss and in the proportion of patients requiring allogenic blood transfusions.

To evaluate the progressive changes in the morphology of traumatic ruptures of the anterior cruciate ligament (ACL) over time. A secondary objective was evaluating their correlation with meniscal tears or chondral lesions. The study included one hundred and one patients who underwent ACL reconstruction surgery of the knee after a definite date of injury. The torn ACL remnant morphological pattern was assessed and classified during arthroscopy. A correlation analysis was performed between the pathological features of the remnant and the time length from injury. In addition, correlation between ACL remnant subtypes and meniscal tears or chondral lesions was evaluated. At surgery there were four distinct ACL tear morphological patterns that were correlated to the time span from injury (r = 0.61, p

This study was designed to compare the results of clavicle fracture open reduction internal fixation (ORIF) with standard horizontal incision versus vertical incision. ORIF surgery performed between October 2012 and August 2016 was included. The surgical approach was chosen according to surgeon preference as vertical or horizontal. Functional outcomes, fracture union, complications, scar appearance, skin irritation, and denervation around the scar were assessed at a minimum follow-up of three months. Thirty-eight patients, age 39 ± 12 years, were operated upon, 22 through vertical incisions and 16 through horizontal incisions. There were no significant group differences in functional scores, fracture union, or complications. Two patients in the vertical incision group had a post-operative haematoma. The scar length was significantly shorter when a vertical incision was used (6.75 ± 1.25 cm vs 8.9 ± 2.3 cm, P = 0.001). The typical distribution of hypoesthetic skin area distal and lateral to the scar represented iatrogenic damage to the supraclavicular nerves and was found in 66% of patients. The mean hypoesthetic surface area was smaller in the vertical incision group (38 ± 29 cm2 vs 48 ± 28 cm2, P = non-significant). Vertical incision results in shorter scars but may be associated with increased incidence of haematomas. Meticulous closure of the subcutaneous tissue is recommended.

Background Previous research has detected an increased risk of stress fractures among subjects who reported previous use of methylphenidate. Conversely, stimulant medication use has been associated with traumatic fracture risk reduction, possibly because of the improved control of the underlying symptoms of attention deficit hyperactivity disorder (ADHD). The goal of this study was to investigate the effect of previous methylphenidate use on the incidence of traumatic and stress fractures among combat soldiers with previously treated and untreated ADHD. Methods The retrospective cohort included 100,000 combat soldiers recruited to the Israeli Defense Forces from 2005 through 2015. Diagnosis of ADHD and previous exposure to methylphenidate were determined on the basis of self-reported recruitment questionnaires and medical records. Accordingly, the cohort was divided into 3 groups: subjects with ADHD who were previously treated with methylphenidate (n = 689), untreated subjects with ADHD reporting no medication use (n = 762), and controls having no ADHD diagnosis (n = 98,549). Logistic regressions were fitted to determine the odds ratios (ORs) of study subjects for stress and non-stress (traumatic) fractures. Multivariate analysis incorporated baseline characteristics, including age, sex, weight, duration of service, and diagnosis of anemia, at some point during the service. Results After adjustment for sex, anemia, weight, age, and duration of service, the risk of traumatic fractures was increased in both subjects with treated ADHD (OR, 1.03 [95% confidence interval (CI), 1.00 to 1.05]) and subjects with untreated ADHD (OR, 1.04 [95% CI, 1.02 to 1.07]) compared with controls. Subjects in the treated ADHD group were at a higher risk of stress fractures (OR, 1.04 [95% CI, 1.02 to 1.07]). Interestingly, a diagnosis of anemia was an independent predictor of stress fractures (OR, 1.05 [95% CI, 1.04 to 1.06]). Conclusions Methylphenidate use is associated with an increased risk of stress fractures but a decreased risk of traumatic fractures in individuals diagnosed with ADHD. These and previous findings may serve as sufficient basis for screening for other risk factors and perhaps taking prevention measures in all those using stimulant medications, especially those planning to engage in strenuous physical activity. Level of evidence Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. Objective To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. Methods The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. Results The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. Conclusions Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.

Amputation of the forefoot is a salvage procedure for several forefoot acute or chronic infection. A good, sensate and durable skin cover is important for quicker and better rehabilitation. The use of filleted flaps (or "spare parts technique") has been published in the past as a creative technique. The purpose of this article is to introduce a reproducible, pre-planned, technique that requires less creativity for the use of the "spare parts". The authors describe a case series of 4 patients with deep infection and osteomyelitis of the forefoot, without involvement of the medial skin that underwent two staged procedure for transmetatarsal amputation with medial forefoot fillet flap. The first procedure was amputation of the 4 lesser metatarsal and the wound was left open. After a few days the second operation was done with amputation of the first metatarsal bone and using the filleted medial skin and subcutaneous tissue for closure of the wound. In conclusion the medial fillet flap is an effective method of covering large wounds after partial, lateral forefoot amputation. This method shortens the healing time of the patient, and in hospital stay. The authors recommend using the staged method when dealing with diabetic patients with partial, central and lateral forefoot deep infection and/or necrosis.

Although homozygosity is well documented in mature teratomas, the genetic zygosity of ovarian immature teratomas and mixed germ cell tumors is less well studied. Ten cases of mature cystic teratomas, eleven cases of grade 2 or 3 immature teratomas, and seven cases of mixed germ cell tumors with an immature teratoma component were investigated by short tandem repeat genotyping to interrogate their genetic zygosity. DNA genotyping was informative in eight mature teratomas, seven immature teratomas and six cases of mixed germ cell tumors. Out of the eight mature teratomas, five cases showed partial or complete homozygosity (63%) with two cases demonstrating complete homozygosity (25%). Of the immature teratomas, six cases showed partial or complete homozygosity (86%) with two cases demonstrating complete homozygosity (29%). For the mixed germ cell tumors, two cases showed partial homozygosity (33%) and none displayed complete homozygosity. Long-term clinical follow-up was available for five immature teratomas (mean follow-up 110 months) and five mixed germ cell tumors (mean follow-up 66 months). None of the five patients with pure immature teratoma had a recurrence; in contrast, four out of five mixed ovarian germ cell tumors recurred between 4 months to 8 years (P=0.048). In conclusion, both immature and mature teratomas harbor frequent genetic homozygosity suggesting a common cellular origin involving germ cells at the same developmental stage. The difference in the rate of homozygosity and tumor recurrence between pure immature teratomas and mixed germ cell tumors suggests that the two entities may involve different pathogenetic pathways and likely pursue different biological behaviors.

Introduction Assessment of urothelial bladder cancer during cystoscopy or transurethral resection of bladder tumour has a significant impact on the urologist's decision-making: treatment with simple outpatient fulguration, required depth of resection, and need of immediate post-surgical intravesical therapy. These choices depend heavily on the urologist's ability to accurately assess pre-biopsy tumour stage and grade. The aim of the study was to determine whether evaluation of photographs taken during transurethral resection of bladder tumour can reliably characterize a tumour’s stage and grade. Methods Smartphone photographs of 50 urothelial bladder cancer cases were taken at the beginning of transurethral resection of bladder tumour and individually presented to seven senior urologists. All urologists were blinded to the final pathological report and to any other urological evaluation. Each one was asked to rate the tumour as low vs high grade and noninvasive Ta vs noninvasive T1 or muscle invasive. Results were compared with final pathology. Individual appraisal and the majority's opinion were evaluated. Results Urologists have correctly predicted tumour stage and grade in 63.5% of cases (222 of 350, average of 32 out of 50 accurate assessments). The final majority assessment was correct in 40 of 50 cases (80%). Sensitivity and specificity of the final results for the diagnosis of T1 or higher were 80% and 88.6%, respectively. Sensitivity and specificity for Ta low grade were 83.3% and 80%, respectively. Conclusions To the best of our knowledge, this is the first documented attempt to evaluate urologists' ability to assess urothelial bladder cancer stage and grade using endoscopic photographs. Urologists can usually identify stage and grade of urothelial bladder cancer but accuracy increases when multiple senior urologists examine the same photographs and achieve majority consensus. Presenting photographs of urothelial bladder cancer to a team of urologists may lead to an excellent decision regarding type and extent of surgical treatment and substantiate appropriate post-surgical management.

This study provides a definite answer to the long-standing question concerning the longevity of the secretory antibody response. Landsverk et al. show that antigenic attrition affects a minor plasma cell subset and that distinct plasma cells are likely maintained for life in the human small intestine., Plasma cells (PCs) produce antibodies that mediate immunity after infection or vaccination. In contrast to PCs in the bone marrow, PCs in the gut have been considered short lived. In this study, we studied PC dynamics in the human small intestine by cell-turnover analysis in organ transplants and by retrospective cell birth dating measuring carbon-14 in genomic DNA. We identified three distinct PC subsets: a CD19+ PC subset was dynamically exchanged, whereas of two CD19− PC subsets, CD45+ PCs exhibited little and CD45− PCs no replacement and had a median age of 11 and 22 yr, respectively. Accumulation of CD45− PCs during ageing and the presence of rotavirus-specific clones entirely within the CD19− PC subsets support selection and maintenance of protective PCs for life in human intestine.

The purpose of the study was to investigate clinical outcomes following a mini-open posterior technique.Patients who received mini-open popliteal cyst excisions between April 1999 and April 2010 were identified. Charts were retrospectively reviewed for postoperative complications, cyst recurrence, previous aspiration, re-operation, intraoperative findings, cyst size, comorbidities, and co-surgeries. Visual Analogue Pain Scale and Rauschning's symptomatic knee criteria were collected prospectively to assess functional outcomes.Twenty-two legs in 21 patients were included in the study [males: 12 (57%); females: 9 (43%); age: 48.23 ± 11.74 years; BMI: 26.7 ± 4.54 kg/m2; follow-up: 4.55 ± 3.01 years]. Average cyst size was 4.16 ± 1.64 cm and were all located in the posteromedial aspect of the leg. All 22 cases had associated intra-articular pathology based on MRI, physical examination, and arthroscopy. Complications after cyst excision included: paresthesia in the distribution of the saphenous nerve (3/22, 14%), keloid formation (1/22, 4%), joint effusion requiring aspiration (1/22, 4%), and one recurrence requiring cystectomy 10 years later (4%). All incidences of paresthesia resolved. Mean visual analog pain score decreased by 6 points (p0.001) and Rauschning and Lindgren score decreased by two categories, from a 2.6 (category 2-3) preoperatively to 0.6 (category 0-1) postoperatively (p0.001).Mini-open popliteal cyst excision is a safe and effective technique for refractory popliteal cysts in patients who desire a decrease in pain, an increase range of motion, and improved function in knee flexion and extension. Further studies are needed to evaluate the clinical outcomes of patients over a longer duration as our one patient with a 10-year follow-up required a repeat procedure.

Autism spectrum disorder (ASD) impacts various developmental domains, requiring interventions by professionals from multiple disciplines. In Israel, ASD community preschools' multidisciplinary teams aim to provide each child with an integrative intervention program. The current study focused on the working experience of 21 professionals from multidisciplinary teams in ASD-preschools, with special emphasis on their perceptions of the intra-staff dialogue in their teams. Interviews were transcribed verbatim and analyzed through grounded theory. Arising themes covered: challenges characterizing the delivery of intervention to children with ASD in a community setting; challenges met by professionals when attempting to navigate multidisciplinary teamwork; and factors that facilitate multidisciplinary work. Practices that support multidisciplinary team cohesion at the team, the organizational, and the policy-making levels are discussed.

Background Mild Cognitive Impairment (MCI) is an intermediate state between normal cognition and dementia that is associated with twice the risk of falls. It is unknown whether white matter integrity (WMI) is associated with increased risk of falls in MCI. The purpose of this study was to evaluate if early changes in WMI were associated with gait impairment and falls. Methods Forty-three participants with MCI from the Gait and Brain Study underwent standardized assessment of cognition, gait performance under single and dual-task conditions (walking while talking), and WMI using 3 Tesla diffusion tensor imaging (DTI). Macro-structural imaging characteristics (white and grey matter morphology) as well as microstructural WMI parameters were examined for associations with falls and gait performance. Significantly associated WM tracts were then used to test the interplay between WMI and history of falls, after adjusting for other important covariates. Results Multiple WM tracts (corpus callosum, forceps minor, and the left inferior fronto-occipital fasciculus) were significantly associated with history of falls and lower dual-task gait performance. A multivariable regression model showed that fall history was associated with the radial diffusivity in the forceps minor, even after adjusting for education, sex, BMI, MMSE scores, comorbidities, gait velocity and WMH volume as covariates. Conclusions Multiple WM tracts that are known to be involved in executive and visuospatial functions were preferentially affected in MCI individuals with history of falls. Our preliminary findings support the notion that WMI in key brain regions may increase risk of falls in older adults with MCI., Highlights • 43 older adults with MCI were assessed for falls, gait, and WMI using 3 T DTI. • Multiple WM tracts were associated with falls and lower dual-task gait performance. • Tracts affected are known to be involved in executive and visuospatial functions.

Synovial IgG-expressing B cells from patients with rheumatoid arthritis show specificity for citrullinated autoantigens., Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II–driven T cell help, remain unclarified. To address these questions, we have used a single B cell–based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA+ RA patients, whereas such antibodies were not found in ACPA− patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA+ antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.

Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer

Interactions between coinfecting parasites1 may take various forms, either direct or indirect, facilitative or competitive, and may be mediated by either bottom-up or top-down mechanisms. While each form of interaction leads to different evolutionary and ecological outcomes, it is challenging to tease them apart throughout the infection period. To establish the first step towards a mechanistic understanding of the interactions between coinfecting limited-term bacterial parasites and lifelong bacterial parasites, we studied the coinfection ofBartonella sp. (limited-term) and Mycoplasma sp. (lifelong), which commonly co-occur in wild rodents. We infected Bartonella and Mycoplasma-free rodents with each species, and simultaneously with both, and quantified the infection dynamics and host responses. Bartonella benefited from the interaction; its infection load decreased more slowly in coinfected rodents than in rodents infected with Bartonella alone. There were no indications for bottom-up effects, but coinfected rodents experienced various changes, depending on the infection stage, in their body mass, stress levels, and activity pattern, which may further affect bacterial replication and transmission. Interestingly, the infection dynamics and changes in the average coinfected rodent traits were more similar to the chronic effects of Mycoplasma infection, whereas coinfection uniquely impaired the host's physiological and behavioral stability. These results suggest that parasites with distinct life history strategies may interact, and their interaction may be asymmetric, non-additive, multifaceted, and dynamic through time. Since multiple, sometimes contrasting, forms of interactions are simultaneously at play and their relative importance alternates throughout the course of infection, the overall outcome may change under different ecological conditions. 1“Parasite” is used throughout the article in its broad definition as an organism that lives in or on an organism of another species (its host) and benefits by consuming parts of the host resources or components. It damages the host but is rarely lethal in the short term. This term includes herein viruses, bacteria, protozoa, helminths, ectoparasites, and other blood-sucking organisms.

This is the peer reviewed version of the following article: Høiland, I.I., Liang, R.A., Brækkan, S.K., Pettersen, K., Ludviksen, J.K., Latysheva, N. ... Hansen, J.-B. (2019). Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism. Journal of thrombosis and haemostasis, 17(6), 934-943, which has been published in final form at https://doi.org/10.1111/jth.14438. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Background- It remains uncertain whether activation of the complement system, assessed by the soluble terminal C5b‐9 complement complex (plasma TCC), is associated with future risk of incident venous thromboembolism (VTE). Objectives- To investigate the association between plasma levels of TCC and future risk of incident VTE in a nested case‐control study, and to explore genetic variants associated with TCC using protein quantitative trait loci analysis of exome sequencing data. Methods - We sampled 415 VTE cases and 848 age‐ and sex‐matched controls from a population‐based cohort, the Tromsø study. Logistic regression models were used to calculate odds ratios with 95% confidence intervals for VTE across quartiles of plasma levels of TCC. Whole exome sequencing was conducted using the Agilent SureSelect 50 Mb capture kit. Results - The risk of VTE increased across increasing quartiles of plasma TCC, particularly for unprovoked VTE. Participants with TCC in the highest quartile (>1.40 complement arbitrary units/mL) had an odds ratio for unprovoked VTE of 1.74 (95% confidence interval: 1.10–2.78) compared with those with TCC in the lowest quartile (≤0.80 complement arbitrary units/mL) in analyses adjusted for age, sex, and body mass index. A substantially higher risk for VTE was observed in samples taken shortly before VTE event. We found no association between genome‐wide or complement‐related gene variants and plasma levels of TCC. Conclusions - We found that high levels of plasma TCC were associated with VTE risk, and unprovoked events in particular. There was no genome‐wide association between gene variants and plasma levels of TCC.

Plasma cells (PCs) are terminally differentiated B-lymphocytes producing antibodies. In coeliac disease (CeD) there is increased density of PCs in the small-intestinal lesion. Many of these PCs produce disease-specific autoantibodies targeting transglutaminase 2 (TG2).The plasmacytosis of CeD motivated us to study the transcriptional programme of PCs from coeliac gut lesions.RNA-seq was performed on the PCs of CeD patients and disease controls, being specific or non-specific for TG2.Being antibody-producing cells, 67% of the PCs' transcript was aligned to immunoglobulin genes. Strikingly, genes encoding ligands and receptors of chemokines and cytokines were abundant. Higher transcript levels of genes associated with cell activation and immune responses were observed in PCs of CeD patients compared to controls. TG2-specific compared to non-TG2 specific PCs expressed increased levels of CXCR3, CXCL10 and interleukin-15; factors that have been implicated in the pathogenesis of CeD yet with production attributed to other cells than PCs. The presence of transcripts of HLA class II and T-cell co-stimulatory molecules suggests that PCs may serve as antigen-presenting cells for CD4 + helper T cells.Our findings shed new light on the biology of intestinal PCs, implicating functions that go beyond the production of immunoglobulins.

Background Animal and observational studies have suggested a pathophysiological role for complement in venous thromboembolism (VTE), but the initiating mechanisms are unknown. Mannose‐binding lectin (MBL) bound to altered host cells leads to activation of the lectin complement pathway, and both high and low MBL levels have been implicated in the pathophysiology of cardiovascular disease. Objectives To investigate the association between plasma MBL levels and future risk of incident VTE. Methods We conducted a nested case‐control study in 417 VTE patients and 849 age‐matched and sex‐matched controls derived from the general population (Tromsø Study). Plasma MBL levels were measured using enzyme‐linked immunosorbent assay. Logistic regression models were used to estimate odds ratio (OR) for VTE across quartiles of plasma MBL levels. Results Subjects with plasma MBL levels in the lowest quartile (

BACKGROUND: Predictions of two different models for suicide attempts (SA) over 12 months, as differentially impacted by specific school-based suicide prevention interventions, were compared. These were as follows: (a) interpersonal theory (IPTS) and (b) a two-pathway model, one path associated with externalizing symptoms and continuum of self-harm behaviors, and the other with internalizing symptoms. METHODS: Self-report questionnaires were completed by 11,110 high school students from ten EU countries enrolled in the Saving and Empowering Young Lives in Europe (SEYLE) study. Baseline measures included perceived burdensomeness, thwarted belongingness from parents and peers, health risk behaviors, self-injury, suicide ideation (SI), and attempts (SA). SI and SA were reassessed at 12-month follow-up. Each model's predictions of SI and SA groups over time (i.e., repeated SA, remitted SA, SA onset, and no SA) were estimated in the no intervention/control group. The superior model was estimated across intervention groups. RESULTS: Interpersonal theory showed better fit compared to the two-pathway model. In partial agreement with IPTS predictions, parental low belongingness but not peer belongingness or burdensomeness predicted greater likelihood of SI. The likelihood of repeated SA versus no SA was higher among adolescents who reported SI, self-injury, risk behaviors, and particularly both SI and self-injury. All three interventions attenuated the combined effect of SI and self-injury. Youth Aware of Mental Health Program (YAM) additionally decreased the effect of risk behaviors on the likelihood of repeated SA. CONCLUSIONS: Interpersonal theory assumptions were partially supported. Perceived interpersonal difficulties with parents were primarily related with SI, and risk behaviors and self-injury were important predictors of SA. Suicide prevention interventions may be effective by mitigating the hazardous effect of varying self-harm behaviors and may be further advanced by increasing parental involvement.