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Summary Background The Crohn's disease exclusion diet (CDED) with partial enteral nutrition is effective for induction of remission in children with mild-to-moderate Crohn's disease. We aimed to assess the CDED in adults with Crohn's disease. Methods We did an open-label, pilot randomised trial at three medical centres in Israel. Eligible patients were biologic naive adults aged 18–55 years with mild-to-moderate Crohn's disease (defined by a Harvey–Bradshaw Index score of 5–14 points), a maximal disease duration of 5 years, with active disease on colonoscopy, or imaging with elevated inflammatory markers (C-reactive protein >5 mg/L or faecal calprotectin concentration >200 μ/g). Patients were randomly assigned (1:1) to CDED plus partial enteral nutrition or CDED alone for 24 weeks. Randomisation was via block randomisation (block sizes of six) using sealed, numbered, and opaque envelopes. Patients and investigators were aware of which group patients were assigned to due to the nature of the different interventions. The primary endpoint was clinical remission, defined as a Harvey–Bradshaw Index score of less than 5 at week 6. The primary endpoint was assessed in the intention-to-treat (ITT) population, which included all patients who used the dietary therapy for at least 48 h. We report results of the final analysis. This trial is registered with ClinicalTrials.gov , NCT02231814 . Findings Between Jan 12, 2017, and May 11, 2020, 91 patients were screened, of whom 44 were randomly assigned to the CDED plus partial enteral nutrition group (n=20) or CDED alone group (n=24). 19 patients in the CDED plus partial enteral nutrition group and 21 patients in the CDED alone group received the allocated intervention for at least 48 h and thus were included in the ITT analysis. At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618). Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group). 14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group). No serious adverse events or treatment-related adverse events were reported in either group. Interpretation CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild-to-moderate biologic naive Crohn's disease and might lead to endoscopic remission. These data suggest that CDED could be used for mild-to-moderate active Crohn's disease and should be assessed in a powered randomised controlled trial. Funding Azrieli Foundation and Nestle Health Science.

Background Conventional first-line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5-6) with paclitaxel (175 mg/m2) every 3 weeks (PC-3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC-3W with a modified protocol of weekly paclitaxel 80 mg/m2 and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28-day cycle (i.e., with 1 week off-treatment [PC-W]). Materials and Methods Medical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity. Results PC-3W was administered to 402 patients (median age, 60.5 years) and PC-W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III–IV. Notwithstanding a higher proportion of residual disease and older patients in the PC-W group, median progression-free survival was 21.4 months and 13.2 months for PC-W and PC-3W, respectively; median overall survival was 75.2 and 54.0 months for PC-W and PC-3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC-W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC-W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia. Conclusion PC-W is as active and better tolerated than the standard PC-3W regimen. PC-W may serve as an alternative option for elderly or frail patients. Implications for Practice Weekly scheduling of paclitaxel 80 mg/m2 and carboplatin AUC2, administered on days 1, 8, and 15 in a 28-day cycle (PC-W) for first-line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m2) every 3 weeks (PC-3W). It is possible that the weekly holiday on day 21 in the PC-W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC-3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.

To assess the risk of adverse maternal and neonatal outcomes as a function of the presenting twin second-stage duration. A retrospective cohort study of deliveries taking place in an academic medical center between 2005 and 2019. The study group included women with twin pregnancies with the first fetus in vertex presentation, who attempted vaginal delivery with epidural analgesia and attained the second stage of labor. Prolonged second stage (PSS) was defined as when exceeding the 95th percentile of presenting twin second-stage duration recorded among all parturients who achieved spontaneous vaginal deliveries in our center during the study period, stratified by parity: 3 h in nulliparas and 1 h in multiparas. Women with and without PSS were compared. The primary outcome was a composite of adverse maternal outcomes. A univariate analysis was conducted and followed by multivariate analysis. During the study period, 1,337 parturients (36% of twin deliveries) met study criteria, of these 22% (298) were nulliparous and 78% (1,039) were multiparous. The second stage of labor of the presenting twin was prolonged in 41 (13.8%) of the nulliparas and 64 (6.2%) multiparas. Prolonged second stage was associated with episiotomy, chorioamnionitis, endometritis, and blood product transfusion, as well as vacuum deliveries of the first and second twin, second-stage cesarean, and a higher rate of composite adverse maternal outcome in nulliparous (41.5% vs. 20.2%, p

Previous epidemiologic investigations suggested that maternal thyroid anomalies are a possible causal factor in attention-deficit hyperactivity disorder (ADHD) in progeny, yet clinical trials indicated that levothyroxine treatment was ineffective in preventing neurodevelopmental impairments. We used an Israeli cohort of 385,542 singleton births from 1999–2012 to explore the interrelated roles of maternal thyroid conditions, laboratory gestational thyroid hormone measurements, use of thyroid medications, and offspring ADHD. Analyses were performed using Cox proportional hazards models. Results indicated that maternal hypothyroidism diagnosis was associated with an elevated progeny ADHD hazard (adjusted hazard ratio = 1.14, 95% confidence interval = 1.10, 1.18). However, this association was unmitigated by gestational use of levothyroxine and was unexplained by maternal gestational thyroid hormone levels. Associations with gestational thyrotropin values and hypothyroxinemia were also observed but were robust only in mothers without other records indicative of a thyroid problem. Results indicated that maternal thyroid hypofunction was associated with progeny ADHD but possibly not due to a direct causal relationship. Instead, maternal thyroid hypofunction may serve as a proxy indicator for other factors that affect neurodevelopment through thyroid hormone independent pathways, which are thus unaffected by pharmaceutical treatments for thyroid hypofunction. Factors known to disrupt thyroid functioning should be examined for their independent ADHD-related effects.

Posttraumatic stress disorder (PTSD) is complicated by high rates of problematic drinking and comorbid alcohol use disorder (AUD). This study examined veterans seeking residential PTSD treatment, comparing those with and without AUD, to determine whether trauma type and/or PTSD symptom changes during treatment were associated with binge drinking at 4-month follow-up. Analyses compared characteristics of veterans (N = 758) in residential treatment, as well as associations of demographic, trauma, and alcohol-related variables, with binge drinking episodes at follow-up. Results showed no differences in PTSD symptom improvements based on AUD diagnosis. Among AUD-diagnosed veterans, 21.3% endorsed binge drinking 4 or more (14.3% endorsed 9 or more) days, while 10.8% of veterans without AUD endorsed binge drinking 4 or more (5.2% endorsed 9 or more) days at follow-up. Among AUD-diagnosed veterans, while PTSD symptom improvements were not associated with binge drinking outcomes, drinking days at admission and military sexual trauma (MST) predicted a greater likelihood of binge drinking. Among veterans without AUD, drinking days at admission, PTSD symptom increases, being unmarried, ‘other’ race, and less education, were associated with a higher likelihood of binge drinking, while MST and combat exposure predicted a lower likelihood of binge drinking. In conclusion, drinking days at admission is a predictor of binge drinking following treatment; thus, alcohol use should be assessed at intake and addressed among those who endorse drinking to reduce the likelihood of alcohol resumption following residential treatment. Furthermore, among AUD-diagnosed veterans, despite PTSD symptom decreases during treatment, MST predicted a greater likelihood of 9 or more binge drinking days at follow-up.

Bicuspid aortic valve (BAV) is the most common congenital heart disease. Calcific aortic valve disease (CAVD) accounts for the majority of aortic stenosis (AS) cases. Half of the patients diagnosed with AS have a BAV, which has an accelerated progression rate. This study aims to develop a computational modeling approach of both the calcification progression in BAV, and its biomechanical response incorporating fluid-structure interaction (FSI) simulations during the disease progression. The calcification is patient-specifically reconstructed from Micro-CT images of excised calcified BAV leaflets, and processed with a novel reverse calcification technique that predicts prior states of CAVD using a density-based criterion, resulting in a multilayered calcified structure. Four progressive multilayered calcified BAV models were generated: healthy, mild, moderate, and severe, and were modeled by FSI simulations during the full cardiac cycle. A valve apparatus model, composed of the excised calcified BAV leaflets, was tested in an in-vitro pulse duplicator, to validate the severe model. The healthy model was validated against echocardiography scans. Progressive AS was characterized by higher systolic jet flow velocities (2.08, 2.3, 3.37, and 3.85 m s(−1)), which induced intense vortices surrounding the jet, coupled with irregular recirculation backflow patterns that elevated viscous shear stresses on the leaflets. This study shed light on the fluid-structure mechanism that drives CAVD progression in BAV patients.

To evaluate the maternal and neonatal outcomes associated with vacuum-assisted vaginal delivery (VAVD) in a subset of parturients with congenital uterine anomalies.A retrospective database study was conducted at a single tertiary center between 2005 and 2019. Parturients with known congenital uterine anomalies who had vaginal deliveries were enrolled, whereas parturients with failed VAVD, didelphic uterus, and delivery after intrauterine fetal death were excluded. Various maternal and neonatal outcomes were compared between parturients who achieved spontaneous vaginal delivery (SVD) and those who delivered via VAVD. The maternal composite outcome was calculated for each group and included one or more of the following: post-partum hemorrhage, hemoglobin drop ≥ 4 gr/dL, blood transfusions, retained placental products, and obstetric anal sphincter injuries. Univariate analysis was performed followed by multivariate logistic regression analysis controlling for potential confounders. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated.After the application of the exclusion criteria, 332 parturients were found eligible. Of those, 289 (87%) had SVD and 43 (13%) had VAVD. VAVD was more common among primiparous parturients and epidural analgesia users. Parturients with VAVD had higher rates of third-degree perineal tear, postpartum hemorrhage, and blood transfusions. The maternal composite outcome was significantly more prevalent in the VAVD group (44.2% vs. 20.8%, p 0.01). After controlling for potential confounders, the maternal composite outcome was found to be independently associated with VAVD (aOR 2.3, 95% CI 1.10-4.60). The neonatal results were overall comparable, except for scalp trauma and Erb's palsy/clavicular fracture, which were more prevalent in the VAVD group.In a special population of parturients with congenital uterine anomalies, VAVD was found to be associated with significantly higher rates of adverse maternal outcomes and perinatal birth trauma. These findings should be presented to parturients during consultations about modes of delivery.

Background Patients with primary hyperparathyroidism (PHPT) treated surgically occasionally have normalized calcium, but persistently high parathyroid hormone (PTH). We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma. Methods Retrospective cohort of patients who underwent parathyroidectomy for PHPT with biopsy of a normal‐appearing parathyroid gland were included. Cellularity level of each biopsy and of the adenoma's rim was determined. Results Forty‐seven patients were included. Of them, 19 (40%) had postoperative normocalcemia but elevated PTH. There was no correlation between cellularity either in the rim or of the normal‐appearing parathyroid gland and postoperative PTH. The postoperative high PTH group had higher preoperative PTH (P = 0.001) and larger adenomas (P = 0.025). Conclusions High PTH levels after successful parathyroidectomy in patients with primary hyperparathyroidism do not appear to result from underlying hyperplasia. A possible alternative explanation is that these patients have a higher preoperative burden of disease., Patients with Primary hyperparathyroidism treated surgically occasionally have normalized calcium, but persistently high PTH. We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma.? Contrary to our hypothesis, there was no correlation between the cellularity of the normal‐appearing parathyroid glands and the parathyroid tissue surrounding the adenoma with PTH levels after surgery.

To assess whether women with mild gestational thrombocytopenia have a higher risk of postpartum hemorrhage.A retrospective computerized database. Primiparous women that delivered at our center (2005-2019) were included; we excluded women with possible etiologies for thrombocytopenia such as systemic lupus or coagulation disorders, and hypertensive disorder of pregnancy. Demographics, obstetric characteristics, and maternal as well as neonatal data were compared between groups. The exposure measure of the study was mild thrombocytopenia (100,000-150,000) versus normal thrombocyte count (150,000) at admission for labor. Postpartum hemorrhage (PPH) is defined as a clinical estimated blood loss of500 mL and/or a hemoglobin drop of ≥ 3 g/dl.Overall, 39,886 primiparous met the study's criteria, 5,209 (13.1%) had mild gestational thrombocytopenia (mean platelet count of 132.4 ± 13.2, study group) while 34,677 (86.9%) had normal platelet count at admission (mean of 221.6 ± 50.6, comparison group.) PPH occurred in 17.6% of the study group as opposed to 14% in the comparison group (Primiparous women with mild gestational thrombocytopenia are at increased risk of peripartum hemorrhage, this should be considered a risk factor when assessing parturients' risk of PPH.

Patients with Parkinson's disease (PD) experience motor and non-motor symptoms, suggesting alterations of the motor and/or limbic system or more probably of their communications. We hypothesized that the communication between the insula (part of the limbic system) and sensorimotor cortex in PD is altered and hemispheric asymmetric. Furthermore, that this asymmetry relates to non-motor symptoms, and specifically, that apathy-related asymmetry is unique to PD. To test these hypotheses, we used a novel multivariate time-frequency analysis method applied to resting-state functional magnetic resonance imaging (MRI) data of 28 controls and 25 participants with PD measured in their OFF medication state. The analysis infers directionality of coupling, that is, afferent or efferent, among four anatomical regions, thus defining directed pathways of information flow, which enables the extension of symmetry measures to include directionality. A major right asymmetry reduction of the dorsal-posterior insula efferent and a slight bilateral increase of insula afferent pathways were observed in participants with PD versus controls. Between-group pathways that correlated with mild cognitive impairments combined the central-executive and default-mode networks through the right insula. Apathy-correlated pathways of the posterior insula in participants with PD versus controls exhibited reduced right efferent and increased left afferent. Because apathy scores were comparable between the groups and effects of the other motor and non-motor symptoms were statistically removed by the analysis, the differences in apathy-correlated pathways were suggested as unique to PD. These pathways could be predictors in the pre-symptomatic phase in patients with apathy.

Background In mid-December 2020, Israel had started a nationwide mass vaccination campaign against COVID-19. In the first few weeks, medical personnel, elderly citizens and patients with chronic diseases were prioritized. As such, patients with primary and secondary immunodeficiencies were encouraged to receive the vaccine. While the efficacy of RNA-based COVID-19 vaccines was demonstrated in the general population, little is known about their efficacy and safety in patients with Inborn Errors of Immunity (IEI). Objectives To evaluate the humoral and cellular immune response to COVID-19 vaccine in a cohort of IEI patients. Methods 26 adult patients were enrolled, and plasma and peripheral blood mononuclear cells were collected two weeks following the second dose of Pfizer-BioNTech COVID-19 vaccine. Humoral response was evaluated by testing anti-SARS-CoV-2 Spike (S) Receptor Binding Domain (RBD) and anti-Nuclear (N) antibody titers, and evaluation of neutralizing ability by inhibition of RBD:ACE2 binding. Cellular immune response was evaluated by ELISpot, estimating IL2 and IFNγ secretion in response to pooled SARS-CoV-2 S or M peptides. Results Our cohort included 18 patients with predominantly antibody deficiency, 2 with combined immunodeficiency, 3 with immune-dysregulation, and 3 with other genetically defined diagnoses. 22/26 were receiving immunoglobulin replacement therapy. 18/26 developed specific antibody response and 19/26 showed S-peptide specific T-cell response. None of the patients reported significant adverse events. Conclusion Vaccinating IEI patients is safe, and most patients were able to develop vaccine specific antibody response, S-protein specific cellular response or both., Effective anti-SARS-CoV-2 vaccine should limit disease spread and protect against severe COVID-19. In this study, most patients with Inborn Errors of Immunity (IEI) were able to safely mount humoral and cellular immune response. Therefore, IEI patients should be encouraged to get vaccinated.

Background Social anxiety disorder (SAD) is a chronic and disabling psychiatric disorder associated with low levels of help-seeking. To date, however, scarce research has examined the epidemiology of SAD in veterans. This study examined the prevalence, comorbidities and incremental burden of SAD in relation to suicidality and functioning in a representative sample of U.S. military veterans. Methods A nationally representative sample of 3,157 U.S. veterans completed a web survey containing measures of SAD symptoms, trauma history, psychiatric history and functioning. Multivariable analyses were conducted to examine associations between SAD and psychiatric comorbidities, suicidality and functioning. Results A total 9.5% (n = 272) of the sample screened positive for lifetime SAD. Veterans with SAD were more likely than those without SAD to be younger, female, single, racial/ethnic minorities and to have experienced childhood abuse. They also had substantially elevated rates of comorbid psychiatric disorders, particularly lifetime major depression (odds ratio [OR]=5.8) and posttraumatic stress disorder (OR=3.1), as well as current suicidal ideation (OR=3.3). Veterans with SAD scored lower on measures of functioning, particularly social, emotional and mental health functioning (d’s=0.21–0.34). Limitations Data were collected cross-sectionally using self-report. Conclusions SAD in U.S. veterans is prevalent and associated with psychiatric comorbidities, functional impairment and a more than 3-fold greater risk for suicidal ideation . Given that SAD is associated with low treatment seeking and engagement, it may be undetected and undertreated relative to other psychiatric morbidities. These results underscore the importance of screening, monitoring and treating SAD in this population along with other prevalent mental disorders.

Objectives Little is known regarding the differences in microbiology associated with cellulitis or abscess with or without lymphangitic streaking. The objective of our study is to assess whether there are differences in the pathogens identified from wound cultures of patients with paronychia with and without associated lymphangitis. Methods Retrospective cross-sectional study at a tertiary pediatric emergency department over 25 years. We opted to assess patients with paronychia of the finger, assuming that these cases will have a greater variety of causative pathogens compared to other cases of cellulitis and soft tissue abscess that are associated with nail biting. Case identification was conducted using a computerized text-screening search that was refined by manual chart review. We included patients from 1 month to 20 years of age who underwent an incision and drainage (I&D) of a paronychia and had a culture obtained. The presence or absence of lymphangitis was determined from the clinical narrative in the medical record. We excluded patients treated with antibiotics prior to I&D as well as immune-compromised patients. We used descriptive statistics for prevalence and χ2 tests for categorical variables. Results Two hundred sixty-six patients met inclusion criteria. The median age was 9.7 years [IQR 4.7, 15.4] and 45.1% were female. Twenty-two patients (8.3%) had lymphangitic streaking associated with their paronychia. Patients with lymphangitis streaking were similar to those without lymphangitis in terms of age and sex (p = 0.52 and p = 0.82, respectively). Overall, the predominant bacteria was MSSA (40%) followed by MRSA (26%). No significant differences were found between the pathogens in the 22 patients with associated lymphangitis compared to the 244 patients without. Conclusion Staphylococcus aureus represent the majority of pathogens in paronychia, although streptococcal species and gram-negative bacteria were also common. Among patients with paronychia of the finger, there seems to be no association between pathogen type and presence of lymphangitic streaking.

Background Bladder dysfunction is the most common autonomic disturbance in people with MS (PwMS). Only a few studies have examined the relationship between bladder dysfunction and falls in PwMS. Bladder dysfunction has been deemed only a secondary outcome measure, and classified by a gross measure providing a limited perspective of this disturbing symptom. Furthermore, no study to date has focused on the relationship between bladder dysfunction and balance performance in PwMS. Research question Determine the relationship between bladder dysfunction with balance, falls and fear of falling in women with MS. Methods The study was observational, including 44 women with MS, mean age 46.3 (SD = 5.7), all with at least a mild bladder dysfunction. Outcome measures included the Urinary Incontinence Quality of Life Scale (I-QoL), Bladder Control Scale (BLCS), Timed Up and Go Test (TUG), Four Square Step Test (FSST), Falls Efficacy Scale International (FES-I), Falls status, and posturography. Results Participants performed the TUG in 14.1 s (S.D. = 11.1), and the FSST in 20.5 s (S.D. = 22.4). A relatively large proportion (68.2 %) of women was classified as fallers. However, no differences were found between those classified as fallers (n = 30) or non-fallers (n = 14) in terms of the I-QoL and the BLCS, controlling for age, EDSS and number of vaginal deliveries. Significant correlations scores were found between the I-QoL, BLCS and FES-I (rho ∼0.47), while controlling for age, EDSS and number of vaginal deliveries. No associations were demonstrated between the bladder dysfunction outcome scores and either the TUG and/or FSST. Significance Women afflicted with MS and suffering from bladder dysfunction tend to fall and present with more balance difficulties compared with disability-matched PwMS. Nevertheless, once bladder dysfunction is detected, the perceived severity of the condition is not associated with balance and prevalence of falling, but rather on fear of falling.

Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children 282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914–706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%–79%, from 110,000–175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.

Diet is a key modifier of risk of inflammatory bowel disease development and potentially a treatment option in patients with established disease. International organisations in gastroenterology and inflammatory bowel disease have published guidelines for the role of diet in disease onset and its management. Here, we discuss the major overarching themes arising from these guidelines and appraise recent literature on the role of diet for inflammatory bowel disease prevention, treatment of active disease and maintenance of remission, considering these themes. Except for exclusive enteral nutrition in active Crohn’s disease, we currently possess very little evidence to make any further dietary recommendations for the management of inflammatory bowel disease. There is also currently uncertainty on the extrapolation of epidemiological dietary signals on risk of disease development and preclinical experiments in animal models to management, once disease is established. Until high-quality evidence from clinical research becomes available, the only specific recommendations for inflammatory bowel disease we might safely give are those of healthy eating which apply for the general population for overall health and well-being.

Introduction For the last three decades, enzyme replacement therapy (ERT) for Gaucher disease (GD) has been available. We aimed to evaluate the effect of ERT on the pregnancy and obstetric outcome in a unique group of multiparous women with type 1 GD (GD1) who had pregnancies with and without ERT. Study design The Gaucher Unit database (1987-2019) was searched for multiparous women who had pregnancies before and after the institution of ERT. Data were collected from the clinic files and study-specific questionnaires. Descriptive, correlation analysis and generalized estimating equations (GEE) were used to study the effect of ERT and confounding variables on study outcomes. Results We identified 19 women with 105 pregnancies, among which 26 (24.7%) terminated in first-trimester miscarriage. The risk for miscarriage was associated with the severity of GD1 genotype and phenotype, but not with ERT usage. Early postpartum hemorrhage (PPH) was reported in 16 (84%) women after 25 deliveries (31.6%, 95% CI 21.6%-43.1%). The risks of early PPH and red blood cell (RBC) transfusions were significantly lower when ERT was used during pregnancy, OR (95% CI) 0.13 (0.03-0.54) and 0.27 (0.08-0.94), respectively, compared to pregnancies without the use of ERT. Conclusion Enzyme replacement therapy during pregnancy is risk reducing for early PPH and RBC transfusions in women with GD1. We suggest considering ERT for the benefit of all pregnant women with GD1, including mild GD1. This article is protected by copyright. All rights reserved.

What is known on the subject Alcohol addiction is manifested by periods of abstinence and relapse in which the individual returns to previous problematic alcohol use. This may lead to unstable and stressful routines for the family and for women who live with a spouse diagnosed with an AUD. AUD may mentally and physically affect women living with a spouse diagnosed with AUD with respect to relapse. However, most studies have focused on the influence of AUD in general, and the way they cope with it; few have dealt with the experience of relapse as a distinctive stage. What the paper adds to existing knowledge Women's experiences of their spouses' relapses are embedded within their broader life experience in the shadow of alcohol addiction. The pattern of transitions from closeness to distance in the ways women think, feel and actively respond to their spouses' relapses shows similarities with the ways in which individuals cope with repeated trauma. This helps relate these women's experiences of their spouses' repeated relapses to the potential complex trauma these women experience and leads to a better understanding of the internal emotional dynamics of these women's behavioural patterns. What are the implications for practice These women need a therapeutic solution that can help them cope with longstanding emotional burdens. Therapists should be sensitive to the complexity of their experience. When relevant, therapy should be based on therapeutic strategies from trauma practice, along with Alcohol Behavioural Couples Therapy that can reinforce the couple's mutual efforts to achieve sobriety or reduce AUD severity ABSTRACT: Introduction Alcohol use disorder (AUD) is manifested by periods of remission and relapse which can serve as a source of continuous stressors on the individuals and family. Women living with a spouse diagnosed with AUD can be mentally and physically affected by this behaviour. Most studies have focused on the general influence of AUD on these women and their attempts to cope with AUD; there are scant data on the influences of relapse as a distinctive stage. Aim To better understand how women whose spouses are diagnosed with AUD experience their relapses. Method A qualitative-naturalistic approach was implemented. Semi-structured, in-depth interviews were conducted with 12 women whose spouses were diagnosed with AUD. Results Content analysis revealed three main categories representing the transitions from: a) ignorance to realization, b) emotional opposition to acceptance and c) activity to inactivity. Each category reflects one cognitive, emotional or behavioural dimension of this experience. The overarching theme emerged as shifts from closeness to distance in the way these women think, feel and actively respond to their spouse's relapses and addiction. Discussion The shift from closeness to distance as manifested by the three transitions is argued to reflect the ways these women experience and cope with the chronic nature of AUD. It is suggested that this experience parallels the phenomenology of symptoms of complex trauma. Implications for practice Nurses should be alert to the potential accumulative stressors experienced by these women and implement intervention strategies developed in the trauma field in addition to Alcohol Behavioural Couples Therapy.

The Aut-Eat Questionnaire (AEQ) provides a novel and comprehensive assessment of eating problems and patterns in children with ASD. To establish the internal consistency and discriminant validity of the AEQ, parents of children with ASD (n = 105, Mage = 40.85, SD = 15.67 months) or typical development (TD; n = 98, Mage = 50.33, SD = 16.50 months) completed the AEQ. Questionnaire construction, content validity, factor analysis, internal consistency and discriminant validity are reported. The AEQ was reliable with high internal consistency in most domains. Significant differences were found between groups in all domains. The AEQ is a reliable and valid tool and may help to characterize eating difficulties in this population.

Introduction Approximately 160–180,000 adults suffer limb loss annually, often due to trauma. The Penn Orthoplastic Limb Salvage Center enables concerted orthopedic/plastic (orthoplastic) surgery care and microvascular expertise for optimal outcomes. The authors review their experience and propose guidelines to facilitate early transfer for lower extremity salvage. Methods A review (2002–2019) was performed of patients who underwent free-flap reconstruction (as a proxy for severity) for lower extremity traumatic injuries. Demographics, risk factors, imaging, operative details, and perioperative outcomes were analyzed. Further analyses were performed comparing patients transferred to our limb salvage center - transfers - and those admitted to our institution first following their trauma – direct admits. Results 178 patients (62.4% transfers, 37.6% direct admits) met inclusion criteria. Osteomyelitis was higher among transfers (46.1% vs. 22%, p = 0.006). There was a greater delay in soft tissue coverage in transferred patients (p = 0.016). On multivariate analysis, flap within 30 days was protective of osteomyelitis (Odds Ratio (OR) = 0.233, 95% Confidence Interval (CI): 0.085–0.639). Limb salvage rates were 94% and 91.8% for the direct admits and transferred patients, respectively (p = 0.584), at median follow-up of 941.5 days. Overall, full weight-bearing status was achieved in 77% of patients, with no difference between groups (p = 0.163). Conclusion Despite microvascular advances, delay in referral for salvage contributes to unnecessary patient morbidity. Microsurgery/flap success is independent of timing, likely attributable to specialized care at a limb salvage center. Similar to American Burn Association guidelines for transferring burn injuries to specialized centers, the authors propose the Lower Extremity Guide for Salvage (L.E.G.S.).

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell–intrinsic epithelial–mesenchymal transition and transforming growth factor-β signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4–6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition., Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance

To examine the association between vaginal delivery of a previous macrosomic neonate (birthweight (BW)≥ 4000) among non-diabetic women and the rate of shoulder dystocia (SD) in the subsequent pregnancy.A historical prospective cohort study in a university affiliated medical center from 2005 to 2019. Women who had a singleton pregnancy and two consecutive deliveries in our medical center were included. Women with previous GDM, SD or cesarean delivery were excluded. Univariate analysis was followed by multivariate logistic regression.A total of 38,942 women were included. SD incidence among the subsequent pregnancies was 0.44 % (172 women). In univariate analysis women with previous delivery of large neonates: BW≥90th percentile for gestational age and BW ≥ 4000 g had higher risk for subsequent SD (odds ratio 2.69 [95 % confidence interval 1.89-3.84], p0.01 and 2.71 [1.66-4.44], p0.01, respectively). However, a backward stepwise multivariate logistic regression model adjusted for significant confounders for SD in the univariate analysis, showed that women with a previous delivery of macrosomic neonate ≥4000 g were not found to have higher or lower risk for SD in the subsequent delivery.Previous uneventful delivery of a macrosomic neonate to a non-diabetic mother should not be regarded as a risk factor for SD in the subsequent delivery.

Background Limited data exist regarding the presentation and bacteriology of nonneonatal pediatric breast abscess. Objective: To determine the bacteriology and characteristic presentation of pediatric breast abscesses in a tertiary care center. Methods: Cross-sectional study of patients age 1 month to 21 years admitted to a pediatric Emergency Department (ED) between 1996 and 2018 with a breast abscess. Patients with pre-existing conditions were excluded. Records were reviewed to determine demographics, history, physical exam findings, wound culture results, imaging and ED disposition. We used descriptive statistics to describe prevalence of different bacteria. Results: We identified 210 patients who met study criteria. Median age was 13.6 years [IQR 6.6, 17.4], and 91% (191/210) were females. Ninety-two patients (43.8%) were ‘pre-treated’ with antibiotics prior to ED visit, and 33/210 (16%) were febrile. Ultrasound was obtained in 85 patients (40.5%), 69 patients had a single abscess and 16 had multiple abscesses. Most patients were treated with antibiotics and 100 had a surgical intervention, of these 89 had I&D and 11 a needle aspiration. Admission rate was 45%. Culture results were available for 75 (75%). Thirty-three (44%) had a negative culture, or grew non-aureus staphylococci or other skin flora. Culture were positive for MSSA 21 (28%), MRSA 13 (17%), Proteus mirabilis 2 (2.6%), Serratia 1 (1.3%). Other organisms include Gram-negative bacilli, group A Streptococcus and enterococcus. Conclusions: Non-neonatal pediatric breast abscess bacteriology is no different than data published on other skin abscesses. MRSA coverage should be considered based on local prevalence in skin infections.

Familial Mediterranean Fever (FMF), the most common monogenic inflammatory disease, is mainly treated by oral Colchicine. However, 5% of patients are considered non-responders and, therefore, candidates for biologic therapy. Intravenous (IV) Colchicine treatment has been shown to be effective and safe in adult patients. The objective of this study was to evaluate the safety of IV Colchicine for pediatric FMF patients in our hospital, refractory to oral Colchicine, by reviewing their medical records. Inclusion criteria were all patients with FMF who commenced treatment with IV Colchicine before the age of 18 years, and received at least 6 months of IV therapy. The patients completed questionnaires to assess the efficacy of the treatment. Between 2004 and 2017, 7 pediatric FMF patients receiving maximal oral Colchicine doses and deemed non-responders were treated with weekly IV Colchicine, including 38 cumulative patient years of follow-up data (a full blood count, renal and liver function tests). All patients were homozygous for the M694V genotype. Long-term follow-up showed normal laboratory results with no Colchicine-related hospital admissions or toxicity. Global health assessment and the number of disease-free days have significantly improved (P

Background: Oral contraceptives (OC) and hormone replacement therapy (HRT) are well-established risk factors for ER positive breast cancer. Infertility is associated with an increased breast cancer risk and there is conflicting data on the influence of fertility treatments on breast cancer risk. The impact of exogenous estrogen exposure on breast cancer characteristics is not well described. Methods: A single center retrospective cohort study comprising all women with ER positive, human epidermal growth factor receptor 2 (HER2) negative, EBC whose tumors were sent to OncotypeDX analysis and were treated in our institute between 2005 and 2012. Data on exogenous estrogen exposure were collected including: OC and HRT use and prior fertility treatments. The impact of these exposures was assessed on pre-specified histopathological features including: tumor size, nodal status, ER and progesterone receptor (PR) staining, grade, Oncotype recurrence score (RS), ki67, lymphovascular and perineural invasion. Results: A total of 620 women were included, 79% (Num) were postmenopausal. Prior exposure to OC, HRT and fertility treatments was documented in 19% (103), 30% (136) and 11% (62), respectively. OC use was associated with smaller (≤1cm) tumors (30% vs. 20%, p=0.023) and were less likely to have grade 3 disease (10% vs. 19%, p=0.049). No other associations were found between exogenous estrogen exposures and tumor characteristics (Table). Conclusions: Use of OC may be associated with breast cancer with a distinct features compared to women with luminal breast cancer without history of OC use. Large scale studies are needed to better characterize these findings. Fertility treatmentHRT ≥ 2 yearsHRTOCPNo (%)Yes(%)PNo(%)Yes (%)PNo (%)Yes (%)PNo(%)Yes(%)0.1722254252165150.7002355222057240.7002255232456200.023205723304426T≤1 cm 12 cm0.85917180.09815200.09815210.6671815Node positive0.06479138891100.29982126761590.29982135771590.207791488795IDC ILC Other0.1671864181473130.5001667181664190.5001667171762210.049186319187310Grade 1 230.18922078329680.70811781122770.70811781221780.7392227732275ER intensity≤1 120.1121470.67116150.67116140.103148PR Negative1.000530.455520.455530.28252PNI present0.772670.351780.351570.056105LVI present0.18620290.36222190.36223180.5282218Ki67 >20%0.85917180.78718160.78717180.5701816Oncotype RS>25 Citation Format: Orly Yariv, Rinat Yerushalmi, Assaf Moore, Tzippy Shohat, Ofer Rotem, Yasmin Korzets Ceder, Hadar Goldvaser. The impact of exogenous estrogen exposure on the characteristics of estrogen receptor (ER) positive, early-stage breast cancer (EBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-21.

Objective Exposure to traumatic life events is associated with increased risk of posttraumatic stress disorder (PTSD) and other mental health problems such as suicidal ideation (SI), alcohol use disorder (AUD), and decreased quality of life (QOL). Mindfulness, which involves attending to the present moment, may help individuals cope with traumatic events by increasing acceptance of trauma-related experiences and decreasing trauma-related negative affect and avoidance of trauma reminders. The current study evaluated whether mindful attention to the present moment mediated the association between number of lifetime traumas and mental health. Method The sample consisted of 1,268 trauma-exposed U.S. veterans who participated in the National Health and Resilience in Veterans Study, a nationally representative study of U.S. veterans. On average, the sample was 60.6 years of age (SD = 15.2, range = 20-94), predominantly male (89.8%), Caucasian (75.0%), and noncombat veterans (59.2%). Results Path analyses revealed that mindfulness partially mediated the relation between number of lifetime traumas and PTSD symptoms (β = -.55), AUD (β = -.17), and QOL (β = .38), and fully mediated the relation between number of lifetime traumas and SI (β = -.36). Conclusions The relationship between lifetime trauma burden and various mental health issues of relevance to U.S. veterans may be mediated by mindfulness, or the ability to pay attention to the present moment. Interventions that bolster mindfulness may help mitigate the negative impact of cumulative traumas in this population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties, including atrial effective refractory period (AERP) and conduction velocity, are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles, and stainless-steel fixating pins. Initial quality validation was performed ex vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4, and 8 wk postimplantation. Capture threshold was stable. Baseline AERP values (38.1 ± 2.3 and 39.5 ± 2.0 using 70-ms and 120-ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are nonphysiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.

Dementia with Lewy bodies is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Dementia with Lewy bodies can provide a diagnostic challenge due to the frequent overlap of clinical signs with other neurodegenerative conditions, namely Parkinson's disease dementia, and Alzheimer's disease. Part of this clinical overlap is due to the neuropathological overlap. Dementia with Lewy bodies is characterized by the accumulation of aggregated α-synuclein protein in Lewy bodies, similar to Parkinson's disease and Parkinson's disease dementia. However, it is also frequently accompanied by aggregation of amyloid-beta and tau, the pathological hallmarks of Alzheimer's disease. Neuroimaging is central to the diagnostic process. This review is an overview of both established and evolving imaging methods that can improve diagnostic accuracy and improve management of this disorder.

To compare clinical pregnancy rate (CPR) and live birth rate (LBR) after frozen-thawed embryo transfer (FET) of day (D-) 6 blastocysts on D-5 versus D-6. A retrospective cohort study. A university-affiliated single-center tertiary hospital. Women undergoing FET of D-6 blastocysts between August 2015 and March 2019 were included in the study. Exclusion criteria were endometriosis and maternal age ≥ 42. Cycles involving embryo transfer (ET) at D-6 were compared to cycles involving ET on D-5. Primary outcomes assessed were CPR and LBR, and the secondary outcomes were spontaneous abortion and chemical pregnancy rates. Forty-two cycles were assessed, 21 in which ET occurred on D-6 and 21 in which ET occurred on D-5. There were no significant differences between groups regarding age, body mass index (BMI), etiology of infertility, number of oocytes aspirated and blastocysts cryopreserved in the fresh cycle, reason for freezing on D-6, endometrial thickness before ET, and blastocyst grade. A comparison of outcomes of ET on D-5 with those involving ET on D-6 revealed that D-5 transfer produced significantly higher CPR (8, 38% vs. 2, 8.5%; P = 0.030) and LBR (6, 28.6% vs. 1, 4.8%; P = 0.038), respectively. FET of D-6 embryos on D-5 compared with D-6 is associated with increased CPR and LBR values. These findings might be related to the limited time window for optimal rates of implantation and indicate that transferring embryos on D-6 of a FET cycle is likely too late.

Introduction: The impact of exogenous estrogen exposure on breast cancer characteristics and outcomes is not well described. We aimed to investigate the effect of prior treatment with oral contraceptives (OCT), hormone replacement therapy (HRT), and fertility treatments on early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: This is a single-center retrospective cohort study comprising all women with ER-positive, HER2-negative, early breast cancer whose tumors were sent to Oncotype DX analysis between 2005 and 2012. Data on prior exposures to OCT, HRT, and fertility treatments were collected. The impact of these exposures on prespecified histopathological features was assessed including tumor size, nodal status, intensity of the hormonal receptors, grade, Oncotype recurrence score, Ki67, and lymphovascular and perineural invasion. The impact of these exposures on disease-free survival (DFS) and overall survival (OS) was also evaluated. Results: A total of 620 women were included, of which 19% had prior exposure to OCT, 30% to HRT, and 11% to fertility treatments. OCT use was associated with smaller (≤1 cm) tumors (p = 0.023) and were less likely to have grade 3 disease (p = 0.049). No other associations were found between exogenous estrogen exposure and tumor characteristics. Median follow-up was 10.4 years. Ten-year DFS was 85.7%, and it was not influenced by exogenous exposure. Ten-year OS was 90.2%, and OCT was associated with improved OS in univariate analysis (HR = 0.31, 95% CI: 0.11–0.85), but this difference did not remain significant in multivariate analysis (p = 0.275). Conclusion: The impact of exogenous estrogen exposure on ER-positive, HER2-negative early breast cancer characteristics is limited. In the long term, none of the evaluated exposures had negative effect on DFS and OS.

More than 50% of individuals who enter treatment for posttraumatic stress disorder (PTSD) are prescribed a psychotropic medication. To date, however, data are limited regarding the prevalence and determinants of discontinuation of psychotropic medication in this population. To address this gap, we analyzed data from 154,953 veterans newly diagnosed with PTSD who were seeking VA treatment and followed them for one year to identify the prevalence and determinants of medication discontinuation. A hazard analysis was conducted to identify factors associated with discontinuation of antidepressant, anxiolytic/hypnotic and antipsychotic medications. Binomial regressions examined the role of these factors in early discontinuation (within 30 days). Results revealed that 71.8% of veterans discontinued medication treatment within 180 days, and 34.6% within 30 days. The strongest risk factors associated with discontinuing medication were no engagement in adjunctive psychotherapy and prescription of a single medication. Older veterans were less likely than younger veterans to discontinue treatment. Similar risk factors were associated with medication discontinuation in the first 30 days. These results suggest that psychiatric comorbidities, age, and race are key risk factors for poor medication adherence, and underscore the importance of early intervention and patient education in promoting adherence to pharmacotherapy for PTSD.

Introduction: Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. Methods: All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, t tests, and χ2 tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. Results: Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01–2.06], p = 0.011, and HR 1.5 [1.08–2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61–1.93], p = 0.79, and HR 1.29 [0.69–2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. Conclusion: Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

Prior vaginal delivery (VD), including vaginal birth after cesarean (VBAC), is one of the greatest predictors of successful trial of labor after cesarean (TOLAC) and uterine rupture. We aimed to evaluate VBAC and uterine rupture rates associated with TOLAC in women with VD prior to cesarean delivery (CD) or with prior VBAC, and the cumulative effect of the number of prior VD's.This retrospective study included women having TOLAC between 2005-2019. The study compared the caesarean and uterine rupture rates of TOLAC in women with only prior VD as compared to women with only prior VBAC. Comparison analysis was performed by univariate analysis and followed by adjusted multiple logistic regression models. Receiver operating characteristic (ROC) and decision tree analyses (chi-square automatic interaction detection algorithm) was conducted to evaluate the influence of the number of prior VD's on the likelihood of successful TOLAC.Overall, 9,038 women met the inclusion criteria. Women with prior VBAC and prior VD showed significantly higher rates of successful VBAC compared to those with no prior VD or prior VBAC (96 % and 86 % vs 76 %; p0.01). However, women with prior VBAC but not women with prior VD showed significantly lower rates of uterine rupture compare to women with no prior VD or VBAC (0.1 % vs 0.6 % and 0.6 %; p0.01). The prevented fraction of TOLAC success was significantly higher in women with prior VBAC than that of women with VD prior to CD (83 % vs. 42 %, p0.01). ROC curve showed that the number of prior VBACs was a better predictor of TOLAC success and uterine rupture than the number of prior VD's. However, each single variable was found to have low positive predictive value (PPV) and requires other variables to improve the prediction. Finally, decision tree analysis demonstrated significant association between TOLAC success rate and prior VBAC, prior VD, and CD indications, without any association with the number of prior deliveries.Prior VBAC has some prediction value for TOLAC success and uterine rupture. However, it has low PPV as a single variable and requires other variables to improve the prediction. The number of prior VDs is not improving prediction.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = −0.111 to −0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.

Dissociative symptoms following trauma exposure, such as derealization (i.e., feeling that one's experience is strange and unreal) and depersonalization (i.e., feeling detached from oneself) have been implicated in the development and maintenance of posttraumatic stress disorder (PTSD). In the current study, we analyzed data from a 3-year prospective cohort study of a nationally representative sample of U.S. veterans to examine whether trait dissociative symptoms, which may impair adaptive emotion regulation following trauma exposure, predict risk for the development of PTSD in trauma-exposed veterans. Results revealed that derealization symptoms predicted a nearly 5-fold increase in relative risk of incident PTSD (relative risk ratio = 4.57, 95% confidence interval = 1.55–13.52), even after adjusting for relevant sociodemographic and trauma-related factors, and severity of PTSD symptoms at baseline. To our knowledge, this study is the first to suggest that trait dissociative symptoms—specifically derealization—may be an important population-based risk factor for the development of PTSD in trauma-exposed U.S. military veterans. These findings add to a body of literature on the prediction of PTSD that largely focuses on stable or immutable risk factors such as sociodemographic and trauma characteristics, or peritraumatic emotional reactions, and underscores the potential clinical utility of assessing, monitoring, and treating derealization symptoms in trauma-exposed U.S. military veterans at risk for PTSD.

BackgroundRheumatoid arthritis (RA) patients have increased risk for cardiovascular disease (CVD). Accurate CVD risk prediction could improve care for RA patients. Our goal is to develop and validate a biomarker-based model for predicting CVD risk in RA patients.MethodsMedicare claims data were linked to multi-biomarker disease activity (MBDA) test results to create an RA patient cohort with age ≥ 40 years that was split 2:1 for training and internal validation. Clinical and RA-related variables, MBDA score, and its 12 biomarkers were evaluated as predictors of a composite CVD outcome: myocardial infarction (MI), stroke, or fatal CVD within 3 years. Model building used Cox proportional hazard regression with backward elimination. The final MBDA-based CVD risk score was internally validated and compared to four clinical CVD risk prediction models.Results30,751 RA patients (904 CVD events) were analyzed. Covariates in the final MBDA-based CVD risk score were age, diabetes, hypertension, tobacco use, history of CVD (excluding MI/stroke), MBDA score, leptin, MMP-3 and TNF-R1. In internal validation, the MBDA-based CVD risk score was a strong predictor of 3-year risk for a CVD event, with hazard ratio (95% CI) of 2.89 (2.46–3.41). The predicted 3-year CVD risk was low for 9.4% of patients, borderline for 10.2%, intermediate for 52.2%, and high for 28.2%.Model fit was good, with mean predicted versus observed 3-year CVD risks of 4.5% versus 4.4%. The MBDA-based CVD risk score significantly improved risk discrimination by the likelihood ratio test, compared to four clinical models. The risk score also improved prediction, reclassifying 42% of patients versus the simplest clinical model (age + sex), with a net reclassification index (NRI) (95% CI) of 0.19 (0.10–0.27); and 28% of patients versus the most comprehensive clinical model (age + sex + diabetes + hypertension + tobacco use + history of CVD + CRP), with an NRI of 0.07 (0.001–0.13). C-index was 0.715 versus 0.661 to 0.696 for the four clinical models.ConclusionA prognostic score has been developed to predict 3-year CVD risk for RA patients by using clinical data, three serum biomarkers and the MBDA score. In internal validation, it had good accuracy and outperformed clinical models with and without CRP. The MBDA-based CVD risk prediction score may improve RA patient care by offering a risk stratification tool that incorporates the effect of RA inflammation.

Background and Objectives Emotion is integral to decision-making, and emotion regulation is associated with improved well-being in older age. Persons with dementia are likely to experience impairments in emotion regulation processes that can potentially contribute to differential decision-making and well-being outcomes. To promote the development of theoretical models of well-being in dementia, we review the quantitative evidence concerning the associations between emotion regulation and decision-making in dementia. Methods Scoping review. Results Seven studies of persons with dementia met our criteria. In persons with frontotemporal lobar degeneration, emotion regulation processes that precede the emotional experience were associated with decision-making in a moral (but not uncertainty) context. Independent of type of dementia, evidence concerning the associations between emotion regulation processes that occur after emotion is experienced and decision-making was mixed and drew on different methodologies. No studies relating to the associations between decision-making in dementia and several emotion regulation processes and strategies were found. Conclusions In this review, we sought to clarify the concept of everyday decision-making in dementia and map the current state of evidence concerning its associations with emotion regulation. Our findings show that emotion regulation processes are associated with decision-making in dementia, depending on type of decision-making assessment and emotional experience. We outline the gaps in the literature to set a research agenda for promoting our understanding of how emotion regulation processes can shape the various decisions that are made by persons with dementia on a daily basis.

BACKGROUND In recent years, a new framework for analyzing and understanding posttraumatic stress disorder (PTSD) was introduced; the network approach. Up until now, network analysis studies of PTSD were largely conducted on small to medium sample sizes (N

The objective of this study is to evaluate the maternal and neonatal outcomes of parturients attempting trial of labor (TOL) after two previous CD versus those who had an elective third repeat CD. A retrospective computerized database cohort study was conducted at a single tertiary center between 2005 and 2019. Various maternal and neonatal outcomes were compared between parturients attempting TOL after two CD versus parturients opting for elective third repeat CD. TOL after two CD was allowed only for those who met all the criteria of our departments’ protocol. Parturients with identified contraindication to vaginal delivery were excluded from the analysis. A univariate analysis was conducted and was followed by a multivariate analysis. A total of 2719 eligible births following two CD were identified, of which 485 (17.8%) had attempted TOL. Successful vaginal delivery rate following two CDs was 86.2%. Uterine rupture rates were higher among those attempting TOL (0.6% vs 0.1% p = 0.04). However, rates of hysterectomy, re-laparotomy, blood product infusion, and intensive care unit admission did not differ significantly between the groups. Neonatal outcomes following elective repeat CD were less favorable (specifically, neonatal intensive care unit admission and composite adverse neonatal outcome). Nonetheless, when controlling for potential confounders, an independent association between composite adverse neonatal outcome and an elective repeat CD was not demonstrated. In a subgroup analysis, diabetes mellitus and hypertensive disorders of pregnancy were found independently associated with failed TOLAC. When following a strict protocol, TOL after two CD is a reasonable alternative and associated with favorable outcomes.

This study sought to identify risk factors for permanent pacemaker implantation (PPMI) after Transcatheter aortic valve implantation (TAVI) and explain their trends over the last decade. TAVI is performed nowadays for severe aortic stenosis in more patients with lower surgical risk. While most TAVI complications have been reduced, PPMI remains common. In this observational, retrospective cohort analysis, 338 TAVI patients treated between 2008 and 2017 were reviewed. Risk factors were compared between the early (2008–2013) and late years (2014–2017), and a multivariable logistic regression model was used. A decreasing trend in PPMI over time was observed (p for trend = 0.008), as was a lower rate of PPMI in the late period (19.3% vs. 31.7%, p = 0.009). Three variables were identified as independent risk factors for PPMI that also decreased significantly in the late period: valve implantation depth ≥ 8 mm (OR = 4.3, 95% CI 2.3–8.2, p

We analyzed data on 879,029 children born in 1999-2017 from a large Israeli health fund to evaluate time-trends in incidence of autism spectrum disorder (ASD). This included examining possible effects associated with the adaptation of the DSM-5 criteria for ASD, and the implementation of regulatory changes affecting eligibility for ASD-related stipends and services. ASD cases were ascertained based on electronic medical records review, with complete verification of ASD case status. Results indicated a substantial increase in ASD incidence rate (IR) over time that was overall not appreciably affected by the above changes. Cumulative incidence through age 8 rose from 0.46% (boys: 0.73; girls: 0.18) in 2007 to 1.30% (boys: 2.12; girls: 0.45) in 2018. Age-specific analyzes indicated that the largest increase in IR occurred in toddlers and preschool children, with a more modest increase at older age groups. Results suggest that the rise in early diagnosed ASD does not stem from a downward shift in the distribution of ages at first diagnosis, but rather from early detection of cases not previously diagnosed. Findings highlight the need to expand research aimed at identifying exogenous factors that may underlie the rise in incidence, and to evaluate factors that may contribute to late diagnosis of some cases. Autism Res 2020, 13: 1893-1901. © 2020 International Society for Autism Research and Wiley Periodicals LLC LAY SUMMARY: In an analysis of nearly 900,000 Israeli children born in 1999-2017, we found that the incidence of autism spectrum disorder (ASD) increased significantly over time, especially among toddlers and preschool children but also at older age groups. We additionally observed that changes affecting diagnostic criteria for ASD and eligibility for ASD-related services did not appreciably affect these trends. Results highlight the need to continue research aimed at identifying factors causing this increase and reasons contributing to late diagnosis of some cases.

Vibrio cholerae, the causative agent of cholera, is commonly isolated, along with other bacterial species, from chironomid insects (Diptera: Chironomidae). Nevertheless, its prevalence in the chironomid egg masses' microbiota is less than 0.5%. V. cholerae secretes haemagglutinin/protease (HAP) that degrades the gelatinous matrix of chironomid egg masses and prevents hatching. Quorum sensing (QS) activates HAP production in response to accumulation of bacterial autoinducers (AIs). Our aim was to define the impact of chironomid microbiota on HAP production by V. cholerae. To study QS signaling, we used V. cholerae bioluminescence reporter strains (QS-proficient O1 El-Tor wild-type and QS-deficient mutants) and different bacterial species that we isolated from chironomid egg masses. These egg mass isolates, as well as a synthetic AI-2, caused an enhancement in lux expression by a V. cholerae QS-deficient mutant. The addition of the egg mass bacterial isolate supernatant to the QS-deficient mutant also enhanced HAP production and egg mass degradation activities. Moreover, the V. cholerae wild-type strain was able to proliferate using egg masses as their sole carbon source, while the QS-deficient was not. The results demonstrate that members of the chironomid bacterial consortium produce external chemical cues that, like AI-2, induce expression of the hapA gene in V. cholerae. Understanding the interactions between V. cholerae and the insects' microbiota may help uncover the interactions between this pathogen and the human gut microbiota.

The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006–2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan–Meier survival curves with log-rank test were used for statistical analyses. Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

In advanced nonsmall cell lung cancer (aNSCLC), stopping nivolumab after 12 months negatively affects outcomes. We performed a world data-based analysis assessing the value of nivolumab continuation and optimal dosing beyond 24 months. Out of 697 consecutive patients with aNSCLC in whom nivolumab was initiated between 2015 and 2018, 45 patients receiving nivolumab for ≥24 months were selected. These were divided into Groups A: nivolumab administered at a dose 3 mg/kg q2 weeks/240 mg q2 weeks/480 mg q4 weeks, n = 25; B: nivolumab re-scheduled to a nonstandard dose 3 mg/kg q3 weeks-q8 weeks, n = 13; C: nivolumab stopped after 24 months, n = 7; (in Groups B and C-for reasons other than progressive disease or intolerable toxicity). Progression-free survival (PFS) (Revised Response Evaluation Criteria in Solid Tumors, version 1.1) and safety (Common Terminology Criteria for Adverse Events, version 4.03) were assessed. With median follow-up of 35.6 months (interquartile range 28.4-41.8), 4%, 31%, 29% and 30% of patients progressed in Groups A, B, C and B+C, respectively. PFS at 36 months since nivolumab initiation comprised 100%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. PFS at 40 months since nivolumab initiation comprised 83%, 67%, 67% and 67%, in Groups A, B, C and B+C, respectively. Allocation to Group A vs Group B, C and B+C was associated with hazard ratio for PFS-0.20 (95% confidence interval [CI], 0.02-1.77, P-.15), 0.20 (95% CI, 0.02-2.25, P-.19) and 0.20 (95% CI, 0.02-1.66, P-.14), respectively. No differences in newly occurring or worsening adverse events between the groups were observed. A trend for worse PFS was observed with alternative nivolumab scheduling or quitting 24 months after initiation. Continuing nivolumab at a standard dose until disease progression or intolerable toxicity remains the standard treatment option.

The aim of this study was to investigate the association of clinical, laboratory, and ultrasound findings with the surgical diagnosis of adnexal torsion in a retrospective cohort of women operated for suspected torsion during pregnancy. A multicenter retrospective study of pregnant women who underwent urgent laparoscopy for suspected adnexal torsion during 2004-2019 in three tertiary medical centers. Adnexal torsion was found in 143/208 (68.8 %) cases. Women with adnexal torsion had lower parity and lower rates of previous cesarean section, but higher rates of fertility treatments and multiple gestations, and were more likely to report right lower abdominal pain, with shorter duration of symptoms ( 24 hrs) and vomiting but not nausea. Women with adnexal torsion were found to have higher rates of sonographic findings suggestive of ovarian edema, while normal-appearing ovaries on ultrasound were more common in women without torsion. A multivariate logistic regression analysis showed that complaints of right abdominal pain were positively associated with adnexal torsion (aOR [95 % CI] 5.03 (1.45-17.49), while previous cesarean delivery and ultrasound findings of normal-appearing ovaries were negatively associated with adnexal torsion (aOR of 0.17 (0.05-0.52) and 0.10 (0.02-0.43), respectively). Clinical characteristics and ultrasound findings may be incorporated into the emergency room workup of pregnant women with suspected adnexal torsion.ZIEL: Ziel dieser Studie war es, den Zusammenhang zwischen klinischen, Labor- und Ultraschallbefunden und der chirurgischen Diagnose der Adnextorsion in einer retrospektiven Kohorte von Frauen zu untersuchen, die während der Schwangerschaft wegen Verdachts auf Torsion operiert wurden. Eine multizentrische retrospektive Studie an schwangeren Frauen, bei denen zwischen 2004 und 2019 in drei tertiären medizinischen Zentren eine Notfall-Laparoskopie wegen Verdachts auf Adnextorsion durchgeführt wurde. Adnexale Torsion wurde in 143/208 (68,8 %) Fällen festgestellt. Frauen mit Adnextorsion hatten eine geringere Parität, niedrigere Raten früherer Kaiserschnitte, aber höhere Raten von Kinderwunschbehandlungen und Mehrlingsschwangerschaften und berichteten häufiger über Schmerzen im rechten Unterleib mit kürzerer Symptomdauer ( 24 Sunden) und über Erbrechen, jedoch nicht über Übelkeit. Frauen mit adnexaler Torsion hatten eine höhere Rate sonografischer Befunde mit Verdacht auf Ovarialödem, während bei Frauen ohne Torsion die Eierstöcke im Ultraschall häufiger normal erscheinen. Eine multivariate logistische Regressionsanalyse zeigte eine positive Assoziation zwischen Beschwerden über Schmerzen im rechten Bauchraum und Adnextorsion (aOR [95 % CI] 5,03 (1,45–17,49), während es eine negative Assoziation zwischen früheren Kaiserschnittgeburten, im Ultraschall normal erscheinenden Eierstöcken und Adnextorsion gab (aOR von 0,17 (0,05–0,52) bzw. 0,10 (0,02–0,43)). Klinische Charakteristika und Ultraschallbefunde können in die Abklärung bei der Notaufnahme von Schwangeren mit Verdacht auf Adnextorsion einbezogen werden.

Over the past years, the prevalence of various risk factors for small for gestational age (SGA) neonates has changed. Little is known if there was also a change in the specific contribution of these risk factors to the prevalence of SGA. We aim to identify trends in the specific contribution of various risk factors for SGA by observing their odds ratios (ORs) throughout different time periods. A nested case–control study was conducted. The ORs for selected known risk factors for SGA occurring in three consecutive 8-year intervals between 1988 and 2014 (T1 – 1988–1996; T2 – 1997–2005; T3 – 2006–2014) were compared. Data were retrieved from the medical centre’s computerized perinatal database. Multivariable logistic regression models were constructed and ORs were compared to identify the specific contribution of independent risk factors for SGA along the study period. During the study period, 285,992 pregnancies met the study's inclusion criteria, of which 15,013 (5.25%) were SGA. Between 1988 and 2014, the incidence of SGA increased from 2.6% in 1988 to 2.9% in 2014. Using logistic regression models, nulliparity, maternal age, gestational age, hypertensive disorders of pregnancy, oligohydramnios and pre-gestational diabetes mellitus were found to be independently associated with SGA. While the adjusted ORs (aOR) of hypertensive disorders of pregnancy and pre-gestational diabetes mellitus had increased, aORs for nulliparity, maternal age and gestational age had remained stable over time. Oligohydramnios had demonstrated a mixed trend of change over the time. In our study, the specific contribution of factors associated with SGA had changed over time. Having a better understating of the changes in the specific contribution of different risk factors for SGA may enable obstetricians to provide consultations.

While student attrition constitutes a major institutional concern at the undergraduate level, this topic is overlooked at the master’s level. Dropout rates have been documented, but no solid predic...

Many countries are currently in a state of lockdown due to the SARS-CoV-2 pandemic. One key requirement to safely transition out of lockdown is the continuous testing of the population to identify infected subjects. Currently, detection is performed at points of care using quantitative reverse-transcription PCR, thus requiring dedicated professionals and equipment. Here, we developed a protocol based on reverse transcribed loop-mediated isothermal amplification for the detection of SARS-CoV-2. This protocol is applied directly to SARS-CoV-2 nose and throat swabs, with no RNA purification step required. We tested this protocol on over 180 suspected patients, and compared the results to those obtained using the standard method. We further succeeded in applying the protocol to self-collected saliva samples from confirmed cases. Since the proposed protocol can detect SARS-CoV-2 from saliva and provides on-the-spot results, it allows simple and continuous surveillance of the community. Impact statement Humanity is currently experiencing a global pandemic with devastating implications on human health and the economy. Most countries are gradually exiting their lockdown state. We are currently lacking rapid and simple viral detections, especially methods that can be performed in the household. Here, we applied RT-LAMP directly on human clinical swabs and self-collected saliva samples. We adjusted the method to allow simple and rapid viral detection, with no RNA purification steps. By testing our method on over 180 human samples, we determined its sensitivity, and by applying it to other viruses, we determined its specificity. We believe this method has a promising potential to be applied world-wide as a simple and cheap surveillance test for SARS-CoV-2.