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OBJECTIVE The primary aims of this study were to identify latent profiles of acute stress disorder (ASD) symptoms and to evaluate postconcussive symptom differences across the identified profiles as measured by the Acute Stress Disorder Scale and the Military Acute Concussion Evaluation, respectively. METHOD Participants (N = 315) in the current study were predominantly active-duty (75.0%), enlisted (97.8%) males (97.4%) serving in the U.S. Army (87.8%). Approximately, half of the sample reported being married or engaged (51.1%) and was on average 25.94 (SD = 6.31) years old. Participants were referred to the Air Force Theater Hospital, 332nd Air Expeditionary Wing, Joint Base Balad, Iraq, to be evaluated as part of routine clinical assessment for neurocognitive and psychological symptoms following exposure to a blast. RESULTS A 3-profile solution was identified as the most parsimonious and best-fitting model based on statistical model fit indices. Blast injured service members in Profile 3 had greater ASD total and subscale severity compared to the other 2 subgroups, with effect size estimates largely differing by hyperarousal and reexperiencing symptoms. Furthermore, Profiles 2 and 3 were more likely to demonstrate postconcussive symptoms compared to Profile 1. CONCLUSIONS Findings provide novel information on heterogenous ASD symptom profiles during the acute phase following a blast injury and highlight the relationship between psychological and physical symptoms. Classification of blast-injured service members may help identify at-risk individuals who would benefit from further clinical care and mitigate long-term psychological and neurocognitive issues. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Over the last decade the manner in which gender dysphoria is defined has changed significantly, as have the presentations of transgender clients to specialist gender services. While the use of patient-reported outcome measures (PROMs) to assess gender dysphoria is widespread, there is a lack of literature that assesses the methodological quality of these measures. To address the limits of the existing literature, the aim of the current study was to conduct a systematic review of PROMs that assess gender dysphoria. The systematic review was performed in accordance with the PRISMA and COSMIN methodologies. Five measurement studies met inclusion criteria. Results suggested that none of the measures could be recommended for use without further development. Poor content validity was evident across all measures and internal validity and construct validity were mixed, ranging from ‘inadequate’ to ‘very good’. Measures that show promise for the future include the Gender Congruence and Life Satisfaction Scale, Gender Identity Reflection and Rumination Scale, Gender Pre-occupation and Stability Questionnaire, and Transgender Adaptation and Integration Measure. A need to develop reliable and valid measures that are appropriate for use with adolescent samples experiencing gender dysphoria was also identified.

We examined whether the analgesic effect of alcohol mediates the association between alcohol and deliberate self-harm (DSH) using data from a larger study on alcohol effects (see Berman et al., 2017). Men (n = 106) and women (n = 104) low-risk alcohol drinkers (ages M = 26.00, SD = 6.98) recruited from the community who had no suicide attempt or episode of deliberate self-harm within the past year were randomly assigned to either a placebo drink condition or a drink calibrated to reach approximately .050%, .075%, or .100% blood alcohol concentration. Notable within-condition BAC variability, as well as overlap between conditions, suggested that BAC would be a more accurate indicator of intoxication compared to condition assignment. Pain tolerance was assessed by increasingly intense 1-second shocks delivered via fingertip electrodes. Self-reported pain associated with the pain tolerance index was also examined. A laboratory task of DSH, the Self-Aggression Paradigm (Berman & Walley, 2003), was then completed, with DSH operationalized as the number of self-administered shocks the participant was led to believe were twice the intensity of his or her pain tolerance and could cause “minor tissue damage that would quickly heal.” A negative binomial parallel mediational model for count data revealed that pain tolerance, but not self-report pain, mediated the effect of alcohol on DSH. As such, the current study provides preliminary experimental evidence that the analgesic effect of alcohol is partially responsible for link between alcohol intoxication and deliberate self-harm.

Partial or complete spontaneous regression (SR) of cancer is unusual, particularly in patients with oesophageal cancer. This case report describes a patient with biopsy-proven squamous cell carcinoma of the oesophagus which spontaneously regressed without any treatment. Regression of the primary tumour was confirmed on histological examination of the resected specimen. The process of SR remains an enigma, but potential mechanisms are considered.

Purpose: Living through cancer can have a profound effect on identity. Among those treated for adult-onset cancer, identifying as a cancer survivor is common and has been linked to positive mental ...

Background Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa). Objective To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden. Design, setting, and participants A cross-sectional study of 2391 localized PrCa patients was carried out. Outcome measurements and statistical analysis Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males. Results and limitations AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort. Conclusions DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing. Patient summary In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.

The first coronavirus disease 2019 (COVID-19) pandemic surge harshly impacted the medically underserved populations of the urbanized northeastern United States. Severe acute respiratory syndrome coronavirus 2 virions infect the gastrointestinal (GI) tract, and GI symptoms are common during acute infection.1 Post-COVID syndromes increasingly are recognized as important public health considerations.2 Postinfectious disorders of gut-brain interaction (DGBIs; formerly known as functional gastrointestinal disorders) can occur after enteric illness; the COVID-19 pandemic is anticipated to provoke DGBI development3 within a rapidly evolving post-COVID framework of illness. Here, we evaluate factors associated with DGBI-like post-COVID gastrointestinal disorders (PCGIDs) in our hospital's surrounding communities comprised predominantly of racial/ethnic minorities and those of reduced socioeconomic status.

BACKGROUND Stroke and diabetes (DM) are significant interrelated healthcare issues but there is a dearth of data on the prevalence of DM among Australia's regional stroke population. AIMS We aimed to determine the prevalence of DM in stroke patients at a large regional centre, including sub-analyses on stroke subtypes, glycaemic control and renal function in ischaemic stroke (IS). METHODS We conducted a retrospective analysis of all patients (n = 323) with IS or transient ischaemic attack (TIA) admitted to Ballarat Base Hospital from January 2015 to December 2016. Demographic data, cardiovascular risk factors, aetiology/territory of IS, pre-morbid DM status, indicators of glycaemic control and renal impairment were recorded. RESULTS DM was present in 28.5% of IS and TIA patients including 4% being newly diagnosed. Among diabetic IS patients, 45.3% had poor glycaemic control (HbA1c ≥7.0%) while 16% had moderate to severe renal impairment (eGFR of

Objective To compare the gut microbiome composition and serum metabolome profile among individuals with spinal cord injury (SCI) and normal glucose tolerance (NGT) or prediabetes/type 2 diabetes (preDM/T2D). Design Cross-sectional design. Setting Research university. Participants A total of 25 adults (N=25) with SCI were included in the analysis and categorized as NGT (n=16) or preDM/T2D (n=9) based on their glucose concentration at minute 120 during a 75-g oral glucose tolerance test. The American Diabetes Association diagnosis guideline was used for grouping participants. Interventions Not applicable. Main Outcome Measures A stool sample was collected and used to assess the gut microbiome composition (alpha and beta diversity, microbial abundance) via the 16s ribosomal RNA sequencing technique. A fasting serum sample was used for liquid chromatography–mass spectrometry–based untargeted metabolomics analysis, the results from which reflect the relative quantity of metabolites detected and identified. Gut microbiome and metabolomics data were analyzed by the Quantitative Insights into Microbial Ecology 2 and Metaboanalyst platforms, respectively. Results Gut microbiome alpha diversity (Pielou's evenness index, Shannon's index) and beta diversity (weighted UniFrac distances) differed between groups. Compared with participants with NGT, participants with preDM/T2D had less evenness in microbial communities. In particular, those with preDM/T2D had a lower abundance of the Clostridiales order and higher abundance of the Akkermansia genus, as well as higher serum levels of gut-derived metabolites, including indoxyl sulfate and phenylacetylglutamine (P Conclusions Our results provide evidence for altered gut microbiome composition and dysregulation of gut-derived metabolites in participants with SCI and preDM/T2D. Both indoxyl sulfate and phenylacetylglutamine have been implicated in the development of cardiovascular diseases in the able-bodied population. These findings may inform future investigations in the field of SCI and cardiometabolic health.

Background : As the COVID-19 pandemic continues, health care systems around the world have changed care delivery in significant ways. Racial and ethnic disparities have emerged for COVID-19 infection rates, morbidity, and mortality. Inequities in care and underutilization of interpretation for patients who use a language other than English (LOE) for care existed prior to this era. We sought to evaluate interpreter use in a pediatric emergency department (ED) as changes associated with COVID-19 were implemented. Methods : ED records were reviewed from December 1, 2019 to July 31, 2020. Patients were classified as having LOE if they preferred a language other than English and consented to interpretation. We used statistical process control to analyze changes in interpreter use over time, relative to the onset of COVID-19–related operational changes. Beginning March 1, 2020, in-person interpreters were no longer available and staff were encouraged to communicate from outside the patient room when possible; this change served as our exposure of interest. Interpreter use for LOE patients, overall and by triage acuity level, was our outcome. Results : A total of 26,787 encounters were included. The weekly mean proportion of encounters that used interpretation for patients with LOE increased from 59% to 73% after the onset of COVID-19; this increase met criteria for special cause variation. Interpretation modality changed to being mostly by phone from previously by video or in-person. Conclusions : Operational changes in the ED related to COVID-19 were associated with increased interpreter use. Possible explanations include lower patient volumes or changes in model of care that encouraged interpreter use by a variety of modalities.

BACKGROUND: Understanding the relationship between patterns of peripheral artery disease patterns and outcomes is an essential step towards improving care and outcomes. We hypothesized that clinician specialty would be associated with occurrence of major adverse vascular events (MAVE). METHODS: Patients with at least 1 peripheral artery disease-related encounter in our health system and fee-for-service Medicare were divided into groups based on the specialty of the clinician (cardiologist, surgeon, podiatrist, primary care, or other) providing a plurality of peripheral artery disease-coded care in the year prior to index encounter. The primary outcome was MAVE (a composite of all-cause mortality, myocardial infarction, stroke, lower extremity revascularization, and lower extremity amputation). RESULTS: The cohort included 1,768 patients, of whom 30.0% were Black, 23.9% were Medicaid dual-enrollment eligible, and 31.1% lived in rural areas. Patients receiving a plurality of their care from podiatrists had the highest 1-year rates of MAVE (34.4%, p

Rationale: Congenital Central Hypoventilation Syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenat...

Objective\ud To determine the characteristics and outcomes of pregnancy in women with Turner Syndrome\ud \ud Design\ud Retrospective 20-year cohort study (2000-2020)\ud \ud Setting\ud 16 tertiary referral maternity units in the UK\ud \ud Population or Sample\ud 81 women with Turner syndrome who became pregnant\ud \ud Methods\ud Retrospective chart analysis\ud \ud Main Outcome Measures\ud Mode of conception, pregnancy outcomes\ud \ud Results\ud We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127 (42.5%)) were by egg donation. Only 9/31 (29%) of pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) with mosaic karyotype 45,X/46,XX (p

AIMS Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P

Introduction TMEM205 is a novel transmembrane protein associated with platinum resistance (PR) in epithelial ovarian carcinoma (OC), however, the specific mechanisms associated with this resistance remain to be elucidated. Methods TMEM205 expression was evaluated in platinum-sensitive (PS) versus platinum resistant (PR) ovarian cancer cell lines and patient serum/tissues. Exosomal efflux of platinum was evaluated with inductively coupled plasma mass spectrometry (ICP-MS) after pre-treatment with small molecule inhibitors (L-2663/L-2797) of TMEM205 prior to treatment with platinum. Cytotoxicity of combination treatment was confirmed in vitro and in an in vivo model. Results TMEM205 expression was 10-20 fold higher in PR compared to PS ovarian cancer cell lines, serum samples, and tissues. Co-localization with CD1B was confirmed by in-situ proximity ligation assay suggesting that TMEM205 may mediate PR via the exosomal pathway. Exosomal secretion was significantly increased 5-10 fold in PR cell lines after treatment with carboplatin compared to PS cell lines. Pre-treatment with L-2663 prior to carboplatin resulted in significantly increased intracellular concentration of fluorescently-labeled cisplatin and decreased exosomal efflux of platinum. Decreased cell survival and tumor growth in vitro and in vivo was observed when PR cells were treated with a combination of L-2663 with carboplatin compared to carboplatin alone. Conclusion TMEM205 appears to be involved in the development of PR in ovarian cancer through the exosomal efflux of platinum agents. This study provides pre-clinical evidence that TMEM205 could serve as a possible biomarker for PR as well as a therapeutic target in combination with platinum agents.

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3–8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291–15 417] vs. 6442 [5156–7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta −0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Background Surgery is regarded as the primary treatment for breast cancer. Chronic post-surgical pain (CPSP) is a recognised complication after breast cancer surgery, and it is estimated to affect 20–30% of women. Pain catastrophizing has emerged as one of the most influential psychological variables associated with CPSP. Methods This trial will be a single-centre, prospective, double-blinded, superiority, randomised controlled trial (RCT). Patients scheduled for elective breast cancer surgery (wide local excision or mastectomy with or without axillary lymph node dissection) will be screened preoperatively for high pain catastrophising. Patients with high pain catastrophising, defined as a score of ≥ 24 on the Pain Catastrophising Scale will be deemed eligible for inclusion in the study. Participants will be randomly assigned to receive either a cognitive behavioural therapy or an educational mindfulness based programme during their perioperative period. The primary outcome is the Brief Pain Inventory short form average pain severity score at 3 months postoperatively. Secondary outcomes include patient-reported quality of recovery at days 1–2 after surgery, levels of pain catastrophising, reported depressed mood and anxiety. Discussion To the best of our knowledge, this protocol describes the first RCT which directly examines the effect of perioperative cognitive behavioural therapy on CPSP among breast cancer patients with high pain catastrophising characteristics. The outcomes of this trial may have significant implications for these patients because perioperative cognitive behavioural therapy has the potential to become an important perioperative intervention to complement patient management. Trial registration ClinicalTrials.govNCT04924010. Registered on 11 June 2021. All item from the World Health Organisation Trial Registration Data set have been included.

Objective To evaluate the quality of YouTube videos depicting distal hypospadias repair. Methods The search terms “distal hypospadias repair” were used to identify surgical videos on YouTube. Videos were sorted by view count and the top 34 videos were reviewed for baseline video characteristics, key surgical steps covered, and conformity to a modified LAParoscopic surgery Video Educational GuidelineS (LAP-VEGaS) checklist. All videos were reviewed and discussed for conformity by 2 attending pediatric urologists and a urology resident. Results Of the 34 videos reviewed, 16 videos were excluded due to content. The median length of videos was 9.94 minutes (range, 2.57-99.12 minutes). Video quality was deemed of high quality in only 39% of videos. The most common type of hypospadias procedures described were tubularized incised plate urethroplasty (n = 13) and meatal advancement and glanuloplasty incorporated (n = 2). The median view count was 7828.5 (range, 1,133-58,619 views). Only 1 video met all modified LAP-VEGaS criteria (range of 33%-100%), and only 2 videos showed every surgical step of distal hypospadias repair (range 33%-100%). Modified LAP-VEGaS score, surgical step score, or quality of the video was not associated with a higher view count. Conclusion Despite being a common procedure, there is a paucity of high-quality videos on YouTube describing distal hypospadias repair techniques. It is unclear how learners select videos for study purposes and the most utilized videos on YouTube are not the most educational videos.

Purpose Infants with short bowel syndrome (SBS) wean from parenteral nutrition (PN) support at variable rates. Small bowel length is a predictor, but the importance of the ileocecal valve (ICV) and colon are unclear. We aim to determine if the ICV and/or colon predict enteral autonomy. Methods Infants from a single intestinal rehabilitation program were retrospectively reviewed. Etiology of SBS, intestinal anatomy, and duration of nutritional support were collected for three years. The primary outcome was time to full enteral nutrition. ANCOVA and Cox proportional hazards model were used, with p Results 55 infants with SBS were included. After accounting for the effect of small bowel, PN duration was shorter for infants with the ICV compared to those without (mean 218 vs. 538 days, p = 0.003), and had a more significant effect on infants with ≤50% of small bowel. Increased small bowel length was a positive predictor of weaning. Patients with ≤50% of colon spent less time on PN with the ICV, compared to without (mean 220 vs 715 days, p = 0.009). Conclusions Preservation of the ICV was associated with shorter duration of PN support, while colon was not. Small bowel length is a positive predictor of enteral autonomy. Level of Evidence Level III retrospective comparative study Type of Study Retrospective review

PurposeTo test effects of positron emission tomography (PET)-based bone marrow-sparing (BMS) image-guided intensity modulated radiation therapy (IG-IMRT) on efficacy and toxicity for patients with locoregionally advanced cervical cancer.Methods and materialsIn an international phase II/III trial, patients with stage IB-IVA cervical carcinoma were treated with either PET-based BMS-IG-IMRT (PET-BMS-IMRT group) or standard image-guided IMRT (IMRT group), with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy. The phase II component nonrandomly assigned patients to PET-BMS-IMRT or standard IMRT. The phase III trial randomized patients to PET-BMS-IMRT versus IMRT, with a primary endpoint of progression-free survival (PFS) but was closed early for futility. Phase III patients were analyzed separately and in combination with phase II patients, comparing acute hematologic toxicity, cisplatin delivery, PFS, overall survival (OS), and patterns of failure. In a post-hoc exploratory analysis, we investigated the association between pretreatment absolute lymphocyte count (ALC) and OS.ResultsIn total, 101 patients were enrolled on the phase II/III trial, including 29 enrolled in phase III (PET-BMS-IMRT group: 16; IMRT group: 13) before early closure. Median follow-up was 33 months for phase III patients and 39 months for all patients. PFS and OS at 5 years for all patients were 73.6% (95% confidence interval [CI], 64.9%-84.3%) and 84% (95% CI, 76%-92.9%]), respectively. There were no differences in number of cisplatin cycles, OS, PFS, or patterns of failure between groups for the combined cohort. The incidence of acute grade ≥ 3 neutropenia was significantly lower in the PET-BMS-IMRT group compared with IMRT for randomized patients (19% vs 54%, χ2P=.048) and in the combined cohort (13% vs 35%, χ2P=.01). Patients with pretreatment ALC ≤ 1.5 k/µL had nonsignificantly worse OS on multivariable analysis (HR 2.85; 95% CI, 0.94-8.62; adjusted P=.216), compared with patients with ALC > 1.5 k/µL. There was no difference in posttreatment ALC by treatment group.ConclusionsPET-BMS-IMRT significantly reduced acute grade ≥3 neutropenia, but not treatment-related lymphopenia, compared with standard IMRT. We found no evidence that PET-BMS-IMRT affected chemotherapy delivery or long-term outcomes, and weak evidence of an association between pretreatment ALC and OS.

Background Prior studies demonstrated reduced risk for venous thromboembolism (VTE) in neurosurgical patients secondary to prophylaxis with both heparin and low-molecular-weight heparin. The ability to monitor low-molecular-weight heparin by obtaining anti–factor Xa (anti-Xa) serum levels provides an opportunity to evaluate safety and efficacy. The aim of this study was to describe characteristics of patients who have anti-Xa levels outside of the goal range (0.2–0.4/0.5 IU/mL) and investigate incidence of major bleeding and VTE. Methods A single-center, retrospective, observational study was conducted on neurosurgical patients receiving enoxaparin for VTE prophylaxis between August 2019 and December 2020. Significance testing was conducted via Fisher exact test and independent samples t test. Results The study included 85 patients. Patients were less likely to have an anti-Xa level in the goal range if they were male, had a higher weight, or were morbidly obese. Three neuroendovascular patients (3.5%) experienced a major bleed. Serum anti-Xa levels were significantly higher in patients who experienced major bleeds compared with patients who did not (0.45 ± 0.16 IU/mL vs. 0.28 ± 0.09 IU/mL, P = 0.003). Patients with a supraprophylactic anti-Xa level (>0.5 IU/mL) were more likely to experience a major bleed (P = 0.005). One VTE event occurred: the patient experienced a pulmonary embolism with anti-Xa level at goal. Conclusions Anti-Xa–guided enoxaparin dosing for VTE prophylaxis in neurosurgical patients may help prevent major bleeding. These data suggest that a higher anti-Xa level may predispose patients to major bleeding. Further evaluation is needed to identify the goal anti-Xa level for VTE prophylaxis in this population.

International audience; Background - Infective endocarditis (IE) is a common and serious complication in patients receiving chronic hemodialysis (HD). Objectives - This study sought to investigate whether there are significant differences in complications, cardiac surgery, relapses, and mortality between IE cases in HD and non-HD patients. Methods - Prospective cohort study (International Collaboration on Endocarditis databases, encompassing 7,715 IE episodes from 2000 to 2006 and from 2008 to 2012). Descriptive analysis of baseline characteristics, epidemiological and etiological features, complications and outcomes, and their comparison between HD and non-HD patients was performed. Risk factors for major embolic events, cardiac surgery, relapses, and in-hospital and 6-month mortality were investigated in HD-patients using multivariable logistic regression. Results - A total of 6,691 patients were included and 553 (8.3%) received HD. North America had a higher HD-IE proportion than the other regions. The predominant microorganism was Staphylococcus aureus (47.8%), followed by enterococci (15.4%). Both in-hospital and 6-month mortality were significantly higher in HD versus non-HD-IE patients (30.4% vs. 17% and 39.8% vs. 20.7%, respectively; p

OBJECTIVE Status epilepticus (SE) is associated with significant mortality, cost, and risk of future seizures. In one of the first studies of SE after neurosurgery, the authors assess the incidence, risk factors, and outcome of postneurosurgical SE (PNSE). METHODS Neurosurgical admissions from the MarketScan Claims and Encounters database (2007 through 2015) were assessed in a longitudinal cross-sectional sample of privately insured patients who underwent qualifying cranial procedures in the US and were older than 18 years of age. The incidence of early (in-hospital) and late (postdischarge readmission) SE and associated mortality was assessed. Procedural, pathological, demographic, and anatomical covariates parameterized multivariable logistic regression and Cox models. Multivariable logistic regression and Cox proportional hazards models were used to study the incidence of early and late PNSE. A risk-stratification simulation was performed, combining individual predictors into singular risk estimates. RESULTS A total of 197,218 admissions (218,217 procedures) were identified. Early PNSE occurred during 637 (0.32%) of 197,218 admissions for cranial neurosurgical procedures. A total of 1045 (0.56%) cases of late PNSE were identified after 187,771 procedure admissions with nonhospice postdischarge follow-up. After correction for comorbidities, craniotomy for trauma, hematoma, or elevated intracranial pressure was associated with increased risk of early PNSE (adjusted OR [aOR] 1.538, 95% CI 1.183–1.999). Craniotomy for meningioma resection was associated with an increased risk of early PNSE compared with resection of metastases and parenchymal primary brain tumors (aOR 2.701, 95% CI 1.388–5.255). Craniotomies for infection or abscess (aHR 1.447, 95% CI 1.016–2.061) and CSF diversion (aHR 1.307, 95% CI 1.076–1.587) were associated with highest risk of late PNSE. Use of continuous electroencephalography in patients with early (p < 0.005) and late (p < 0.001) PNSE rose significantly over the study time period. The simulation regression model predicted that patients at high risk for early PNSE experienced a 1.10% event rate compared with those at low risk (0.07%). Similarly, patients predicted to be at highest risk for late PNSE were significantly more likely to eventually develop late PNSE than those at lowest risk (HR 54.16, 95% CI 24.99–104.80). CONCLUSIONS Occurrence of early and late PNSE was associated with discrete neurosurgical pathologies and increased mortality. These data provide a framework for prospective validation of clinical and perioperative risk factors and indicate patients for heightened diagnostic suspicion of PNSE.

Pandemic preparedness is a key function of any health care facility. Activities pertaining to pandemic preparedness should be developed and maintained within a broader emergency management plan. The use of a Hospital Incident Command System can centralize coordination of the response and facilitate internal and external communication. This review addresses several components of pandemic preparedness, including incident management, health care personnel safety, strategies to support ongoing clinical activities, and organizational communication during a pandemic. Preparations addressing potential ethical challenges and the psychological impact associated with pandemic response are also reviewed.

Reports conflict on how HIV infection influences the clinical course of COVID-19. The New York City (NYC) public hospital system provides care for over 14,000 people with HIV, was central in responding to the COVID-19 pandemic, and is therefore in a unique position to evaluate the intersection of these concurrent infections. Retrospective chart review of patients presenting to NYC Health and Hospitals (NYC H+H) diagnosed with COVID-19 infection from March 1, 2020, through April 28, 2020, compared people living with HIV (PLWH) and a propensity-matched (PM) control group of patients without HIV to evaluate associations between HIV status and COVID-19 outcomes. Two hundred thirty-four PLWH presented for COVID-19 testing and 110 (47%) were diagnosed with COVID-19. Among 17,413 patients with COVID-19 and without HIV, 1:n nearest neighbor propensity score matching identified 194 patients matched on age, sex, race, and any comorbidity. In the sample with COVID-19 (N = 304), PLWH (9.1%) had lower rates of mortality than controls [19.1%; PM odds ratio (PM-OR): 0.41, 95% confidence interval (CI): 0.19-0.86]. Among hospitalized COVID-19 patients (N = 179), HIV infection was associated with lower rates of mechanical ventilation (PM-OR: 0.31, 95% CI: 0.11-0.84) and mortality (PM-OR: 0.40, 95% CI: 0. 17-0.95). In the extended pandemic period through April 2021, aggregate data by HIV status suggested elevated hospitalization and mortality rates in PLWH versus people without HIV. These results suggest that the direct biological impacts of the HIV virus do not negatively influence COVID-19-related outcomes when controlling for comorbidity and demographic variables.

OBJECTIVE To evaluate race and ethnicity differences in cesarean birth and maternal morbidity in low-risk nulliparous people at term. METHODS We conducted a secondary analysis of a randomized trial of expectant management compared with induction of labor in low-risk nulliparous people at term. The primary outcome was cesarean birth. Secondary outcome was maternal morbidity, defined as: transfusion of 4 or more units of red blood cells, any transfusion of other products, postpartum infection, intensive care unit admission, hysterectomy, venous thromboembolism, or maternal death. Multivariable modified Poisson regression was used to evaluate associations between race and ethnicity, cesarean birth, and maternal morbidity. Indication for cesarean birth was assessed using multivariable multinomial logistic regression. A mediation model was used to estimate the portion of maternal morbidity attributable to cesarean birth by race and ethnicity. RESULTS Of 5,759 included participants, 1,158 (20.1%) underwent cesarean birth; 1,404 (24.3%) identified as non-Hispanic Black, 1,670 (29.0%) as Hispanic, and 2,685 (46.6%) as non-Hispanic White. Adjusted models showed increased relative risk of cesarean birth among non-Hispanic Black (adjusted relative risk [aRR] 1.21, 95% CI 1.03-1.42) and Hispanic (aRR 1.26, 95% CI 1.08-1.46) people compared with non-Hispanic White people. Maternal morbidity affected 132 (2.3%) individuals, and was increased among non-Hispanic Black (aRR 2.05, 95% CI 1.21-3.47) and Hispanic (aRR 1.92, 95% CI 1.17-3.14) people compared with non-Hispanic White people. Cesarean birth accounted for an estimated 15.8% (95% CI 2.1-48.7%) and 16.5% (95% CI 4.0-44.0%) of excess maternal morbidity among non-Hispanic Black and Hispanic people, respectively. CONCLUSION Non-Hispanic Black and Hispanic nulliparous people who are low-risk at term undergo cesarean birth more frequently than low-risk non-Hispanic White nulliparous people. This difference accounts for a modest portion of excess maternal morbidity.

The provision of mental health care for people living in low- and middle-income countries presents a particularly complex problem because of fractured service availability and provision, widespread stigma associated with mental illness, and the economic burden inherent in conventional mental health service delivery. People with serious mental illness in these settings are among the most marginalized in their societies and are at risk of becoming increasingly powerless in the face of top-down, service-oriented systems. Innovative intersectoral approaches that are based on asset development and entrepreneurism and that embrace the power of peer-driven networks hold promise to effect transformative and meaningful change.

The remarkably thin rostrum in the Indian gharial (Gavialis gangeticus) imparts challenges to nasal physiology. Competition for space in the slim jaws necessitates a thin nasal septum, leaving this taxon susceptible to nasal passage abnormalities such as septal deviation. Here we describe the nasal anatomy of gharials based on multiple individuals including one that showcases an extreme instance of nasal septum deviation. We found that gharials have both confluent nostrils and choanae, which may be important for their unique nasal acoustics. The deviated nasal septum in the female showed distinct waviness that affected the nasal passages by alternately compressing them. We performed a computational fluid dynamic analysis on the nasal passages to visualize the effects of septal deviation on airflow. Our analysis found the deviated septum increased nasal resistance and wall shear stress during respiration, resulting in unequal distribution of the air field between both sides of the nasal passage. Our findings indicate that gharials-and potentially other longirostrine crocodylians-may be particularly susceptible to septal deviations. Lastly, we observed pterygoid bullae to be present in both sexes, though their morphology differed. Airflow in the male pterygoid bullae produced a Bernoulli effect which may be responsible for the unique "pop" sounds recorded in this species.

Key Points During severe anemia with malaria, children with SCA have decreased parasite burden and inflammation but more endothelial dysregulation.In children with SCA, host response to malaria with severe anemia may reduce acute disease severity but increase long-term sequelae risk., Visual Abstract, Plasmodium falciparum malaria causes morbidity and mortality in African children with sickle cell anemia (SCA), but comparisons of host responses to P falciparum between children with SCA (homozygous sickle cell disease/hemoglobin SS [HbSS]) and normal hemoglobin genotype/hemoglobin AA (HbAA) are limited. We assessed parasite biomass and plasma markers of inflammation and endothelial activation in children with HbAA (n = 208) or HbSS (n = 22) who presented with severe anemia and P falciparum parasitemia to Mulago Hospital in Kampala, Uganda. Genotyping was performed at study completion. No child had known SCA at enrollment. Children with HbSS did not differ from children with HbAA in peripheral parasite density, but had significantly lower sequestered parasite biomass. Children with HbSS had greater leukocytosis but significantly lower concentrations of several plasma inflammatory cytokines, including tumor necrosis factor α (TNF-α). In contrast, children with HbSS had threefold greater concentrations of angiopoietin-2 (Angpt-2), a marker of endothelial dysregulation associated with mortality in severe malaria. Lower TNF-α concentrations were associated with increased risk of postdischarge mortality or readmission, whereas higher Angpt-2 concentrations were associated with increased risk of recurrent clinical malaria. Children with SCA have decreased parasite sequestration and inflammation but increased endothelial dysregulation during severe anemia with P falciparum parasitemia, which may ameliorate acute infectious complications but predispose to harmful long-term sequelae.

Objective Prospective evaluation of 2 clinical-molecular models in patients with unknown pathology who underwent endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for a cystic lesion of the pancreas. Summary of background data Preoperative prediction of histologic subtype (mucinous vs nonmucinous) and grade of dysplasia in patients with pancreatic cystic neoplasms is challenging. Our group has previously published 2 clinical-molecular nomograms for intraductal papillary mucinous neoplasms (IPMN) that incorporated both clinical/radiographic features and cyst fluid protein markers (sFASL, CA72-4, MMP9, IL-4). Methods This multiinstitutional study enrolled patients who underwent EUS-FNA for a cystic lesion of the pancreas. Treatment recommendations regarding resection were based on standard clinical, radiographic, and endoscopic features. Predicted probabilities of high-risk IPMN (high-grade dysplasia/invasive cancer) were calculated using the previously developed clinical-molecular nomograms. Results Cyst fluid was obtained from 100 patients who underwent diagnostic EUS-FNA. Within this group there were 35 patients who underwent resection, and 65 were monitored radiographically. Within the group that underwent resection, 26 had low-risk IPMN or benign non-IPMN lesions, and 9 had high-risk IPMN. Within the surveillance group, no patient progressed to resection or developed cancer after a median follow-up of 12 months (range: 0.5-38). Using the clinical/radiographic nomogram alone, 2 out of 9 patients with high-risk IPMN had a predicted probability >0.5. In the clinical-molecular models, 6 of 9 patients in model 1, and 6 of 9 in model 2, had scores >0.5. Conclusions This prospective study of patients with unknown cyst pathology further demonstrates the importance of cyst fluid protein analysis in the preoperative identification of patients with high-risk IPMN. Longer follow-up is necessary to determine if this model will be useful in clinical practice.

Purpose: Following updates to the Infectious Diseases Society of America (IDSA) practice guidelines for the Diagnosis and Treatment of Adults with Community-acquired Pneumonia in 2019, Hartford HealthCare implemented changes to the community acquired pneumonia (CAP) order-set in August 2020 to reflect criteria for the prescribing of broad-spectrum antimicrobial therapy. The objective of the study was to evaluate changes in broad-spectrum antibiotic days of therapy (DOT) following these order-set updates with accompanying provider education. Methods: This was a multi-center, quasi-experimental, retrospective study of patients with a diagnosis of CAP from September 1, 2019 to October 31, 2019 (pre-intervention) and September 1, 2020 to October 31, 2020 (post-intervention). Patients were identified using ICD-10 codes (A48.1, J10.00-J18.9) indicating lower respiratory tract infection. Data collected included demographics, labs and vitals, radiographic, microbiological, and antibiotic data. The primary outcome was change in broad-spectrum antibiotic DOT, specifically anti-pseudomonal β-lactams and anti-MRSA antibiotics. Secondary outcomes included guideline-concordance of initial antibiotics, utilization of an order-set to prescribe antibiotics, and length of stay (LOS). Results: A total of 331 and 352 patients were included in the pre- and post-intervention cohorts, respectively. There were no differences in order-set usage (10% vs 11.3%, P = .642) between the pre- and post-intervention cohort, respectively. The overall duration of broad-spectrum therapy was a median of 2 days (IQR 0-8 days) in the pre-intervention period and 0 days (IQR 0-4 days) in the post-intervention period ( P

Purpose Prostate cancer is the second most common cancer in men and a leading cause of cancer mortality worldwide. Men with drug use disorders (DUD) may potentially be at high risk for prostate cancer mortality because of delayed diagnosis and/or undertreatment. In this study, we aimed to investigate prostate cancer incidence, mortality, and stage at time of diagnosis among men with DUD compared to the general male population in Sweden. Methods We performed a follow-up study based on Swedish national register data for the period January 1997–December 2016. The study was based on 1,361,532 men aged 50–75 years at inclusion, of whom 9,259 were registered with DUD. Cox regression analysis was used to compute adjusted hazard ratios (HRs) for incident and fatal prostate cancer, and cancer stage at time of diagnosis, associated with DUD. Results DUD was associated with a slightly increased risk of incident prostate cancer (HR: 1.07, 95% confidence interval [CI] 1.00–1.14, p = 0.048) and substantially higher risk of fatal prostate cancer (HR: 1.59, 95% CI 1.40–1.82, p Conclusions Men with DUD have an increased risk of fatal prostate cancer, possibly related to undertreatment in this patient population. Our findings should raise attention among medical staff and decision-makers towards a disadvantaged group of men in need of easily accessible prostate cancer evaluation and treatment.

[Image: see text] The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

Background Patients with single ventricle (SV) congenital heart disease (CHD) undergo several interventions in the first years of life. Advanced diagnostics are required for interstage assessment of anatomy, but are associated with significant diagnostic risk. We sought to evaluate image quality, risk, and accuracy of cardiac computed tomography (CCT) for evaluation of anatomy prior to superior cavopulmonary connection (SCPC) compared to surgical findings across 2 institutions. Methods A retrospective evaluation of image quality, risk, and accuracy of pre-SCPC CCT was performed at 2 institutions between January 1, 2010 and September 30, 2016. Results CCT was performed in 90 SV CHD patients with a median age of 4.03 months (interquartile range [IQR] 3.36, 5.33) prior to SCPC. Image quality was optimal (84%) or good (16%) in all patients, without significant discrepancy compared to surgical findings. 7 patients (8%) required interventional cardiac catheterization subsequent to CCT and before surgical intervention. 49% of scans were performed without sedation, 43% of scans were performed with mild to moderate sedation, and 8% of scans were performed with general anesthesia. The median total procedural dose-length product (DLP) was 18 (IQR 14, 26) mGy*cm, estimating an age adjusted radiation dose of 1.4 millisievert (mSv). One minor (1%) adverse event was reported within 24 h of the CCT. Surgical complications were unrelated to the presurgical findings. Conclusions CCT for pre-SCPC evaluation is safe, with excellent accuracy for anatomy at the time of surgical intervention across 2 institutions. In select patients, noninvasive evaluation with CCT may be indicated.

Circadian disruption increased insulin resistance and decreased mammary development in late gestation, nonlactating (dry) cows. The objective was to measure the effect of circadian disruption on transcriptomes of the liver and mammary gland. At 35 days before expected calving (BEC), multiparous dry cows were assigned to either control (CON) or phase-shifted treatments (PS). CON was exposed to 16-h light and 8-h dark. PS was exposed to 16-h light to 8-h dark, but phase of the light-dark cycle was shifted 6 h every 3 days. On day 21 BEC, liver and mammary were biopsied. RNA was isolated ( n = 6 CON, n = 6 PS per tissue), and libraries were prepared and sequenced using paired-end reads. Reads mapping to bovine genome averaged 27 ± 2 million and aligned to 14,222 protein-coding genes in liver and 15,480 in mammary analysis. In the liver, 834 genes, and in the mammary gland, 862 genes were different (nominal P < 0.05) between PS and CON. In the liver, genes upregulated in PS functioned in cholesterol biosynthesis, endoplasmic reticulum stress, wound healing, and inflammation. Genes downregulated in liver function in cholesterol efflux. In the mammary gland, genes upregulated functioned in mRNA processing and transcription and downregulated genes encoded extracellular matrix proteins and proteases, cathepsins and lysosomal proteases, lipid transporters, and regulated oxidative phosphorylation. Increased cholesterol synthesis and decreased efflux suggest that circadian disruption potentially increases the risk of fatty liver in cows. Decreased remodeling and lipid transport in mammary may decrease milk production capacity during lactation.

OBJECTIVE Medical students often feel inadequately prepared for the responsibilities of surgical internship because of insufficient exposure to resident responsibilities prior to starting residency. This lack of preparation may contribute to burnout and attrition early in residency. Sub-internships should provide these experiences. Significant variation, however, exists in the structure of these rotations. We conducted a targeted needs assessment to inform the development of a didactic curriculum to address gaps in the surgical sub-internship experience and better prepare students for general surgery residency. DESIGN A 25-item needs assessment survey was developed and distributed to senior medical students in their surgical sub-internship, current junior residents, and prior students (alumni) from the past 4 years who matched into general surgery residencies at other institutions. SETTING Geisel School of Medicine at Dartmouth/Dartmouth-Hitchcock Medical Center, a tertiary-care academic medical center. PARTICIPANTS Nine senior medical students; 12 current residents and 14 alumni, including 9 PGY-1, 13 PGY-2, and 4 PGY-3 residents. RESULTS The topics rated most important by medical students were floor management topics, specifically lines, tubes, and drains, hypotension, post-operative fever, chest pain, oliguria, and post-operative pain. In contrast, there was a wider variety of topics rated highly by residents. Residents emphasized non-technical communication and documentation skills. Residents at every training level rated presenting patients on rounds as the most important skill for incoming interns to acquire, whereas only one-third of medical students considered this to be an essential topic. CONCLUSIONS Medical students rank management of common clinical problems as the most critical aspect in their preparation for residency. Residents recognized these topics as important, but also placed high emphasis on non-technical communication and documentation skills. The findings from this need's assessment can be used to guide content structure for a sub-intern curriculum.

There are concerns that simultaneous pancreas-kidney (SPK) transplants from donation after circulatory death (DCD) donors have a higher risk of graft failure than those from donation after brain death (DBD) donors. A UK registry analysis of SPK transplants between 2005 and 2018 was performed. Pancreas survivals of those receiving organs from DCD or DBD donors were compared. Multivariable analyses were used to adjust for baseline differences between the two groups and to identify factors associated with pancreas graft loss. A total of 2228 SPK transplants were implanted; 403 (18.1%) were from DCD donors. DCD donors were generally younger, slimmer, less likely to have stroke as a cause of death, with lower terminal creatinines and shorter pancreas cold ischemic times than DBD donors. Median (IQR) follow-up was 4.2 (1.6-8.1) years. On univariable analysis, there were no statistically significant differences in 5-year death-censored pancreas graft survival between the two donor types (79.5% versus 80.4%; p = .86). Multivariable analysis showed no statistically significant differences in 5-year pancreas graft loss between transplants from DCD (n = 343) and DBD (n = 1492) donors (hazard ratio 1.26, 95% CI 0.76-1.23; p = .12). The findings from this study support the increased use of SPK transplants from DCD donors.

Substance use and addiction are prominent global health concerns and are associated with abnormalities in reward sensitivity. Reward sensitivity and approach motivation are supported by a fronto-striatal neural circuit including the orbitofrontal cortex (OFC), ventral striatum (VS), and dorsal striatum (DS). Although research highlights abnormalities in reward neural circuitry among individuals with problematic substance use, questions remain about whether such use arises from excessively high, or excessively low, reward sensitivity. This study examined whether reward-related brain function predicted subsequent substance use course. Participants were 79 right-handed individuals (Mage = 21.52, SD = 2.19 years), who completed a monetary incentive delay (MID) fMRI task, and follow-up measures assessing substance use frequency and impairment. The average duration of the follow-up period was 9.1 months. Regions-of-interest analyses focused on the reward anticipation phase of the MID. Decreased activation in the VS during reward anticipation predicted increased substance use frequency at follow-up. Decreased DS activation during reward anticipation predicted increased substance use frequency at follow-up, but this finding did not pass correction for multiple comparisons. Analyses adjusted for relevant covariates, including baseline substance use and the presence or absence of a lifetime substance use disorder prior to MRI scanning. Results support the reward hyposensitivity theory, suggesting that decreased reward-related brain function is a risk factor for increased substance use. Results have implications for understanding the pathophysiology of problematic substance use and highlight the importance of the fronto-striatal reward circuit in the development and maintenance of addiction. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction Colistin is used to treat severe antibiotic-resistant Gram-negative infections (GNIs). With the rise of antibiotic resistance, colistin has been used increasingly as a ‘last-line’ therapy for multidrug-resistant GNIs. We evaluated the incidence of acute kidney injury (AKI) and mortality among patients receiving colistin or one of the new β-lactam/β-lactamase inhibitors (βL + βLI) (ceftazidime/avibactam, ceftolozane/tazobactam, or meropenem/vaborbactam). Methods This retrospective cohort study used data from the Premier Healthcare Database. The cohort included propensity score-matched adults with an inpatient stay between January 2016 and December 2018. Patients given both colistin and BL + BLI as treatment for ≥ 72 h were excluded. AKI was defined as acute renal failure or dialysis during hospitalization with antibiotic administration. Propensity score matching was used to control for selection bias and confounding. Logistic regression evaluated associations between treatment, AKI, and in-hospital mortality. Results The total number of patients in the matched cohorts were 256 in each. Overall, 23.8% and 13.3% of patients receiving colistin or new βL + βLI agents, respectively, experienced AKI during hospitalization (p = 0.002); odds of AKI for colistin were 3.0 (95% CI 1.71, 5.21). Following propensity score-matching, patients without baseline renal disease experienced AKI during hospitalization to a higher degree in the colistin group compared to the βL + βLI group (17.1% vs. 6.8%); colistin use was associated with 3.7 times higher odds (95% CI 1.84, 7.42) of AKI compared to βL + βLI agents. The odds of mortality in patients on colistin developing AKI were more than three times that of patients receiving a BL + BLI agent who developed AKI. Among patients receiving colistin, incident AKI was associated with 6.1 times higher odds (95% CI 2.53, 14.71) of mortality. Conclusions Patients receiving colistin for GNIs had significantly higher odds of AKI and mortality than those receiving βL + βLI. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00556-x.

Autism Spectrum disorder is one of the commonest and most important neurodevelopmental conditions affecting children today. With an increasing prevalence and an unclear aetiology, it is imperative we find early markers of autism, which may facilitate early identification and intervention. Alterations of gestational cytokine profiles have been reported in mothers of autistic children. Increasing evidence suggests that the intrauterine environment is an important determinant of autism risk. This study aims to examine the mid-gestational serum cytokine profiles of the mothers of autistic children from a well-characterised birth cohort. A nested sub-cohort within a large mother–child birth cohort were identified based on a confirmed multi-disciplinary diagnosis of autism before the age 10 years and neuro-typical matched controls in a 2:1 ratio. IFN-γ, IL-1β, IL-4, IL-6, IL-8, IL-17A, GMCSF and TNFα were measured in archived maternal 20-week serum using MesoScale Diagnostics multiplex technology and validation of our IL-17A measurements was performed using an ultrasensitive assay. From a cohort of 2137 children, 25 had confirmed autism before 10 years and stored maternal serum from mid-gestation. We examined the sera of these 25 cases and 50 matched controls. The sex ratio was 4:1 males to females in each group, and the mean age at diagnosis was 5.09 years (SD 2.13). We found that concentrations of IL-4 were significantly altered between groups. The other analytes did not differ significantly using either multiplex or ultra-sensitive assays. In our well-characterised prospective cohort of autistic children, we confirmed mid-gestational alterations in maternal IL-4 concentrations in autism affected pregnancies versus matched controls. These findings add to promising evidence from animal models and retrospective screening programmes and adds to the knowledge in this field.

Patients with familial arrhythmogenic cardiomyopathy typically present with ventricular arrhythmias or progressive heart failure. This paper characterizes a rare presentation of an underlying genetic cardiomyopathy with clinical manifestations mimicking an acute myocardial infarction in 2 siblings, each with the same mutation in the desmoplakin (DSP) gene. (Level of Difficulty: Advanced.), Central Illustration

Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5+/CD19+ leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis., Some genes that are part of balanced translocations are reported as drivers for tumourigenesis. Here, the authors report a translocation involving MTCP1 in chronic lymphocytic leukemia and show that MTCP1 overexpression leads to the disease in a murine model.

PURPOSE Clinical utility of up-front multigene panel testing (MGPT) is directly related to the frequency of pathogenic variants (PVs) in the population screened and how genetic findings can be used to guide treatment decision making and cancer prevention efforts. The benefit of MGPT for many common malignancies remains to be determined. In this study, we evaluated up-front MGPT in unselected patients with endometrial cancer (EC) to determine the frequency of PVs in cancer susceptibility genes. METHODS Patients with EC were prospectively enrolled at nine Ohio institutions from October 1, 2017, to December 31, 2020. Nine hundred and sixty-one patients with newly diagnosed EC underwent clinical germline MGPT for 47 cancer susceptibility genes. In addition to estimating the prevalence of germline PVs, the number of individuals identified with Lynch syndrome (LS) was compared between MGPT and tumor-based screening. RESULTS Likely pathogenic variants or PVs were identified in 97 of 961 women (10.1%). LS was diagnosed in 29 of 961 patients (3%; 95% CI, 2.1 to 4.3), with PVs in PMS2 most frequent. MGPT revealed nine patients with LS in addition to the 20 identified through routine tumor-based screening. BRCA1 and BRCA2 PVs were found in 1% (10 of 961; 95% CI, 0.6 to 1.9) of patients and that group was significantly enriched for type II ECs. CONCLUSION This prospective, multicenter study revealed potentially actionable germline variants in 10% of unselected women with newly diagnosed EC, supporting the use of up-front MGPT for all EC patients. The discovery that BRCA1 or BRCA2 heterozygotes frequently had type II cancers points to therapeutic opportunities for women with aggressive histologic EC subtypes.

Background The University of Limerick Cancer network (ULCaN) was established in 2019 with funding from the Health Research Institute at the University of Limerick in order to build a network between individuals in academia, primary and secondary care and the general public so that cancer services can be coordinated and more effective. The aim of this paper is to outline our experience of engaging with stakeholders to identify gaps in the cancer journey locally. Methods Four focus group discussions were conducted with patients; their carers; members of the public; and healthcare providers with 2 main aims: 1) to investigate gaps in cancer services; 2) to identify knowledge, attitudes and opportunities available to promote cancer research. The focus groups were audio recorded, transcribed and thematically analysed. Results 15 themes within the topics of cancer care, palliation, communication, clinical trials, diet and exercise and public and patient involvement in research and advocacy were identified. These include directing people to reliable information and navigating misinformation and stigma linked with cancer, promoting awareness of clinical trials and palliative care services and improving communication when multiple healthcare providers are involved. Conclusion The need to make more coherent, efficient and integrated cancer research amongst local stakeholders was evident. Embedding patients and members of the public into ULCaN is an important deliverable for collaborative research.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

The COVID-19 pandemic has increased demand for physicians, leading to widespread redeployment of specialty physicians to care for patients with COVID-19. These redeployments highlight an important question: How do physicians balance competing obligations to their own health, their own patients, and society during a public health crisis? How can physicians, specifically subspecialists, navigate this tension? In this article, we analyse a clinical scenario in which an orthopaedic sports surgeon is redeployed to care for patients with COVID-19. This case raises questions about physicians’ obligations to their own patients compared with society at large, the relative value of specialty physicians during a global pandemic, and the ethical permissibility of compulsory redeployment. Using the orthopaedic surgery specialty as a model, we build a redeployment framework for surgical specialists that is both ethical and equitable. We argue that although orthopaedic surgeons have a moral obligation to participate in physician redeployment schemes, the scope of this obligation is limited and contingent on the following conditions: (1) the number of local COVID-19 cases is high; (2) obligations to their own patients or orthopaedic patients requiring urgent or emergency care have been fulfilled; (3) their value as physicians exceeds their value as specialists because of the pandemic climate; (4) voluntary redeployments are exhausted before compulsory redeployments are implemented; and (5) redeployment would not put the physicians at unreasonable risk of harm.

BACKGROUND Most dogs with primary hypoadrenocorticism (HA) have a mineralocorticoid deficiency, which decreases renal tubular sodium reabsorption and potassium excretion. Limited information is available concerning the clinical value of measuring urine electrolytes to aid in an HA diagnosis. OBJECTIVES We aimed to evaluate the diagnostic utility of urine electrolyte measurements in dogs with HA. METHODS Urine sodium and potassium concentrations were measured in 89 dogs, including 39 dogs with HA and 50 controls with nonadrenal illness. Fractional excretions of sodium (FENa ) and potassium (FEK ) were also calculated. Urine electrolytes and fractional excretion values were compared between the groups. Sensitivities and specificities were determined for various cut-points. RESULTS The median urine sodium to potassium (Na:K) ratio was twofold greater (P 90% sensitivity or specificity provided a corresponding specificity or sensitivity of >50%. When only dogs with abnormal serum or plasma electrolytes were included in the analyses, absolute urine electrolyte concentrations and FENa were not different between study populations (P > .05 for all comparisons), but the FEK was increased (P = .005) and the urine potassium:creatinine ratio was decreased (P