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BACKGROUND: Treatment options for adolescents with obesity are limited. Yet, therapies previously reserved for adults, such as medications and bariatric surgery, are increasingly available to adolescents in tertiary obesity treatment settings. We aimed to identify the factors associated with selecting an advanced obesity treatment (diets, medications, and surgery) beyond lifestyle therapy among adolescents presenting to a tertiary, pediatric weight management program. METHODS: We conducted a secondary analysis of adolescents (N = 220) who participated in a longitudinal, observational case–control study within a pediatric weight management program. The exposures were potential individual and clinical factors, including sociodemographic characteristics and comorbidities. The outcome was treatment selection, dichotomized into lifestyle vs. advanced treatment. We modeled associations between these factors and treatment selection using logistic regression, controlling for confounding variables (age, race/ethnicity, sex, and insurance). RESULTS: The study population included a majority of non-Hispanic Black (50.5%) and Hispanic/Latino (19.5%) adolescents, of whom 25.5% selected advanced treatment. Adolescents were more likely to choose an advanced treatment option if they had a greater BMI [odds ratio (OR) 1.09, 95% confidence interval (95% CI) 1.04–1.15], lived further from the clinic (OR 1.03, 95% CI 1.00–1.05), and had an elevated glycohemoglobin level (OR 2.46, 95% CI 1.24–4.92). CONCLUSIONS: A significant fraction of adolescents seeking obesity treatment in a specialized care setting chose new and emerging obesity treatments, particularly those at high risk of developing diabetes. These findings can inform patient–clinician obesity treatment discussions in specialty care settings. Clinical Trial Registration number: NCT03139877.

We examined whether a policy banning corporal punishment enacted in Kenya in 2010 is associated with changes in Kenyan caregivers’ use of corporal punishment and beliefs in its effectiveness and normativeness, and compared to caregivers in six countries without bans in the same period. Using a longitudinal study with six waves of panel data (2008–2016), mothers ( N = 1086) in Colombia, Italy, Jordan, Kenya, Philippines, Thailand, and United States reported household use of corporal punishment and beliefs about its effectiveness and normativeness. Random intercept models and multi-group piecewise growth curve models indicated that the proportion of corporal punishment behaviors used by the Kenyan caregivers decreased post-ban at a significantly different rate compared to the caregivers in other countries in the same period. Beliefs of effectiveness of corporal punishment were declining among the caregivers in all sites, whereas the Kenyan mothers reported increasing perceptions of normativeness of corporal punishment post-ban, different from the other sites. While other contributing factors cannot be ruled out, our natural experiment suggests that corporal punishment decreased after a national ban, a shift that was not evident in sites without bans in the same period.

Summary: Background: Obesity is associated with suboptimal levels in vitamin D, a nutrient important for bone health and immune function. Seasonal variation in vitamin D may exacerbate this deficiency in persons with obesity, as exposure to ultraviolet B rays in sunlight is necessary for the conversion of vitamin D to its active form in the body. The aim of this study was to determine the relationship between season and vitamin D levels in persons with obesity pursuing bariatric surgery. Materials and Methods: This retrospective cohort study from a single academic medical center investigated adult patients undergoing either primary sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) over a 20-year period. Demographics and serum 25-hydroxyvitamin D3 levels were collected from the first presenting visit to the bariatrics center. Continuous vitamin D3 levels were compared across seasons using a one-way Analysis of Variance (ANOVA). Vitamin D3 categories were examined across seasons using a Chi square test of independence. Results: 1,256 persons pursuing bariatric surgery (SG: N=697, RYGB: N=559) met the inclusion criteria. Baseline vitamin D values were available in 1,071 of the eligible patients. Overall, serum 25-hydroxyvitamin D3 levels showed a significant variation across the seasons of the year (P

Aim: Analyze the impact of nationwide implementation of teledermatological care for psoriasis. Methods: Develop a Markov model that estimates the impact of telehealth technology for treatment of moderate-to-severe psoriasis on health and healthcare expenditures compared with in-person clinical care. Results: Lower medical costs by US$1.5 billion and total social costs of US$4.3 billion over 5 years. Patients save more than 67 million hours in work absenteeism and travel time, valued at US$598 million. Employers save US$1.2 billion over 5 years due to decreased employee absenteeism. Conclusion: National implementation of telehealth for psoriasis care has the potential to substantially reduce both formal healthcare costs and informal costs for families and patients, while maintaining equivalent clinical outcomes as traditional in-person care.

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs. The anticancer HDAC inhibitor AR-42, as its racemate (rac-AR-42), and 36 analogues were investigated for in vitro activity against P. falciparum. Rac-AR-42 and selected compounds were assessed for cytotoxicity against human cells, histone hyperacetylation, human HDAC1 inhibition and oral activity in a murine malaria model. Rac-AR-42 was tested for ex vivo asexual and in vitro exoerythrocytic stage activity against P. berghei murine malaria parasites. Rac-AR-42 and 13 achiral analogues were potent inhibitors of asexual intraerythrocytic stage P. falciparum 3D7 growth in vitro (IC50 5–50 nM), with four of these compounds having >50-fold selectivity for P. falciparum versus human cells (selectivity index 56–118). Rac-AR-42 induced in situ hyperacetylation of P. falciparum histone H4, consistent with PfHDAC(s) inhibition. Furthermore, rac-AR-42 potently inhibited P. berghei infected erythrocyte growth ex vivo (IC50 40 nM) and P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). Oral administration of rac-AR-42 and two achiral analogues inhibited P. berghei growth in mice, with rac-AR-42 (50 mg/kg/day single dose for four days) curing all infections. These findings demonstrate curative properties for HDAC inhibitors in the oral treatment of experimental mouse malaria., Graphical abstract Image 1, Highlights • HDAC inhibitors rac-AR-42 and 13 analogues inhibit P. falciparum growth in vitro. • Rac-AR-42 inhibits P. berghei exoerythrocytic forms in hepatocytes (IC50 1 nM). • Rac-AR-42 causes in situ hyperacetylation of P. falciparum histone H4. • Rac-AR-42 cures P. berghei infected mice with oral dosing.

OBJECTIVES Translingual neurostimulation (TLNS) studies indicate improved outcomes in neurodegenerative disease or spinal cord injury patients. This study was designed to assess the safety and efficacy of TLNS plus targeted physical therapy (PT) in people with a chronic balance deficit after mild-to-moderate traumatic brain injury (mmTBI). MATERIALS AND METHODS This international, multicenter, randomized study enrolled 122 participants with a chronic balance deficit who had undergone PT following an mmTBI and had plateaued in recovery. Randomized participants received PT plus either high-frequency pulse (HFP; n = 59) or low-frequency pulse (LFP; n = 63) TLNS. The primary efficacy and safety endpoints were the proportion of sensory organization test (SOT) responders (SOT composite score improvement of ≥15 points) and fall frequency after five weeks of treatment, respectively. RESULTS The proportion of SOT responders was significant in the HFP + PT (71.2%) and LFP + PT (63.5%) groups compared with baseline (p

OBJECTIVETo evaluate outcomes of dogs with parathyroid carcinoma (PTC) treated by surgical excision and to describe the incidence of postoperative hypocalcemia, degree of hypocalcemia, duration of hospitalization, duration of calcium supplementation, and survival timeANIMALS100 client-owned dogs with PTC admitted to academic, referral veterinary institutions.PROCEDURESIn a retrospective multi-institutional study, medical records of dogs undergoing surgical excision of PTC between 2010 to 2019 were reviewed. Signalment, relevant medical history, clinical signs, clinicopathologic testing, imaging, surgical findings, intraoperative complications, histologic examination, and survival time were recorded.RESULTS100 dogs with PTC were included, and 96 dogs had clinical or incidental hypercalcemia. Common clinical signs included polyuria (44%), polydipsia (43%), hind limb paresis (22%), lethargy (21%), and hyporexia (20%). Cervical ultrasonography detected a parathyroid nodule in 91 of 91 dogs, with a single nodule in 70.3% (64/91), 2 nodules in 25.3% (23/91), and ≥ 3 nodules in 4 (4/91)% of dogs. Hypercalcemia resolved in 89 of 96 dogs within 7 days after surgery. Thirty-four percent of dogs developed hypocalcemia, on the basis of individual analyzer ranges, within 1 week after surgery. One dog had metastatic PTC to the prescapular lymph node, and 3 dogs were euthanized for refractory postoperative hypocalcemia. Estimated 1-, 2-, and 3-year survival rates were 84%, 65%, and 51% respectively, with a median survival time of 2 years.CONCLUSIONS AND CLINICAL RELEVANCEExcision of PTC results in resolution of hypercalcemia and excellent long-term tumor control. Surgical excision of PTC is recommended because of resolution of hypercalcemia and a good long-term prognosis. Future prospective studies and long-term follow-up are needed to further assess primary tumor recurrence, metastasis, and incidence of postoperative hypocalcemia.

Introduction Insulin pump therapy can improve quality of life and glycaemic outcomes for many people with type 1 diabetes (T1D). The multidimensional Steno Tech Survey study aims to investigate why some insulin pump users do not achieve treatment goals. In this article, we present the study design and analyse differences in population characteristics between responders and non-responders. Methods In June 2020, all 1591 insulin pump users (≥ 18 years) in the Capital Region of Denmark were invited to participate in an online questionnaire that evaluated several dimensions of insulin pump self-management and psychosocial health. Demographic, socioeconomic and clinical characteristics, including age, sex and HbA1c, of the cohort were identified via national registries. Predictors of questionnaire response/non-response were explored with logistic regression analysis. Results In the full study population, 58% were female, median age was 42 years and median HbA1c was 58 mmol/mol (7.5%); 30% had HbA1c

In 2003, randomized trials demonstrated potentially improved outcomes when local instead of general anesthesia is used for inguinal hernia repair. Our study aimed to evaluate how the use of local anesthesia for this procedure changed over time following the publication of the trials' level 1 evidence.We used the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database to identify adults who underwent open, unilateral inguinal hernia repair under local or general anesthesia. Our primary outcome was the percentage of cases performed under local anesthesia. We used a time-series design to examine the trend and rate of change of the use of local anesthesia.We included 97,437 veterans, of which 22,333 (22.9%) had hernia surgery under local anesthesia. The median age of veterans receiving local anesthesia remained stable at 64-67 years over time. The use of local anesthesia decreased steadily, from 38.2% at the beginning year to 15.1% in the final year (P 0.0001). The publication of results from randomized trials (in 2003) did not appear to increase the overall use or change the rate of decline in the use of local anesthesia. Overall, we found that the use of local anesthesia decreased by about 1.5% per year.The utilization of local anesthesia for inguinal hernia repair in the VA has steadily declined over the last 20 + years, despite data showing equivalence or superiority to general anesthesia. Future studies should explore barriers to the use of local anesthesia for hernia repair.

Dysfunctional immune activation accumulates during chronic viral infection and contributes to disease pathogenesis. In HIV-1, immune activation is exacerbated by concurrent infection with hepatitis C virus (HCV), accelerating depletion of CD4+ T cells. HIV-1 suppression with antiretroviral therapy (ART) generally reconstitutes CD4+ T cell counts, while also reducing the proportion that is activated. Whether this immune reconstitution also reduces the complexity of the CD4+ T cell population is unknown. We sought to characterize the relationship between activated CD4+ T cell repertoire diversity and immune reconstitution following ART in HIV-1/HCV coinfection. We extracted T cell receptor (TCR) sequences from RNA sequencing data obtained from activated CD4+ T cells of HIV-1/HCV coinfected individuals before and after treatment with ART (clinical trial NCT01285050). There was notable heterogeneity in both the extent of CD4+ T cell reconstitution and in the change in activated CD4+ TCR repertoire diversity following ART. Decreases in activated CD4+ TCR repertoire diversity following ART were predictive of the degree of CD4+ T cell reconstitution. The association of decreased activated CD4+ TCR repertoire diversity and improved CD4+ T cell reconstitution may represent loss of nonspecifically activated TCR clonotypes, and possibly selective expansion of specifically activated CD4+ clones. These results provide insight into the dynamic relationship between activated CD4+ TCR diversity and CD4+ T cell recovery of HIV-1/HCV coinfected individuals after suppression of HIV-1 viremia.

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.

BACKGROUND Abnormal chloride (Cl- ) transport dehydrates airway surface liquid (ASL) in sinonasal epithelium leading to mucus stasis and chronic rhinosinusitis. As an experimental epithelium, rabbit tissue provides an excellent representation of human sinus disease, and the rabbit sinusitis model is both established and well suited for therapeutic interventions in vivo. Our objective in this study was to evaluate whether ivacaftor reverses the consequences of Pseudomonas aeruginosa-induced acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. METHODS Rabbit nasal cavities were assessed for responsiveness to ivacaftor in vivo (by nasal potential difference [NPD] assay). Rabbit nasal epithelial (RNE) cultures were incubated with an ultrafiltrate of P aeruginosa (PAO1 strain) for 4 hours and tested for acquired CFTR dysfunction. Markers of mucociliary function, including airway surface liquid depth (ASL), periciliary liquid depth (PCL), ciliary beat frequency (CBF), and mucociliary transport (MCT), were measured by micro-optical coherence tomography (μOCT) after PAO1 and/or ivacaftor incubation. RESULTS Ivacaftor resulted in a significant mean NPD polarization of 21.8 ± 2.1 mV, which was significantly greater than that seen in the low Cl- control (12.9 ± 1.3; p = 0.01). PAO1 exposure induced a state of acquired CFTR dysfunction in rabbit nasal epithelium as measured by forskolin-stimulated short-circuit current (ISC ) (control, 37.0 ± 1.1 μA/cm2 ; PAO1, 24.4 ± 1.1 μA/cm2 ; p

Background Preoperative education and breathing exercise training by a physiotherapist minimises pulmonary complications after abdominal surgery. Effects on specific clinical outcomes such as antibiotic prescriptions, chest imaging, sputum cultures, oxygen requirements, and diagnostic coding are unknown. Methods This post hoc analysis of prospectively collected data within a double-blinded, multicentre, randomised controlled trial involving 432 participants having major abdominal surgery explored effects of preoperative education and breathing exercise training with a physiotherapist on postoperative antibiotic prescriptions, hypoxemia, sputum cultures, chest imaging, auscultation, leukocytosis, pyrexia, oxygen therapy, and diagnostic coding, compared to a control group who received a booklet alone. All participants received standardised postoperative early ambulation. Outcomes were assessed daily for 14 postoperative days. Analyses were intention-to-treat using adjusted generalised multivariate linear regression. Results Preoperative physiotherapy was associated with fewer antibiotic prescriptions specific for a respiratory infection (RR 0.52; 95% CI 0.31 to 0.85, p = 0.01), less purulent sputum on the third and fourth postoperative days (RR 0.50; 95% CI 0.34 to 0.73, p = 0.01), fewer positive sputum cultures from the third to fifth postoperative day (RR 0.17; 95% CI 0.04 to 0.77, p = 0.01), and less oxygen therapy requirements (RR 0.49; 95% CI 0.31 to 0.78, p = 0.002). Treatment effects were specific to respiratory clinical coding domains. Conclusions Preoperative physiotherapy prevents postoperative pulmonary complications and is associated with the minimisation of signs and symptoms of pulmonary collapse/consolidation and airway infection and specifically results in reduced oxygen therapy requirements and antibiotic prescriptions. Trial registration ANZCTR 12613000664741; 19/06/2013.

Background Coronary artery disease (CAD) is a concerning late outcome for cancer survivors. However, uniform surveillance guidelines are lacking. Aim To harmonise international recommendations for CAD surveillance for survivors of childhood, adolescent and young adult (CAYA) cancers. Methods A systematic literature review was performed and evidence graded using the Grading of Recommendations, Assessment, Development and Evaluation criteria. Eligibility included English language studies, a minimum of 20 off-therapy cancer survivors assessed for CAD, and 75% diagnosed prior to age 35 years. All study designs were included, and a multidisciplinary guideline panel formulated and graded recommendations. Results 32 of 522 identified articles met eligibility criteria. The prevalence of CAD ranged from 0 to 72% and was significantly increased compared to control populations. The risk of CAD was increased among survivors who received radiotherapy exposing the heart, especially at doses ≥15 Gy (moderate-quality evidence). The guideline panel agreed that healthcare providers and CAYA cancer survivors treated with radiotherapy exposing the heart should be counselled about the increased risk for premature CAD. While the evidence is insufficient to support primary screening, monitoring and early management of modifiable cardiovascular risk factors are recommended. Initiation and frequency of surveillance should be based on the intensity of treatment exposures, family history, and presence of co-morbidities but at least by age 40 years and at a minimum of every 5 years. All were strong recommendations. Conclusion These systematically assessed and harmonised recommendations for CAD surveillance will inform care and guide research concerning this critical outcome for CAYA cancer survivors.

BackgroundSchools are the primary setting for the delivery of adolescent HPV vaccination in Australia. Although this strategy has achieved generally high vaccination coverage, gaps persist for reasons that are mostly unknown. This study sought to identify school-level correlates of low vaccination course initiation and completion in New South Wales, Tasmania, and Western Australia to inform initiatives to increase uptake.MethodsInitiation was defined as the number of first doses given in a school in 2016 divided by vaccine-eligible student enrolments. Completion was the number of third doses given in a school in 2015-2016 divided by the number of first doses. Low initiation and completion were defined as coverage ≤ 25thpercentile of all reporting schools. We investigated correlations between covariates using Spearman's rank correlation coefficients. Due to multicollinearity, we used univariable logistic regression to investigate associations between school characteristics and low coverage.ResultsMedian initiation was 84.7% (IQR: 75.0%-90.4%) across 1,286 schools and median completion was 93.8% (IQR: 86.0%-97.3%) across 1,295 schools. There were strong correlations between a number of school characteristics, particularly higher Indigenous student enrolments and lower attendance, increasing remoteness, higher postcode socioeconomic disadvantage, and smaller school size. Characteristics most strongly associated with low initiation in univariate analyses were small school size, location in Tasmania, and schools catering for special educational needs. Low completion was most strongly associated with schools in Tasmania and Western Australia, remote location, small size, high proportion of Indigenous student enrolments, and low attendance rates.ConclusionThis study provides indicative evidence that characteristics of schools and school populations are associated with the likelihood of low initiation and completion of the HPV vaccination course. The findings will guide further research and help target initiatives to improve vaccination uptake in schools with profiles associated with lower coverage.

Background The optimal anesthesia modality for umbilical hernia repair is unclear. We hypothesized that using local rather than general anesthesia would be associated with improved outcomes, especially for frail patients. Methods We utilized the 1998-2018 Veterans Affairs Surgical Quality Improvement Program to identify patients who underwent elective, open umbilical hernia repair under general or local anesthesia. We used the Risk Analysis Index to measure frailty. Outcomes included complications and operative time. Results There were 4958 Veterans (13%) whose hernias were repaired under local anesthesia. Compared to general anesthesia, local was associated with a 12%-24% faster operative time for all patients, and an 86% lower (OR 0.14, 95%CI 0.03-0.72) complication rate for frail patients. Conclusions Local anesthesia may reduce the operative time for all patients and complications for frail patients having umbilical hernia repair.

Aims Acetabular edge-loading was a cause of increased wear rates in metal-on-metal hip arthroplasties, ultimately contributing to their failure. Although such wear patterns have been regularly reported in retrieval analyses, this study aimed to determine their in vivo location and investigate their relationship with acetabular component positioning. Methods 3D CT imaging was combined with a recently validated method of mapping bearing surface wear in retrieved hip implants. The asymmetrical stabilizing fins of Birmingham hip replacements (BHRs) allowed the co-registration of their acetabular wear maps and their computational models, segmented from CT scans. The in vivo location of edge-wear was measured within a standardized coordinate system, defined using the anterior pelvic plane. Results Edge-wear was found predominantly along the superior acetabular edge in all cases, while its median location was 8° (interquartile range (IQR) -59° to 25°) within the anterosuperior quadrant. The deepest point of these scars had a median location of 16° (IQR -58° to 26°), which was statistically comparable to their centres (p = 0.496). Edge-wear was in closer proximity to the superior apex of the cups with greater angles of acetabular inclination, while a greater degree of anteversion influenced a more anteriorly centred scar. Conclusion The anterosuperior location of edge-wear was comparable to the degradation patterns observed in acetabular cartilage, supporting previous findings that hip joint forces are directed anteriorly during a greater portion of walking gait. The further application of this novel method could improve the current definition of optimal and safe acetabular component positioning. Cite this article: Bone Joint Res 2021;10(10):639–649.

Lay abstract This study included 308 patients with early-stage triple-negative breast cancer treated in the USA at community oncology practices. Patients were female, 18 years or older and diagnosed with stage II, IIIA or IIIB breast cancer between March 2008 and March 2016, and the breast cancer was determined to be triple negative (i.e., negative for estrogen receptors, progesterone receptors and excess HER2 protein). There were 236 patients who received neoadjuvant treatment without subsequent adjuvant treatment (the Neo group) and 72 patients who received neoadjuvant treatment followed by adjuvant treatment (the Neo + adj group). The study looked at healthcare resource use and costs of care during two time periods: from neoadjuvant treatment start date to surgery (Time 1) and after surgery to recurrence or death (Time 2). Average monthly healthcare resource use and average monthly costs of care per patient were higher in Time 1 compared with Time 2 for both groups. These results demonstrate the economic and resource burden of early-stage triple-negative breast cancer especially in the time from neoadjuvant treatment initiation until surgery.

Rare, chronic diseases such as hemophilia and other congenital coagulation disorders require coordinated delivery of services for optimal outcomes. Hemophilia Treatment Centers (HTCs) are specialized, multidisciplinary health-care centers providing team-based care to meet the physical, psychosocial, and emotional needs of people with hemophilia (PWH) and may serve as a model for other rare coagulation disorders. Health-care purchasers, as well as the general medical community, may not appreciate the breadth and quality of services provided by HTCs. They exemplify the acculturalization and actualization of integrated care by providing comprehensive diagnostic and treatment services that reduce morbidity, mortality, avoidable emergency room visits, hospitalizations, and overall costs, while promoting a longer lifespan and improved patient functioning and outcomes. This is accomplished by a team-based approach relying upon a shared decision-making model to effectively prevent complications and manage symptoms in PWH, who are dependent on high-cost treatments. This article provides a concise yet comprehensive description of the core components of an HTC and the regional and national networks in the United States, which together achieve their incomparable value for all stakeholders., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/_Nx_76pDKLw

The course of 187 individuals ages 3–21 years with Autistic Disorder was traced through a period of 20 years (enrollment: 1995–1998, follow up: 2014–2019). Specific genetic and environmental causes were identified in only a minority. Intellectual disability coexisted in 84%. Few became independent with 99% living at home with relatives, in disability group homes or in residential facilities. Seven individuals (3.7%) attained postsecondary education, two receiving baccalaureate degrees, two receiving associate degrees, and three receiving certificates from college disability programs. It may be anticipated that the long term outcome for individuals currently diagnosed with Autism Spectrum Disorder (ASD) will be substantially better than for individuals with Autistic Disorder in this cohort.

Background Knowledge about sexual health, difficulty with sexual activity and intimacy (sexual difficulty), in people with hemophilia is little understood. Objectives The objectives were to determine the prevalence of sexual difficulty in people living with hemophilia (PWH) compared to people with no bleeding disorders (PWNoBD), and to determine factors associated with it. Methods This was an analysis of the PROBE study. We recruited individuals who had hemophilia A or B (PWH) and PWNoBD who were 18 years old or older. We calculated proportions of participants with sexual difficulty and odds ratios (ORs) adjusted for sex and age with 95% confidence intervals. Results There were 2007 PWH and 1972 PWNoBD. Mean (standard deviation) age was 41 (15) years in PWH and 42 (13) years in PWNoBD. Sexual difficulty was reported in 302 (15.1%) PWH and 79 (4.0%) PWNoBD. The odds of sexual difficulty were significantly higher in PWH (OR 3.82, 95% CI 2.85, 5.11). Among PWH, older age, experiencing acute or chronic pain in the past 12 months, bleeds within the past two weeks, ≥3 spontaneous joint bleeds (past six months), limitation of range of motion of any joints, and any life- or limb-threatening bleeds in the past 12 months were associated with sexual difficulty. Conclusions Sexual difficulty is more prevalent in people living with hemophilia and associated with markers of disease severity. Sexual health issues should be incorporated in comprehensive hemophilia care, future research, and hemophilia related health policy.

Internationally, increasing numbers of children and adolescents with gender dysphoria are presenting for care. In response, gender-affirming therapeutic interventions that seek to align bodily characteristics with an individual’s gender identity are more commonly being used. Depending on a young person’s circumstances and goals, hormonal interventions may aim to achieve full pubertal suppression, modulation of endogenous pubertal sex hormone effects, and/or development of secondary sex characteristics congruent with their affirmed gender. This is a relatively novel therapeutic area and, although short-term outcomes are encouraging, longer term data from prospective longitudinal adolescent cohorts are still lacking, which may create clinical and ethical decision-making challenges. Here, we review current treatment options, reported outcomes, and clinical challenges in the pharmacological management of trans and gender-diverse adolescents.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, children and families have had to adapt their daily lives. The purpose of this study was to describe changes in the weight-related behaviors of children with obesity after the onset of the COVID-19 pandemic. Methods: Semistructured interviews (n = 51) were conducted from April to June 2020 with parents of children with obesity. Families were participants in a randomized trial testing a clinic-community pediatric obesity treatment model. During interviews, families described their experience during the COVID-19 pandemic, with a particular emphasis on children's diet, physical activity, sleep, and screen time behaviors. Rapid qualitative analysis methods were used to identify themes around changes in children's weight-related behaviors. Results: The mean child age was 9.7 (±2.8) years and the majority of children were Black (46%) or Hispanic (39%) and from low-income families (62%). Most parent participants were mothers (88%). There were differences in the perceived physical activity level of children, with some parents attributing increases in activity or maintenance of activity level to increased outdoor time, whereas others reported a decline due to lack of outdoor time, school, and structured activities. Key dietary changes included increased snacking and more meals prepared and consumed at home. There was a shift in sleep schedules with children going to bed and waking up later and an increase in leisure-based screen time. Parents played a role in promoting activity and managing children's screen time. Conclusions: The COVID-19 pandemic has created unique lifestyle challenges and opportunities for lifestyle modification. Clinical Trials ID: NCT03339440.

Distant recurrence is a devastating occurrence after colorectal cancer resection. This study aimed to identify the risk factors for distant recurrence following surgery. All consecutive colorectal cancer resections with curative intent were included from a prospectively maintained colorectal cancer database. The primary outcome was to identify predictive factors for distant recurrence of colorectal cancer. A total of 670 eligible cases were identified with 88 (13.1%) developing distant recurrence during the follow-up period. The median time to distant recurrence was 1.2 years with the most common sites of distant recurrence being the lung (44.3%) and liver (44.3%). Predictive factors for distant recurrence in colon cancer included a high tumor, nodal, and overall stage of the primary cancer (p

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers, vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

Promoting residential cells, particularly endogenous neural stem and progenitor cells (NSPCs), for tissue regeneration represents a potential strategy for the treatment of spinal cord injury (SCI). However, adult NSPCs differentiate mainly into glial cells and contribute to glial scar formation at the site of injury. Gsx1 is known to regulate the generation of excitatory and inhibitory interneurons during embryonic development of the spinal cord. In this study, we show that lentivirus-mediated expression of Gsx1 increases the number of NSPCs in a mouse model of lateral hemisection SCI during the acute stage. Subsequently, Gsx1 expression increases the generation of glutamatergic and cholinergic interneurons and decreases the generation of GABAergic interneurons in the chronic stage of SCI. Importantly, Gsx1 reduces reactive astrogliosis and glial scar formation, promotes serotonin (5-HT) neuronal activity, and improves the locomotor function of the injured mice. Moreover, RNA sequencing (RNA-seq) analysis reveals that Gsx1-induced transcriptome regulation correlates with NSPC signaling, NSPC activation, neuronal differentiation, and inhibition of astrogliosis and scar formation. Collectively, our study provides molecular insights for Gsx1-mediated functional recovery and identifies the potential of Gsx1 gene therapy for injuries in the spinal cord and possibly other parts of the central nervous system.

Objective: An emerging group of people with type 1 diabetes are building and using their own artificial pancreas systems (APS). Currently, these “user-led,” open-source systems are not endorsed by ...

Background Native allergen extracts or chemically modified allergoids are routinely used to induce allergen tolerance in allergen-specific immunotherapy (AIT), although mechanistic side-by-side studies are rare. It is paramount to balance optimal dose and allergenicity to achieve efficacy warranting safety. AIT safety and efficacy could be addressed by allergen dose reduction and/or use of allergoids and immunostimulatory adjuvants, respectively. In this study, immunological effects of experimental house dust mite (HDM) AIT were investigated applying high-dose HDM extract and low-dose HDM allergoids with and without the adjuvants microcrystalline tyrosine (MCT) and monophosphoryl lipid A (MPL) in a murine model of HDM allergy. Methods Cellular, humoral, and clinical effects of the different AIT strategies were assessed applying a new experimental AIT model of murine allergic asthma based on physiological, adjuvant-free intranasal sensitization followed by subcutaneous AIT. Results While low-dose allergoid and high-dose extract AIT demonstrated comparable potency to suppress allergic airway inflammation and Th2-type cytokine secretion of lung-resident lymphocytes and draining lymph node cells, low-dose allergoid AIT was less effective in inducing a potentially protective IgG1 response. Combining low-dose allergoid AIT with MCT or MCT and dose-adjusted MPL promoted Th1-inducing mechanisms and robust B-cell activation counterbalancing the allergic Th2 immune response. Conclusion Low allergen doses induce cellular and humoral mechanisms counteracting Th2-driven inflammation by using allergoids and dose-adjusted adjuvants. In light of safety and efficacy improvement, future therapeutic approaches may use low-dose allergoid strategies to drive cellular tolerance and adjuvants to modulate humoral responses.

Individuals receiving long-term hemodialysis are at increased risk of developing cardiovascular disease (CVD). Traditional cardiovascular risk factors do not fully explain the high CVD risk in this population. During hemodialysis, blood interacts with the biomaterials of the hemodialysis circuit. This interaction can activate the complement system and the factor XII-driven contact system. FXII activation triggers both the intrinsic pathway of coagulation and the kallikrein-kinin pathway, resulting in thrombin and bradykinin production, respectively. The complement system plays a key role in the innate immune response, but also contributes to the pathogenesis of numerous disease states. Components of the complement pathway, including mannose binding lectin and C3, are associated with CVD risk in people with end-stage kidney disease (ESKD). Both the complement system and the factor XII-driven contact coagulation system mediate proinflammatory and procoagulant responses that could contribute to or accelerate CVD in hemodialysis recipents. This review summarizes what is already known about hemodialysis-mediated activation of the complement system and in particular the coagulation contact system, emphasizing the potential role these systems play in the identification of new biomarkers for CVD risk stratification and the development of potential therapeutic targets or innovative therapies that decrease CVD risk in ESKD patients.

Sepsis is a major cause of mortality among hospitalized patients worldwide. Shorter time to administration of broad‐spectrum antibiotics is associated with improved outcomes, but early recognition of sepsis remains a major challenge. In a two‐center cohort study with prospective sample collection from 1400 adult patients in emergency departments suspected of sepsis, we sought to determine the diagnostic and prognostic capabilities of a machine‐learning algorithm based on clinical data and a set of uncommonly measured biomarkers. Specifically, we demonstrate that a machine‐learning model developed using this dataset outputs a score with not only diagnostic capability but also prognostic power with respect to hospital length of stay (LOS), 30‐day mortality, and 3‐day inpatient re‐admission both in our entire testing cohort and various subpopulations. The area under the receiver operating curve (AUROC) for diagnosis of sepsis was 0.83. Predicted risk scores for patients with septic shock were higher compared with patients with sepsis but without shock (p

We report the case of a 61-year-old man who had presented with acute unilateral limb swelling. Computed tomography venography and duplex ultrasound demonstrated compression of the right common femoral vein by a common femoral vein adventitial cyst. Before intervention, the patient had developed an acute deep vein thrombosis of the right common femoral vein and great saphenous vein. Preoperative magnetic resonance imaging demonstrated concern for synovial connection. After 6 months of anticoagulation therapy, the patient underwent adventitial cyst excision with ligation of the hip joint articular connection. At 4 months postoperatively, the patient was symptom free without cyst recurrence. The findings from the present case support the synovial theory for adventitial cystic disease.

Invasive pneumococcal disease (IPD) is responsible for serious illnesses such as bacteremia, sepsis, meningitis, and pneumonia in young children, older adults, and persons with immunocompromising conditions and often leads to death. Although the most recent pneumococcal conjugate vaccines (PCVs) have been designed to target serotypes identified as the primary causative agents of IPD, the epidemiological landscape continues to change stressing the need to develop new PCVs. We have developed an investigational 24-valent PCV (PCV24) including serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F all conjugated to CRM197 and evaluated this vaccine in adult monkeys. PCV24 was shown to be immunogenic and induced functional antibody for all vaccine serotypes. Of the serotypes common to PCV13 and V114 (PCV15), PCV24 had a similar immunogenic response with the exceptions of 23F which had higher IgG GMCs for PCV13 and V114, and 7F which had higher GMCs for PCV13. Functional antibody responses were similar for the serotypes in common between PCV24, PCV13 and V114 vaccines, with the exception of serotype 7F which was greater for PCV13. Overall, this study shows that PCV24 provided similar immunogenicity as the lower valent vaccines in adult monkeys with no apparent serotype interference. In addition, PCV24 also provided protection against pneumococcal infection in a mouse challenge model.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

MEF2C-related disorders (aka MEF2C-haploinsufficiency) are caused by variations in or involving the MEF2C gene and are characterized by intellectual disability, developmental delay, lack of speech, limited walking, and seizures. Despite these findings, the disorder is not easily recognized clinically. We performed a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assemble the most comprehensive list of patients and their phenotypes. Through searching PubMed, Web of Science, and MEDLINE, 43 articles met the inclusion criteria and were fully reviewed. One hundred and seventeen patients were identified from these publications with most having a phenotype of intellectual disability, developmental delay, seizures, hypotonia, absent speech, inability to walk, stereotypic movements, and MRI abnormalities. Nonclassical findings included one patient with a question mark ear, two patients with a jugular pit, one patient with a unique neuroendocrine finding, and nine patients that did not have MEF2C deletions or disruptions but may be affected due to a positional effect on MEF2C. This systematic review characterizes the phenotype of MEF2C-related disorders, documents the severity of this condition, and will help providers to better diagnose and care for patients and their families. Additionally, this compiled information provides a comprehensive resource for investigators interested in pursuing specific genotype-phenotype correlations.

Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.

BACKGROUND: The demographics of heart failure are changing. The rate of growth of the “older” heart failure population, specifically those ≥ 75, has outpaced that of any other age group. These older patients were underrepresented in the early beta-blocker trials. There are several reasons, including a decreased potential for mortality benefit and increased risk of side effects, why the risk/benefit tradeoff may be different in this population. OBJECTIVE: We aimed to determine the association between receipt of a beta-blocker after heart failure discharge and early mortality and readmission rates among patients with heart failure and reduced ejection fraction (HFrEF), specifically patients aged 75+. DESIGN AND PARTICIPANTS: We used 100% Medicare Parts A and B and a random 40% sample of Part D to create a cohort of beneficiaries with ≥ 1 hospitalization for HFrEF between 2008 and 2016 to run an instrumental variable analysis. MAIN MEASURE: The primary measure was 90-day, all-cause mortality; the secondary measure was 90-day, all-cause readmission. KEY RESULTS: Using the two-stage least squared methodology, among all HFrEF patients, receipt of a beta-blocker within 30-day of discharge was associated with a − 4.35% (95% CI − 6.27 to − 2.42%, p < 0.001) decrease in 90-day mortality and a − 4.66% (95% CI − 7.40 to − 1.91%, p = 0.001) decrease in 90-day readmission rates. Even among patients ≥ 75 years old, receipt of a beta-blocker at discharge was also associated with a significant decrease in 90-day mortality, − 4.78% (95% CI − 7.19 to − 2.40%, p < 0.001) and 90-day readmissions, − 4.67% (95% CI − 7.89 to − 1.45%, p < 0.001). CONCLUSION: Patients aged ≥ 75 years who receive a beta-blocker after HFrEF hospitalization have significantly lower 90-day mortality and readmission rates. The magnitude of benefit does not appear to wane with age. Absent a strong contraindication, all patients with HFrEF should attempt beta-blocker therapy at/after hospital discharge, regardless of age. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06901-7

Geographic variation in fracture risk may be due to divergent profiles of dietary, lifestyle, and other risk factors between populations. We investigated differences in fracture rates between two older-population cohorts: the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk cohort (n = 7732) in the United Kingdom (UK), and the Mr and Ms Os cohort (n = 3956) in Hong Kong (HK). Data were collected by questionnaires, laboratory assessments, and hospital records. Incidence of hip, spine, and wrist fractures in the two cohorts was calculated and multivariable regression was used to explore variables important to fracture risk. Total hip, spine, and wrist fracture incidence was higher in the UK vs HK for women (13.70 vs 8.76 per 1000 person-years; p p = 0.337), and the proportions of different fractures also varied between cohorts (p

Objective To evaluate the feasibility of implementing an integrated multicomponent survivorship care model for men affected by prostate cancer. Methods Using a single arm prospective cohort study design, men with prostate cancer were recruited from two regional public hospitals in Australia for a 6‐months program that provided information and decision support, exercise and nutrition management, specialised clinical support, and practical support through localised and central care coordination. Carers of the men were also invited to the program. Data were collected from multiple sources to evaluate: (1) recruitment capability and participant characteristics; (2) appropriateness and feasibility of delivering the specific intervention components using an electronic care management tool; and (3) suitability of data collection procedures and proposed outcome measures. Results Of the 105 eligible men, 51 (consent rate 49%) participated in the program. Of the 31 carers nominated by the men, 13 consented (consent rate 42%). All carers and 50 (98%) men completed the program. Most (92%) men were newly diagnosed with localised prostate cancer. All men attended initial screening and assessment for supportive care needs; a total of 838 episodes of contact/consultation were made by the intervention team either in person (9%) or remotely (91%). The intervention was implemented as proposed with no adverse events. The proposed outcome measures and evaluation procedures were found to be appropriate. Conclusions Our results support the feasibility of implementing this integrated multicomponent care model for men affected by prostate cancer.

Working with a post-secondary student with intellectual disability, an adapted alternating treatments design was used to compare sight-word acquisition across three computer-delivered learning trial interventions: one with fixed 5-s response intervals, another with fixed 1-s response intervals, and a third with self-determined intervals. Visual analysis of session-series graphs suggest that all three interventions increased sight-word acquisition with the 5-s and self-determined interventions causing more steady and consistent learning per session than the 1-s intervention. Analysis of the time-series graph suggests that the self-determined intervention caused superior learning rates to the other interventions. From an applied perspective, the self-determined intervention is the most appropriate remedial procedure for this student because it resulted in the most rapid learning. Discussion focuses on the value of making relative-effectiveness decisions based on measures of learning as a function of time spent learning (learning speed) versus measures of learning as a function of sessions or trials.

Non-alcoholic fatty liver disease and alcoholic liver disease, the two most prevalent liver diseases worldwide, share a common pathology but have largely been considered disparate diseases. Liver diseases are widely underestimated, but their prevalence is increasing worldwide. The Western diet (high-fat, high-sugar) and binge drinking (rapid consumption of alcohol in a short period of time) are two highly prevalent features of standard life in the United States, and both are linked to the development and progression of liver disease. Yet, few studies have been conducted to elucidate their potential interactions. Data shows binge drinking is on the rise in several age groups, and poor dietary trends continue to be prevalent. This review serves to summarize the sparse findings on the hepatic consequences of the combination of binge drinking and consuming a Western diet, while also drawing conclusions on potential future impacts. The data suggest the potential for a looming liver disease epidemic, indicating that more research on its progression as well as its prevention is needed on this critical topic.

Background Inguinal hernia repair is the most common general surgery procedure and can be performed under local or general anesthesia. We hypothesized that using local rather than general anesthesia would improve outcomes, especially for older adults. Methods This is a retrospective review of 97,437 patients in the Veterans Affairs Surgical Quality Improvement Program who had open inguinal hernia surgery under local or general anesthesia. Outcomes included 30-day postoperative complications, operative time, and recovery time. Results Our cohort included 22,333 (23%) Veterans who received local and 75,104 (77%) who received general anesthesia. Mean age was 62 years. Local anesthesia was associated with a 37% decrease in the odds of postoperative complications (95% CI 0.54–0.73), a 13% decrease in operative time (95% CI 17.5–7.5), and a 27% shorter recovery room stay (95% CI 27.5–25.5), regardless of age. Conclusions Using local rather than general anesthesia is associated with a profound decrease in complications (equivalent to “de-aging” patients by 30 years) and could significantly reduce costs for this common procedure.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

Northeastern US heat waves have usually been considered in terms of a single circulation pattern, the high-pressure circulation typical of most heat waves occurring in other parts of the world. However, k-means clustering analysis from 1980–2018 shows there are four distinct patterns of Northeast heat wave daily circulation, each of which has its own seasonality, heat-producing mechanisms (associated moisture, subsidence, and temperature advection), and impact on electricity demand. Monthly analysis shows statistically-significant positive trends occur in late summer for two of the patterns and early summer for a third pattern, while the fourth pattern shows a statistically significant negative trend in early summer. These results demonstrate that heat waves in a particular geographic area can be initiated and maintained by a variety of mechanisms, resulting in heat wave types with distinct impacts and potential links to climate change, and that pattern analysis is an effective tool to distinguish these differences.

Highlights • Techniques for non-lead scalp-shielding in total skin therapy are lacking. • 3D-printing is a promising technique for patient-specific conformal shielding. • We present a case of effective scalp shielding with 3D-printing.

This international multidisciplinary document intends to provide clinicians with evidence‐based practical patient‐centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

A geographically and temporally widespread pattern of repetitive episodes of developmental stress, recorded as furrows of linear enamel hypoplasia (LEH) in most recent and fossil apes, requires explanation. I compared observations of LEH recurrence among museum specimens of Pan troglodytes and Pan paniscus with historical weather records of seasonally recurrent combinations of lower temperature, higher rain and wind (“cold discomfort”). I imaged samples of 34 canine teeth (N = 20 animals, 54 independent LEH) from P. troglodytes from Fongoli, Senegal, and Tai Forest, Cote d’Ivoire and P. paniscus from the Democratic Republic of Congo with a scanning electron microscope and counted perikymata between and within LEH events. I converted counts to time using published Retzius periodicities (the number of days taken to form enamel layers, visible in thin sections) and compared their recurrence and duration to seasonal peaks of incidence and the intensity of cold discomfort. Using the longest Retzius periodicity (9 days), chimpanzees and bonobos show LEH lasting about 7–9 weeks, respectively, recurring annually. Most bonobos also show just-under semiannual recurrence of LEH. “Colder, wetter, windier” weeks recur annually at the P. troglodytes locations and semiannually at P. paniscus sites. When the combination of “below median temperatures, above median rain and winds” peaks in intensity and incidence over a 7-week period, daily “minimum hourly” temperatures average 20–21°C (7–9°C below lower critical body temperature for chimpanzees) with wind 3 times and rainfall 30 times higher than usual. These findings suggest that seasonal cold discomfort may be an important factor in episodic enamel hypoplasia in many nonhuman primates.

Objective: To assess changes in walking function and walking-related prefrontal cortical activity following two post-stroke rehabilitation interventions: an accurate adaptability (ACC) walking intervention and a steady state (SS) walking intervention. Design: Randomized, single blind, parallel group clinical trial. Setting: Hospital research setting. Subjects: Adults with chronic post-stroke hemiparesis and walking deficits. Interventions: ACC emphasized stepping accuracy and walking adaptability, while SS emphasized steady state, symmetrical stepping. Both included 36 sessions led by a licensed physical therapist. ACC walking tasks recruit cortical regions that increase corticospinal tract activation, while SS walking activates the corticospinal tract less intensely. Main measures: The primary functional outcome measure was preferred steady state walking speed. Prefrontal brain activity during walking was measured with functional near infrared spectroscopy to assess executive control demands. Assessments were conducted at baseline, post-intervention (three months), and follow-up (six months). Results: Thirty-eight participants were randomized to the study interventions (mean age 59.6 ± 9.1 years; mean months post-stroke 18.0 ± 10.5). Preferred walking speed increased from baseline to post-intervention by 0.13 ± 0.11 m/s in the ACC group and by 0.14 ± 0.13 m/s in the SS group. The Time × Group interaction was not statistically significant ( P = 0.86). Prefrontal fNIRS during walking decreased from baseline to post-intervention, with a marginally larger effect in the ACC group ( P = 0.05). Conclusions: The ACC and SS interventions produced similar changes in walking function. fNIRS suggested a potential benefit of ACC training for reducing demand on prefrontal (executive) resources during walking.

Purpose (I) To evaluate the clinical efficacy of three different BCG strains in patients with intermediate-/high-risk non-muscle-invasive bladder cancer (NMIBC). (II) To determine the importance of performing routine secondary resection (re-TUR) in the setting of BCG maintenance protocol for the three strains. Methods NMIBCs who received an adjuvant induction followed by a maintenance schedule of intravesical immunotherapy with BCG Connaught, TICE and RIVM. Only BCG-naïve and those treated with the same strain over the course of follow-up were included. Cox proportional hazards model was developed according to prognostic factors by the Spanish Urological Oncology Group (CUETO) as well as by adjusting for the implementation of re-TUR. Results n = 422 Ta-T1 patients (Connaught, n = 146; TICE, n = 112 and RIVM, n = 164) with a median (IQR) follow-up of 72 (60–85) were reviewed. Re-TUR was associated with improved recurrence and progression outcomes (HRRFS: 0.63; 95% CI 0.46–0.86; HRPFS: 0.55; 95% CI 0.31–0.86). Adjusting for CUETO risk factors and re-TUR, BGC TICE and RIVM provided longer RFS compared to Connaught (HRTICE: 0.58, 95% CI 0.39–0.86; HRRIVM: 0.61, 95% CI 0.42–0.87) while no differences were identified between strains for PFS and CSS. Sub-analysis of only re-TUR cases (n = 190, 45%) showed TICE the sole to achieve longer RFS compared to both Connaught and RIVM. Conclusion Re-TUR was confirmed to ensure longer RFS and PFS in intermediate-/high-risk NMIBCs but did not influence the relative single BCG strain efficacy. When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to the other strains for RFS outcomes.

Objective: To examine whether symptoms of depression or anxiety predict glycaemia and incident diabetes complications four years later, and whether diabetes self-care behaviours mediate these associations, in adults with type 1 diabetes (T1DM). Methods: Data of 205 adults with T1DM from the 2011 and 2015 Diabetes MILES–Australia surveys were analysed. Variables of interest were: baseline depression and anxiety (PHQ-8 and GAD-7, respectively) symptoms; HbA1c and incident complications at four-year follow-up; and self-care behaviours at both time points. Longitudinal associations were analysed using structural equation modelling. Results: Forty-two participants (20.6%) reported incident complications. Baseline depressive symptoms predicted higher HbA1c at follow-up indirectly via less optimal self-care at follow-up (β = 0.19, P = 0.011). Baseline anxiety was not independently associated with HbA1c or self-care at follow-up (P ≥ 0.64). Neither depressive nor anxiety symptoms predicted incident complications, although depressive symptoms were associated with less optimal self-care at baseline (β = -0.67, P < 0.001), and this predicted microvascular complications (β = -0.38, P = 0.044); however, the indirect association via self-care was not significant (β = 0.25, P = 0.067). Limitations: Participants were self-selected; all study variables were assessed using self-report measures; and adjusting for baseline HbA1c was not possible. Conclusions: Depressive symptoms predicted suboptimal self-care behaviour and glycaemic outcome four years later, while anxiety symptoms did not. The findings suggest that tailored diabetes care should take the potential impact of comorbid depression into consideration to help people improve their diabetes self-care and achieve best possible health outcomes.