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In this perspective, we argue that pubertal suppression with gonadotropin-releasing hormone analogues is a safe reversible intervention that should be made available to transgender and gender-diverse youth starting at early puberty. Recent data suggest puberty suppression is generally initiated among individuals once puberty has significantly progressed, thus reducing the effectiveness of the intervention. Delays and barriers to such care may systematically introduce permanent avoidable disadvantages for this vulnerable and marginalized group.

Introduction Rehabilitation therapies are critical for optimizing quality-of-life and daily functions for individuals living with Parkinson's disease (PD). Thus, understanding the patterns of and under what conditions physicians make rehabilitation referrals is important for optimizing care. Method We analyzed data from 5020 participants (4 countries) collected from 1/3/2016 to 4/20/2018 as part of the Parkinson's Foundation Quality Improvement Initiative (PF QII). Data were analyzed for single discipline and multidiscipline referrals to speech language pathology (SLP), physical therapy (PT), and occupational therapy (OT). Group comparisons (referred vs. not-referred) and regression procedures were implemented to determine demographic and clinical variables that were associated with an increased likelihood of rehabilitation referral. Results 35.3% of participants were referred to rehabilitation services. Of these, 25.1% received a multidiscipline referral. There was a statistically significant effect of disease stage on both single discipline (χ2(2) = 45.1, p ≥ 1, Range = 1.08 to 1.62). Conclusions Despite evidence supporting multidiscipline and proactive rehabilitation in PD, the majority of referrals were made to a single service and may be reactions to falls or advancing disease. Data suggest there may be missed opportunities for optimizing care through proactive rehabilitation interventions.

Rationale: Restriction or prohibition of family visiting intensive care units (ICUs) during the coronavirus disease (COVID-19) pandemic poses substantial barriers to communication and family- and patient-centered care. Objectives: To understand how communication among families, patients, and the ICU team was enabled during the pandemic. The secondary objectives were to understand strategies used to facilitate virtual visiting and associated benefits and barriers. Methods: A multicenter, cross-sectional, and self-administered electronic survey was sent (June 2020) to all 217 UK hospitals with at least one ICU. Results: The survey response rate was 54%; 117 of 217 hospitals (182 ICUs) responded. All hospitals imposed visiting restrictions, with visits not permitted under any circumstance in 16% of hospitals (28 ICUs); 63% (112 ICUs) of hospitals permitted family presence at the end of life. The responsibility for communicating with families shifted with decreased bedside nurse involvement. A dedicated ICU family-liaison team was established in 50% (106 ICUs) of hospitals. All but three hospitals instituted virtual visiting, although there was substantial heterogeneity in the videoconferencing platform used. Unconscious or sedated ICU patients were deemed ineligible for virtual visits in 23% of ICUs. Patients at the end of life were deemed ineligible for virtual visits in 7% of ICUs. Commonly reported benefits of virtual visiting were reducing patient psychological distress (78%), improving staff morale (68%), and reorientation of patients with delirium (47%). Common barriers to virtual visiting were related to insufficient staff time, rapid implementation of videoconferencing technology, and challenges associated with family members’ ability to use videoconferencing technology or access a device. Conclusions: Virtual visiting and dedicated communication teams were common COVID-19 pandemic innovations addressing the restrictions to family ICU visiting, and they resulted in valuable benefits in terms of patient recovery and staff morale. Enhancing access and developing a more consistent approach to family virtual ICU visits could improve the quality of care, both during and outside of pandemic conditions.

Botulinum neurotoxins (BoNTs) are paralytic agents used to treat a variety of conditions in jaw muscles. Although their effect is considered temporary, there are reports of persistent functional changes. Using rabbits that received BoNT injection in one masseter muscle, the recovery of neuromuscular connection was investigated using nerve stimulation to evoke an electromyographic (EMG) response, and the recovery of muscle fibers was investigated using histological morphometry and bromodeoxyuridine (BrdU) immunohistochemistry. One month after treatment, evoked EMG was greatly reduced in both amplitude and duration, indicating that little reinnervation had taken place. Muscle fibers were atrophied and collagenous tissue was increased. Three months after treatment, evoked EMG duration was normal, indicating that at least some neuromuscular junctions were functional. Histologically, some muscle fibers were hypertrophied, some were still atrophied, and some appeared to have died. Fibrosis was still apparent amid slight increases in dividing cells and regenerating fibers. The histological effects of BoNT were evident although attenuated at a distance of about 1 cm from the injection level, but no regional differences could be discerned for the evoked EMGs. In conclusion, there were persistent muscular deficits seen 3 months after BoNT treatment that may have been caused by the failure of some affected muscle fibers to become reinnervated.

PURPOSE To compare demographics, self-reported symptom burden, Health-Related Quality of Life (HRQL), and Self-Efficacy for Exercise (SEE) between participants and non-participants of Rock Steady Boxing (RSB), a non-contact boxing program for individuals with Parkinson's disease (PD) that focuses on agility, balance, and speed training. MATERIALS AND METHODS Adults with PD who had heard of RSB completed a 20 min, 61-question electronic survey including the Parkinson's Disease Questionnaire-39 (PDQ-39) and the Self-Efficacy for Exercise (SEE) scale. Differences between participants and never-participants were analyzed using chi-squared test, fisher's exact test and Wilcoxon test. RESULTS Of 2054 individuals enrolled in the survey, 1709 were eligible for analysis. 1333 were current participants, 166 previous-participants, and 210 never-participants. RSB participants were median age 69, 59% male, and 97% Caucasian. The majority of current participants reported that RSB improved their social life (70%), fatigue (63%), fear of falling (62%), depression (60%), and anxiety (59%). Compared to previous and never-participants, current participants had better median PDQ-39 scores (36 and 32 vs 25, p

The COVID-19 pandemic has affected how clinical trials are managed, both within existing portfolios and for the rapidly developed COVID-19 trials. Sponsors or delegated organisations responsible for monitoring trials have needed to consider and implement alternative ways of working due to the national infection risk necessitating restricted movement of staff and public, reduced clinical staff resource as research staff moved to clinical areas, and amended working arrangements for sponsor and sponsor delegates as staff moved to working from home.Organisations have often worked in isolation to fast track mitigations required for the conduct of clinical trials during the pandemic; this paper describes many of the learnings from a group of monitoring leads based in United Kingdom Clinical Research Collaboration (UKCRC) Clinical Trials Unit (CTUs) within the UK.The UKCRC Monitoring Task and Finish Group, comprising monitoring leads from 9 CTUs, met repeatedly to identify how COVID-19 had affected clinical trial monitoring. Informed consent is included as a specific issue within this paper, as review of completed consent documentation is often required within trial monitoring plans (TMPs). Monitoring is defined as involving on-site monitoring, central monitoring or/and remote monitoring.Monitoring, required to protect the safety of the patients and the integrity of the trial and ensure the protocol is followed, is often best done by a combination of central, remote and on-site monitoring. However, if on-site monitoring is not possible, workable solutions can be found using only central or central and remote monitoring. eConsent, consent by a third person, or via remote means is plausible. Minimising datasets to the critical data reduces workload for sites and CTU staff. Home working caused by COVID-19 has made electronic trial master files (TMFs) more inviting. Allowing sites to book and attend protocol training at a time convenient to them has been successful and worth pursuing for trials with many sites in the future.The arrival of COVID-19 in the UK has forced consideration of and changes to how clinical trials are conducted in relation to monitoring. Some developed practices will be useful in other pandemics and others should be incorporated into regular use.

KEY POINTS People with type 2 diabetes (T2D) have impaired skeletal muscle oxidative flux due to limited oxygen delivery. In the current study, this impairment in oxidative flux in people with T2D was abrogated with a single-leg exercise training protocol. Additionally, single-leg exercise training increased skeletal muscle CD31 content, calf blood flow and state 4 mitochondrial respiration in all participants. ABSTRACT Cardiorespiratory fitness is impaired in type 2 diabetes (T2D), conferring significant cardiovascular risk in this population; interventions are needed. Previously, we reported that a T2D-associated decrement in skeletal muscle oxidative flux is ameliorated with acute use of supplemental oxygen, suggesting that skeletal muscle oxygenation is rate-limiting to in vivo mitochondrial oxidative flux during exercise in T2D. We hypothesized that single-leg exercise training (SLET) would improve the T2D-specific impairment in in vivo mitochondrial oxidative flux during exercise. Adults with (n = 19) and without T2D (n = 22) with similar body mass indexes and levels of physical activity participated in two weeks of SLET. Following SLET, in vivo oxidative flux measured by 31 P-MRS increased in participants with T2D, but not people without T2D, measured by the increase in initial phosphocreatine synthesis (P = 0.0455 for the group × exercise interaction) and maximum rate of oxidative ATP synthesis (P = 0.0286 for the interaction). Additionally, oxidative phosphorylation increased in all participants with SLET (P = 0.0209). After SLET, there was no effect of supplemental oxygen on any of the in vivo oxidative flux measurements in either group (P > 0.02), consistent with resolution of the T2D-associated oxygen limitation previously observed at baseline in subjects with T2D. State 4 mitochondrial respiration also improved in muscle fibres ex vivo. Skeletal muscle vasculature content and calf blood flow increased in all participants with SLET (P

Objectives: In this study, we sought to elucidate the influenza and pneumonia vaccination practices of adults with diabetes in North Carolina. Methods: Using North Carolina Behavioral Risk Factor Surveillance System data, we examined 2011-2018 trend data and demographic and health factors (2014-2018) in influenza (influenza vaccine receipt in the past year among adults ages 18+ years) and pneumonia (lifetime pneumonia vaccination receipt for adults ages 65+ years) vaccination adherence. Results: Influenza and pneumonia vaccination adherence rates were consistently higher for adults with versus without diabetes and remained relatively stable over the study period for both groups. Among adults with diabetes, factors associated with higher influenza vaccination rates included non-Hispanic white race, age 65+ years, poorer health, having insurance, and being a non-smoker. Pneumonia vaccination rates among adults with diabetes were higher for non-Hispanic Whites and those in poorer health. Conclusions: Adults with diabetes may be more likely to receive influenza and pneumonia vaccinations compared to adults without diabetes, but these rates remain below recommended levels. African Americans, younger adults, those without health insurance and cigarette smokers are vulnerable to being non-compliant with vaccination recommendations that could reduce their risk of developing and suffering complications from these diseases

Financial support provided by the Craig H. Neilsen Foundation.© Copyright 2020, Paralyzed Veterans of AmericaThese guidelines have been prepared based on scientific and professional information ava...

Develop a screening battery for persons with Parkinson's Disease (PD) that is easily administered in a short amount of time by community exercise professionals and measures changes in function.An integrated, stakeholder-engaged, mixed methods approach included interviews and meetings with community exercise professionals on the development of a screening battery. Persons with PD (Current barriers for functional screenings included time and space. Using this feedback, we developed a screening battery that took under 20 min, required little equipment, had been previously validated, could be performed in individual and group settings, and provided objective feedback that was motivating for persons with PD to continue exercising. Persons with PD demonstrated improved functional performance on sit-to-stand (Test results can be a motivator for persons with PD and lead to increased exercise adherence. Easily administered tests can show improvements in this population. Community exercise professionals are able to safely screen persons with PD to detect functional deficits and assist with programming.Implications for RehabilitationRegular exercise can slow declines in physical function and quality of life in people with Parkinson's disease.Use of physical assessments in community exercise programs can improve motivation to exercise for this population.Physical assessments such as sit-to-stand and arm curls can be used to demonstrate improvements in people with Parkinson's disease.

Reproductive health outcomes are indicators of larger social processes and researchers have long documented inequalities in these outcomes among Blacks and Whites in the United States. However, we do not fully understand the underlying mechanisms responsible for these inequalities. We believe that this is partially due to the treatment of the Black population as a monolith, which masks underlying variation in health risks and outcomes. By examining the variation that exists beneath the average, we can begin to develop a better understanding of the potential sources of health inequalities between Blacks and other racialized populations. We provide an application of this perspective through a geographic examination of reproductive health outcomes within the Black population. Using national birth records data from 2013 to 2016, we examine differences in low birth weight, preterm birth, gestational hypertension, and gestational diabetes by nativity (i.e., US- or foreign-born), region of origin (e.g., Sub-Saharan Africa, the Caribbean), and current US division of residence (e.g., Middle Atlantic, South Atlantic) within the Black population. While foreign-born Blacks are at a lower risk for low birth weight, preterm birth, and gestational hypertension, they are at an elevated risk for gestational diabetes compared to US-born Blacks. Moreover, we find substantial variation in this general pattern across region of origin and division of residence in the US. These findings demonstrate the potential role of migration, context, and selectivity in the health of foreign-born Blacks and demonstrate that national averages mask geographic variation, limiting our understanding of the contributions of these and other social processes to the health of racialized groups in the US.

Screening mammography reduces breast cancer mortality; however, when used to examine women with dense breasts, its performance and resulting benefits are reduced. Increased breast density is an independent risk factor for breast cancer. Digital breast tomosynthesis (DBT), ultrasound (US), molecular breast imaging (MBI), MRI, and contrast-enhanced mammography (CEM) each have shown improved cancer detection in dense breasts when compared with 2D digital mammography (DM). DBT is the preferred mammographic technique for producing a simultaneous reduction in recalls (i.e., additional imaging). US further increases cancer detection after DM or DBT and reduces interval cancers (cancers detected in the interval between recommended screening examinations), but it also produces substantial additional false-positive findings. MBI improves cancer detection with an effective radiation dose that is approximately fourfold that of DM or DBT but is still within accepted limits. MRI provides the greatest increase in cancer detection and reduces interval cancers and late-stage disease; abbreviated techniques will reduce cost and improve availability. CEM appears to offer performance similar to that of MRI, but further validation is needed. Dense breast notification will soon be a national standard; therefore, understanding the performance of mammography and supplemental modalities is necessary to optimize screening for women with dense breasts.

BACKGROUND: Little or no research currently exists investigating musculoskeletal strength, joint flexibility and cardiopulmonary capacity post-operative adolescent idiopathic scoliosis (AIS) patients. PURPOSE: To explore if AIS patients following spinal fusion surgery have deficiencies in strength, endurance joint flexibility and pulmonary capacity (>12-month post-operative) compared to a matched sample of the general population. METHODS: This retrospective case control study; AIS group (n = 20) and control group (n = 20) matched for gender, age and anthropometrics. Participants underwent standardised tests to establish pulmonary capacity via spirometry, upper and lower limb strength via manual muscle testing, upper and lower limb endurance via press-up and wall squat tests and joint flexibility via manual goniometry. Within session reliability and reproducibility of variables were assessed. RESULTS: No significant differences between AIS and control cohorts were identified for mass (57.1±9.0 vs. 62.8±9.0kg), height (164.7±6.3 vs. 165.6±6.0cm) or BMI (21.2±4.0 vs. 22.9±2.7). Pulmonary and musculoskeletal deficiencies in the AIS cohort were identified, including significantly lower forced vital capacity (FVC; 2.6±0.5 vs. 3.3±0.5L, P

In traditional medicine marine extracts are extensively used as therapies for diabetes. With the increasing rate of incidence of type 2 diabetes mellitus and rising cost of treatments, we investigated the anti-diabetic properties of extracts of common edible seaweeds in Europe including their ability to inhibit alpha-glucosidase and dipeptidyl peptidase 4 (DPP-4) enzymatic activity, block sodium glucose transporter-2 (SGLT-2) activity and stimulate glucagon-like peptide-1 (GLP-1) secretion and synthesis. The most promising seaweed extracts were tested for anti-hyperglycaemic activity in vivo. Some brown seaweed (Phaeophyceae) extracts had inhibitory effects on alpha-glucosidase ranging from 13.9 ± 0.2% to 89.5 ± 0.4% (p

To investigate potential relationships between neuropsychologic functioning and cardiac, gastroenterologic/hepatologic, and pulmonary complications in the single ventricle heart disease (SVHD) post-Fontan population.Following the initiation of a Fontan Multidisciplinary Clinic, patients with SVHD were evaluated systematically according to a clinical care pathway, and data from multiple subspecialty evaluations were collected prospectively from 2016 to 2019. Biomarkers of cardiology, pulmonary, and hepatology/gastroenterology functioning were abstracted, along with neuropsychologic testing results. Bivariate correlations and regression analyses examined cross-sectional relationships between physiologic predictors and neuropsychologic outcomes.The sample included a cohort of 68 youth with SVHD age 3-19 years, after Fontan palliation. Sleep-disordered breathing was related to poorer visual-motor integration skills (r = -0.33; P .05) and marginally related to poorer executive functioning (r = -0.33; P = .05). Lower arterial blood oxygen content was related to poorer executive functioning (r = .45; P .05). Greater atrioventricular valve regurgitation was related to lower parent-rated adaptive functioning (ρ = -0.34; P .01). These results were maintained in regression analyses controlling for history of stroke and/or seizures.We demonstrated associations between neuropsychologic functioning and potentially modifiable aspects of physiologic functioning in a prospectively evaluated cohort of patients with SVHD with Fontan physiology. Our findings emphasize the importance of multidisciplinary screening and care after a Fontan procedure and suggest avenues for intervention that may improve patient outcomes and quality of life.

Introduction Patients with Parkinson's disease (PD) are at increased risk for hospitalization and often experience worsening of PD when hospitalized. It is therefore important to identify strategies to prevent hospitalization. Methods Hospital encounter rates in different Parkinson's Foundation Centers of Excellence in United States, Canada, Israel and the Netherlands were analyzed as part of the Parkinson Foundation Parkinson's Outcomes Project (PF-POP). Multivariate logistic regression was used to estimate the odds ratio for hospitalization, adjusted for risk factors. Results Baseline age, disease duration, other relative than spouse/partner as care giver, cancer, arthritis, other comorbidities, falls, use of levodopa, use of dopamine agonist, use of COMT inhibitor, occupational therapy before the baseline visit, PDQ-39, MSCI total score and time between visits were significantly associated with the risk of hospital encounters. After adjustment for these factors, two centers had significantly lower odds for hospitalization admission and ER visit (minimum OR 0.3) and four centers had significantly higher odds (maximum OR 1.5) than the average center. Four centers had significantly lower hazard ratios for time to re-hospitalization compared to the average center. Reducing hospital admission rates in those centers with higher than average rates would reduce overall hospitalizations by 11%. Applied to PD patients over 65 nationwide this represents a potential for cost savings of greater than $1 billion over 48 months. Conclusion Encounter rates vary even across expert centers and suggest that practices carried out in some centers may reduce the risk of hospitalization. Further research will be necessary to identify these practices and implement them more widely to improve care for people with PD.

Transbronchial lung biopsy (TBLB) using forceps is one of the most common procedures used to obtain lung tissue. The procedure's usefulness remains limited when diagnosing interstitial lung diseases. This retrospective descriptive study analyzed the feasibility and safety of using large forceps for TBLB in all patients who underwent TBLB from 2014 to 2018 for diffuse lung disease where the diagnosis could not be made by high-resolution chest computed tomography. We excluded patients with radiographic features of usual interstitial pneumonia. Among the 35 study patients, 7 were men and 28 were women. Diagnoses included respiratory associated bronchiolitis (7), diffuse alveolar damage (4), organizing pneumonia (4), nonspecific interstitial pneumonitis (3), acute fibrinous organizing pneumonia (3), sarcoidosis (2), hypersensitivity pneumonitis (2), IgG4 interstitial lung disease (1), eosinophilic pneumonia (1), pulmonary alveolar proteinosis (1), pulmonary fibrosis (1), pneumocystis (1), plasma-rich bronchiolitis (1), and diffuse alveolar hemorrhage (1). In three cases, the biopsies were nondiagnostic. Two patients developed a pneumothorax, and one required chest tube placement. There was one episode of minor bleeding. No escalation of care or hospitalization was required. Large-forceps TBLB is a feasible and safe method for obtaining parenchymal lung biopsies.

PURPOSE: This study aimed to report recent trends in self-reported diabetes self-management education (DSME) participation rates among adults in North Carolina and to compare these rates between rural and urban residents. METHODS: Data for this analysis were obtained from the NC Behavioral Risk Factor Surveillance System (BRFSS) for the years 2012, 2013, 2015, and 2017, when the survey included the diabetes module. Respondents were classified as having participated in DSME if they answered "Yes" to the question, "Have you ever taken a course or class in how to manage your diabetes yourself?" We used the Rural Urban Continuum Code to classify urban and rural residence. The study sample included 4368 adults 18 years or older with self-reported diabetes. We assessed the changes in DSME participation from 2012 to 2017. We used multiple logistic regression modeling to assess the association between rural residence and DSME participation. All analyses were conducted in Stata 14 and accounted for the survey design of the BRFSS. Statistical significance was set at P < .01. RESULTS: Overall, the DSME participation rates decreased slightly in the study period, from 55.8% in 2012 to 55.6% in 2013 to 56.5% in 2015 to 52.1% in 2017. By rural-urban residence, the rates were 52.3% versus 57.8% in 2012, 54.0% versus 56.5% in 2013, 48.8% versus 62.0% in 2015, and 46.7% versus 56.1% in 2017. The multiple logistic regression model results showed that rural residents were less likely to have participated in DSME (adjusted odds ratio = 0.78; 95% confidence interval, 0.64-0.94) than urban residents. Adults with higher income and education levels were also more likely to have participated in DSME (P < .01). CONCLUSIONS: The recent BRFSS data showed that the DSME participation rate declined slightly in North Carolina. There were persistent rural-urban disparities in DSME participation, with rural residents showing lower rates, and the gaps seemed to be widening. IMPLICATIONS FOR POLICY OR PRACTICE: Continuous efforts are needed to bring more American Diabetes Association/American Association of Diabetes Educators programs to rural communities and assist persons with diabetes to participate in DSME training to reduce the burden of diabetes. Furthermore, those in rural areas may need additional support.

Background Fathers of children with autism spectrum disorder (ASD) report more challenges than fathers of typically developing children, which also negatively impacts their psychological well-being. Although not studied to the same extent in fathers of children with ASD, the challenges experienced by fathers of typically developing children have been shown to impact parenting behaviours. Many children with ASD also have intellectual disability (ID), which adds additional parenting stress. The purpose of this qualitative study was to examine perceptions of parenting roles and father-child relationship quality in fathers of children with ASD and ASD/ID. Methods Twenty-eight fathers of children with ASD (n = 12) and ASD/ID (n = 16) completed a telephone interview. A phenomenological approach was used by two investigators to analyse the interviews. Both investigators coded the interviews and then discussed the final themes. Results Five major themes emerged. One theme that emerged was pre-birth expectations, and the remaining themes related to the post-diagnosis period: adjustments, experiences, co-parenting and quality of father-child relationship. Both fathers of a child with ASD and ASD/ID reported on all themes. Conclusions Overall, fathers of children with ASD and ASD/ID reported similarly on the themes that emerged. Future research with more diverse samples is needed to continue to understand the fatherhood experience. The findings of this study have implications for the development of parent-focused programmes that are tailored to fathers' unique experiences.

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na(+) current (I(Na)) and repolarizing K(+) current (I(K)) carried by voltage gated K(+) (K(v)1.5) channels were reduced. The reduction in I(Na) occurred in association with reduced expression of SCN5a and voltage gated Na(+) (Na(V)1.5) channels as well as a shift in I(Na) activation kinetics. Insulin potently and selectively increased I(Na) in Akita mice without affecting I(K). Chronic insulin treatment increased I(Na) in association with increased expression of Na(V)1.5. Acute insulin also increased I(Na), although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP(3)). Our study reveals a critical, selective role for insulin in regulating atrial I(Na), which impacts susceptibility to AF in type 1 DM.

Children with single-ventricle heart disease (SVHD) are at risk for morbidity across multiple organ systems. A single-ventricle multidisciplinary clinic (SVMDC) may address complex health-care needs by providing access to, and coordination among, pediatric subspecialties. However, the patient and family experience of multidisciplinary care for SVHD remains unexplored. We e-mailed a 26-question survey to families after an SVMDC visit, which included evaluation with subspecialists from cardiology, pulmonology, gastroenterology, neuropsychology, and pediatric psychology, as well as social activities during clinic. Responses were anonymized to protect privacy, and data were analyzed quantitatively and qualitatively. Over 3 years, 22% (27/122) of families completed the survey. Overall, families’ experiences were positive, with 100% reporting that they would recommend the SVMDC to others. Qualitative themes emerged regarding logistics, multidisciplinary care, key takeaways from clinic, and connection-making with other families. A multidisciplinary clinic demonstrated overall acceptability and perceived benefit to families of children with SVHD. Considerations for mixed experiences regarding financial commitment and connection-making among parents are discussed, as are the benefits of the synergy achieved through multidisciplinary care.

BACKGROUND Low health literacy is a recognized contributor to health disparities. Significant proportions of the adult population, especially the underserved, have low health literacy. The purpose of this study was to examine health literacy and its associations with health status and chronic health conditions among North Carolina adults.METHODS The 2016 North Carolina Behavioral Risk Factor Surveillance System included health literacy questions that focused on accessing and understanding health information. Using these self-reported data, we estimated the prevalence of low health literacy and assessed its associations with general health status and chronic health conditions after adjusting for sociodemographic characteristics and health care access.RESULTS Overall, 4.8% of adults reported having difficulty getting health information or advice, 7.5% understanding oral information from health professionals, and 8.3% understanding written health information; 14.8% reported having difficulty with at least one of these tasks. The adjusted odds of low health literacy were moderately higher for those who had been diagnosed with the following conditions compared to those not diagnosed: heart attack, coronary heart disease, or stroke (AOR = 1.81, 95% CI=1.33, 2.47); COPD (AOR = 1.67, 95% CI = 1.19, 2.34); arthritis (AOR = 1.68, 95% CI = 1.32, 2.15); depression (AOR = 1.95, 95% CI=1.52, 2.50); and kidney disease (AOR = 1.62, 95% CI = 1.02, 2.60).LIMITATIONS All data were self-reported.CONCLUSIONS A notable segment of the North Carolina adult population has low health literacy, and those who do are particularly vulnerable to adverse health status. Targeted efforts are needed to identify strategies to improve health literacy and decrease health disparities.

The intrauterine environment can have a significant impact on fetal and maternal well-being, both during pregnancy and in later life. We aimed to identify how fetal sex and maternal body mass index (BMI) influence insulin resistance and metabolic function during pregnancy with maternal BMI > 25 kg/m2. This secondary analysis assessed data from the PEARS-randomized controlled trial that recruited pregnant women with body mass indexes 25-39.9 kg/m2. Longitudinal measurements of maternal and fetal insulin resistance and metabolic function were recorded throughout pregnancy. Regression models tested the effects of fetal sex and maternal BMI on markers of metabolic function and insulin regulation. A total of 484 women and their newborns (252 (52%) males vs. 232 (48%) females) were included in the analysis. A total of 333 (69%) women were overweight and 151 (31%) were obese. Male newborns were heavier and larger than females, and had a higher rate of instrumental delivery. Males had a lower LDL, but no other markers of insulin resistance or metabolic function were affected by fetal sex. Women with obesity had elevated markers of insulin resistance and metabolic dysfunction compared with women that were overweight, but maternal BMI did not impact these variables in the fetus. Fetal sex did not impact maternal and fetal metabolic parameters in women with BMI > 25 kg/m2. However, a higher BMI caused increasingly deranged maternal blood lipid concentrations and markers of insulin resistance as pregnancy progressed. Lipid monitoring and interventions to reduce lipids during pregnancy therefore require further evaluation.

Graphical abstract Image, graphical abstract, Highlights • Children's weight gain and fitness loss accelerate during the summer. • According to the structured days hypothesis, structured programming during the summer may mitigate this accelerated weight gain and fitness loss. • Year-round school calendars are a way to provide structure during the summer because they take more frequent shorter breaks throughout the calendar year. • Students attending a year-round school experienced less weight gain and fitness loss during the traditional 3-month summer but these benefits were erased over the traditional school year., Purpose To evaluate the potential of a year-round school calendar (180-day school year distributed across 12 months) as an intervention compared to a traditional school calendar (180-day school year distributed across 9 months) for mitigating children's weight gain and fitness loss via a natural experiment. Methods Height, weight, and cardiorespiratory fitness (CRF) (i.e., Fitnessgram Progressive Aerobic Cardiovascular Endurance Run) were measured in children (5–12 years old) in 3 schools (2 traditional, 1 year-round, n = 990 students, age = 8.6 ± 2.4 years, 53.1% male, 68.9% African American) from 1 school district. Structure (represented by the presence of a school day) was the independent variable. Changes in body mass index (BMI), age- and sex-specific BMI z-scores (zBMI), BMI percentile, percent of overweight or obese children, and CRF (Progressive Aerobic Cardiovascular Endurance Run laps completed) were assessed for summer 2017 (May–August 2017), school year 2017/2018 (August 2017–May 2018), and summer 2018 (May–August 2018). Primary analyses examined the overall change in weight and CRF from summer 2017 until summer 2018 via multilevel mixed effects regression, with group (traditional vs. year-round calendar), time, and a group-by-time interaction as the independent variables. Secondary regression analyses estimated differences in change within and between groups during each time period, separately. Results Year-round students gained less BMI (difference in ∆ = –0.44, 95% confidence interval (CI): –0.67 to –0.03) and less CRF (difference in ∆ = –1.92, 95%CI: –3.56 to –0.28) than students attending a traditional school overall. Compared with traditional students, during both summers, year-round students gained less BMI (summer 2017 difference in ∆ = –0.15, 95%CI: –0.21 to –0.08; summer 2018 difference in ∆ = –0.16, 95%CI: –0.24 to –0.07) and zBMI (summer 2017 difference in ∆ = –0.032, 95%CI: –0.050 to –0.010; summer 2018 difference in ∆ = –0.033, 95%CI: –0.056 to –0.009), and increased CRF (summer 2017 difference in ∆ = 0.40, 95%CI: 0.02–0.85; summer 2018 difference in ∆ = 0.23, 95%CI: –0.25 to 0.74). However, the opposite was observed for the school year, with traditional students gaining less BMI and zBMI and increasing CRF compared with year-round students (difference in BMI ∆ = 0.05, 95%CI: 0.03–0.07; difference in zBMI ∆ = 0.012, 95%CI: 0.005–0.019; difference in Progressive Aerobic Cardiovascular Endurance Run laps ∆ = –0.43, 95%CI: –0.58 to –0.28). Conclusion The year-round school calendar had a small beneficial impact on children's weight status but not CRF. It is unclear if this benefit to children's weight would be maintained because gains made in the summer were largely erased during the school year. Trajectories of weight and CRF gain/loss were consistent with the structured days hypothesis.

Epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (TF) are well known for their ability to induce mesenchymal states associated with increased migratory and invasive properties. Unexpectedly, nuclear expression of the EMT-TF ZEB2 in human primary melanoma has been shown to correlate with reduced invasion. We report here that ZEB2 is required for outgrowth for primary melanomas and metastases at secondary sites. Ablation of Zeb2 hampered outgrowth of primary melanomas in vivo, whereas ectopic expression enhanced proliferation and growth at both primary and secondary sites. Gain of Zeb2 expression in pulmonary-residing melanoma cells promoted the development of macroscopic lesions. In vivo fate mapping made clear that melanoma cells undergo a conversion in state where ZEB2 expression is replaced by ZEB1 expression associated with gain of an invasive phenotype. These findings suggest that reversible switching of the ZEB2/ZEB1 ratio enhances melanoma metastatic dissemination. Significance: ZEB2 function exerts opposing behaviors in melanoma by promoting proliferation and expansion and conversely inhibiting invasiveness, which could be of future clinical relevance.

To the editor, The SARS-CoV-2, which causes COVID-19, has resulted in over 100 million cases of infection and more than 2 million deaths globally, as of February 2021. Diabetes and uncontrolled hyperglycemia are risk factors for poor outcomes in patients with COVID-19 including increased risk of severe illness or death.1 One observational study described glycemic and clinical outcomes in 1122 patients with and without diabetes and/or acute uncontrolled hyperglycemia in 88 US hospitals. Among 570 patients who expired or were discharged, the mortality rate was 28.8% in 184 patients with diabetes and/or uncontrolled hyperglycemia, compared with 6.2% of 386 patients without diabetes or hyperglycemia (p

Objective To improve patient experience of chemotherapy-induced peripheral neuropathy (CIPN), it is crucial to identify how patients develop their understanding and perception of CIPN. A wider understanding of the experiences of clinicians who provide CIPN information and support is also needed. This study explored clinician and patient experience of the provision of care, information and support for CIPN. Methods Data were collected between July and November 2019 using multiple qualitative methods. Non-participant observations were undertaken in colorectal and breast cancer clinics and at clinician stations, including the observation of chemotherapy consultations between patients and clinicians. Semi-structured interviews with people with cancer and clinicians were also conducted. Data were analysed using inductive reflexive thematic analysis. Results Three major themes emerged: (1) CIPN is a hidden chemotherapy side effect, (2) assessment and management of CIPN is disconnected and (3) patients and clinicians expect openness in CIPN symptom reporting, information provision and management. Conclusion Findings show the need to address the lack of patients' overall familiarity with CIPN. Echoing earlier studies, our findings suggest that knowledge and understanding about CIPN among clinicians are limited or lacking. These insights from patient and clinicians' CIPN experiences can inform future interventions that may address the genuine needs of patients and enhance CIPN support.

Background: Atrial fibrillation is prevalent in aging populations; however, not all individuals age at the same rate. Rather, health status during aging can vary from fit to frail. Frailty can be quantified using a frailty index (FI). Natriuretic peptides modulate atrial function in part by activating NP (natriuretic peptide) receptor C (NPR-C). The impacts of NPR-C on atrial structure and arrhythmogenesis in aging and as a function of frailty are unknown. Methods: Frailty was measured in aging wildtype and NPR-C knockout (NPR-C − /− ) mice. Atrial structure and function were studied using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology. Results: NPR-C −/− mice had a shortened lifespan and more rapidly became frail compared with wildtype mice. Atrial fibrillation burden and P wave duration were increased in older versus younger wildtype mice and further increased in older NPR-C −/− mice; however, there was substantial variability among age groups and genotypes. P wave duration was strongly correlated with FI score regardless of age or genotype. Optical mapping of the atria demonstrated reduced conduction velocity and changes in action potential duration that were also graded by FI score. Atrial fibrosis was increased in aged and NPR-C −/− mice and was strongly correlated with FI score. Atrial fibrosis was associated with changes in expression of profibrotic genes, including MMPs (matrix metalloproteinases), TIMPs (tissue inhibitors of metalloproteinases), and TGFβ (transforming growth factor β). Gene expression changes were also correlated with FI scores. Conclusions: NPR-C plays an essential role in the aging-dependent decline in health status as well as alterations in atrial function and arrhythmogenesis. Frailty assessment is a highly effective approach for identifying age-dependent heterogeneity in atrial structure and function, including in the setting of shortened lifespan because of loss of NPR-C.

The prevalence of ectopic thyroid tissue, based on autopsy studies, is between 7% and 10%, but there are rare cases reported in the thoracic region. Here, we encountered a case of thoracic ectopic thyroid tissue presenting as a presumed enlarged mediastinal lymph node. A 50-year-old female with a history of lung adenocarcinoma, status post resection, presented with complaints of headache, dizziness, and nausea. Magnetic resonance imaging found two brain lesions consistent with metastasis. Computed tomography scan showed enlarged mediastinal lymph nodes and thyroid nodules. Fine-needle aspiration (FNA) of one thyroid nodule was positive for papillary thyroid carcinoma. FNA of the mediastinal lymph nodes were negative for metastatic carcinoma but revealed thyroid tissue in the 2.9 × 1.6 cm presumed 2 L lymph node. The morphological features and immunohistochemical stains confirmed thyroid tissue, and there were no cytological features of thyroid carcinoma. In patients with a history of a pulmonary tumor (such as adenocarcinoma, low-grade neuroendocrine tumor), ectopic thyroid tissue, although a rare event, could represent a pitfall in the cytologic evaluation of mediastinal lymph nodes aspirates obtained from staging procedures. Careful morphologic examination with a panel of immunohistochemical studies are useful in making the correct diagnosis, leading to appropriate patient management.

Background Female genital schistosomiasis (FGS) is a neglected tropical gynaecological disease that affects millions of women in sub-Saharan Africa (SSA). FGS is caused by Schistosoma haematobium, a parasitic carcinogen involved in the pathogenesis of squamous cell carcinoma of the bladder. Cervical cancer incidence and mortality are highest in SSA, where pre-cancerous cervical dysplasia is often detected on screening with visual inspection with acetic acid (VIA). There are no studies evaluating the association between VIA positivity and FGS diagnosed by genital PCR. Methods Women were recruited from the Bilharzia and HIV (BILHIV) study in Zambia a community-based study comparing genital self-sampling to provider obtained cervicovaginal-lavage for the diagnosis of FGS in women aged 18–31. FGS was defined as positive Schistosoma DNA from any genital PCR. Urogenital schistosomiasis diagnostics included urine circulating anodic antigen, urine microscopy and portable colposcopy. Participants were offered cervical cancer screening using VIA at Livingstone Central Hospital. Associations of PCR confirmed FGS and other diagnostics with VIA positivity were assessed using multivariable logistic regression. Results VIA results were available from 237 BILHIV participants. A positive Schistosoma PCR in any genital specimen was detected in 14 women (5.9%), 28.6% (4/14) of these women had positive VIA compared to 9.0% without PCR evidence of schistosome infection (20/223). Schistosoma PCR positivity in any genital specimen was strongly associated with VIA positivity (OR: 6.08, 95% CI: 1.58–23.37, P = 0.02). Conclusions This is the first study to find an association between FGS and positive VIA, a relationship that may be causal. Further longitudinal studies are needed.

Prediction models for population-based screening need, for global usage, to be resource-driven, involving predictors that are affordably resourced. Here, we report the development and validation of three resource-driven risk models to identify people with type 2 diabetes (T2DM) at risk of stage 3 CKD defined by a decline in estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73m2. The observational study cohort used for model development consisted of data from a primary care dataset of 20,510 multi-ethnic individuals with T2DM from London, UK (2007–2018). Discrimination and calibration of the resulting prediction models developed using cox regression were assessed using the c-statistic and calibration slope, respectively. Models were internally validated using tenfold cross-validation and externally validated on 13,346 primary care individuals from Wales, UK. The simplest model was simplified into a risk score to enable implementation in community-based medicine. The derived full model included demographic, laboratory parameters, medication-use, cardiovascular disease history (CVD) and sight threatening retinopathy status (STDR). Two less resource-intense models were developed by excluding CVD and STDR in the second model and HbA1c and HDL in the third model. All three 5-year risk models had good internal discrimination and calibration (optimism adjusted C-statistics were each 0.85 and calibration slopes 0.999–1.002). In Wales, models achieved excellent discrimination(c-statistics ranged 0.82–0.83). Calibration slopes at 5-years suggested models over-predicted risks, however were successfully updated to accommodate reduced incidence of stage 3 CKD in Wales, which improved their alignment with the observed rates in Wales (E/O ratios near to 1). The risk score demonstrated similar model performance compared to direct evaluation of the cox model. These resource-driven risk prediction models may enable universal screening for Stage 3 CKD to enable targeted early optimisation of risk factors for CKD.

Type 2 diabetes (T2D) is a global epidemic leading to excess cardiovascular (CV) mortality. CV risk factor modification does not prevent progression to non-ischemic heart failure (HF), so early detection and intervention are needed. Our group has identified preclinical cardiac dysfunction associated with central arterial stiffness and decreased cardiorespiratory fitness which is responsive to exercise training (ET) intervention. Cardiac parameters were measured in BMI-similar participants with and without T2D, before and after a 90-day progressive aerobic ET program and compared to lean nondiabetic historical controls. Left ventricular end systolic volume (LV ESV), end diastolic volume (EDV), stroke volume, and cardiac output for both groups pre- and post-exercise training were significantly lower than those of lean controls (Table 1). ESV and EDV increased post-exercise in T2D but not in the control group. While ejection fraction did not differ between groups, decreased heart rate in people with T2D following ET suggests compensation. Pulse wave velocity (PWV) by carotid to femoral tonometry (SphygmoCor) did not change with ET, but thoracic aortic PWV from 4D flow MRI significantly improved with ET across both groups. Cardiac and central arterial function are deleteriously and differently impacted by obesity and T2D. Advanced imaging may be a useful tool to longitudinally assess function and response to intervention. Disclosure D. Enge: None. K. Jarvis: None. T. Fujiwara: None. M. Markl: None. K. S. Hunter: None. A. J. Barker: None. K. J. Nadeau: None. J. G. Regensteiner: None. J. E. Reusch: Advisory Panel; Self; Medtronic. M. Schafer: None. R. L. Scalzo: None. D. Rafferty: None. I. E. Schauer: None. L. Abushamat: None. M. O. Whipple: None. E. Johnson: None. M. B. Scott: None. Funding National Institutes of Health (R01DK124344, R01HL133504)

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and fatal spongiform encephalopathy characterized by rapidly progressive dementia and myoclonus. The rarity of this disease and its variable initial presentation make early diagnosis fairly challenging, especially considering it is a diagnosis of exclusion. We present a case of a patient initially admitted for sudden onset of confusion, memory loss, dysmetria, and ataxia after a recent diagnosis of Waldenstrom’s Macroglobulinemia. Within four weeks, after work-up for suspected Bing-Neel syndrome and failure to respond to appropriate symptomatic treatment, acute deterioration of mental status, akinetic mutism, and myoclonus were evident & Cerebrospinal fluid (CSF) analysis was positive for protein 14-3-3. Brain magnetic resonance imaging (MRI) showed hyperintensities in the cortex and basal ganglia in diffusion-weighted imaging (DWI). The probable diagnosis of sCJD was reached based on the patient’s unresponsiveness to treatment, clinical features, characteristic findings on MRI, as well as positive 14-3-3 CSF assay.

Aim Postprandial hyperglycaemia is a challenge for people living with Type 1 diabetes. In addition to carbohydrate, dietary protein has been shown to contribute to postprandial glycaemic excursions with recommendations to consider protein when calculating mealtime insulin doses. The aim of this review is to identify and synthesize evidence about the glycaemic impact of dietary protein and insulin requirements for individuals with Type 1 diabetes. Methods A systematic literature search of relevant biomedical databases was performed to identify research on the glycaemic impact of dietary protein when consumed alone, and in combination with other macronutrients in individuals with Type 1 diabetes. Results The review included 14 published studies dated from 1992 to 2018, and included studies that researched the impact of protein alone (n = 2) and protein in a mixed meal (n = 12). When protein was consumed alone a glycaemic effect was not seen until ≥ 75 g. In a carbohydrate-containing meal ≥ 12.5 g of protein impacted the postprandial glucose. Inclusion of fat in a high-protein meal enhanced the glycaemic response and further increased insulin requirements. The timing of the glycaemic effect from dietary protein ranged from 90 to 240 min. Studies indicate that the postprandial glycaemic response and insulin requirements for protein are different when protein is consumed alone or with carbohydrate and/or fat. Conclusions This systematic review provides evidence that dietary protein contributes to postprandial glycaemic excursions and insulin requirements. These insights have important implications for the education of people with Type 1 diabetes and highlights the need for more effective insulin dosing strategies for mixed macronutrient meals.

Background Hip fractures are common in older adults and are associated with increased mortality and morbidity resulting in medical and socioeconomic burden for healthcare system and patient alike. Methods A retrospective study was conducted on patients admitted to a Dublin hospital for hip fracture repair between October 2018 and February 2019. Data on sociodemographic characteristics such as; gender; age; pre-admission residence; fracture history; bone protection medication use; pre-fracture mobility; discharge mobility and destination; length of stay and mortality rate was collected. Results 50 patients admitted between 01/10/19 and 31/01/2019. 2:1 female to male. Average age 78 ranging from 48-93. 88% admitted from home. 44% had previous fractures. Vertebral (36%), wrist (23%) and pelvic (23%) most common fractures. 27% of these were on bone protection medication on admission. 41% were taking Calcium and Vit D or Vitamin D only. 70% of participants were independently mobile pre-fracture. 94% required some form of mobility aid on discharge. The average length of stay was 32 days ranging from 2 to 160 days. 38% went home whilst 36% were discharged to rehabilitation. 88% were discharged on bone protection medication - 70% received IV Zoledronic acid as inpatients, 14% commenced Prolia 6 monthly injections and 4% on oral bisphosphonates. Mortality rate was 6% Conclusion Hip fractures have a negative effect on a person’s mobility. Whilst many guidelines for the assessment and treatment of osteoporosis recommend intervention be considered in men and women who have sustained a fragility fracture, it is clear from this study that an osteoporosis care gap exists and further work is required to better identify, assess and treat patients following their first fracture in the hope of reducing further fractures, particularly hip and vertebral fractures.

Background People with type 2 diabetes mellitus (T2D) have preclinical cardiac and vascular dysfunction associated with low cardiorespiratory fitness (CRF). This is especially concerning because CRF is a powerful predictor of cardiovascular mortality, a primary issue in T2D management. Glucagon-like pepetide-1 (GLP-1) augments cardiovascular function and our previous data in rodents demonstrate that potentiating the GLP-1 signal with a dipeptidyl peptidase-4 (DPP4) inhibitor augments CRF. Lacking are pharmacological treatments which can target T2D-specific physiological barriers to exercise to potentially permit adaptations necessary to improve CRF and thereby health outcomes in people with T2D. We therefore hypothesized that administration of a DPP4-inhibitor (sitagliptin) would improve CRF in adults with T2D. Methods and Results Thirty-eight participants (64 ± 1 years; mean ± SE) with T2D were randomized in a double-blinded study to receive 100 mg/day sitagliptin, 2 mg/day glimepiride, or placebo for 3 months after baseline measurements. Fasting glucose decreased with both glimepiride and sitagliptin compared with placebo (P = 0.002). CRF did not change in any group (Placebo: Pre: 15.4 ± 0.9 vs. Post: 16.1 ± 1.1 ml/kg/min vs. Glimepiride: 18.5 ± 1.0 vs. 17.7 ± 1.2 ml/kg/min vs. Sitagliptin: 19.1 ± 1.2 vs. 18.3 ± 1.1 ml/kg/min; P = 0.3). Sitagliptin improved measures of cardiac diastolic function, however, measures of vascular function did not change with any treatment. Conclusions Three months of sitagliptin improved diastolic cardiac function, however, CRF did not change. These data suggest that targeting the physiological contributors to CRF with sitagliptin alone is not an adequate strategy to improve CRF in people with T2D. Clinical trials registration www.clinicaltrials.gov NCT01951339.

Aim The aim of this study was to critically review research literature investigating the role of practice nurses in the early identification and management of chronic kidney disease (CKD) in the general practice setting. Method An integrative review was performed to determine the extent to which the topic has been investigated. Quantitative and qualitative research papers were systematically located in peer-reviewed journals in electronic databases. Included papers were critically appraised using the relevant CASP appraisal tools. Findings There is a paucity of research investigating the role of practice nurses in the early identification and management of CKD in primary health care. Three articles published between 2013 and 2017 were identified: two quantitative studies and one qualitative study. One study from The Netherlands quantified positive outcomes of practice nurse-centred management of CKD in general practice. Conclusion Practice nurses may be effective in the early identification and management of CKD, including improving blood pressure control. Providing education to practice nurses appears to be a key factor in increasing practice nurses’ involvement in identification and management of CKD. Further research is warranted to see if the results are transferable to other jurisdictions.

Individuals with type 1 diabetes represent only ∼6% of all patients with diabetes in the United States and require characteristically complex treatment modalities (1). Autoimmune pancreatic β-cell destruction ultimately results in an absolute insulin deficiency, the presence of autoimmune markers, and little to no residual C-peptide (2,3). Additionally, pancreatic α-cell dysfunction is present, resulting in excess glucagon in both the fasting and postprandial states, and the gastric emptying rate is altered in many patients. Exogenous insulin serves as the foundation of therapy for type 1 diabetes and is commonly delivered via a multiple-dose regimen or an insulin pump. The two most common adverse effects associated with insulin use are hypoglycemia and weight gain. Recent data suggest that 68% of people with type 1 diabetes are overweight or obese and that severe hypoglycemia occurs at a rate of 9–20% (4). The latter complication is considered a limiting factor to achieving glycemic targets in the type 1 diabetes population. Indeed, the average A1C for adults ≥18 years of age with type 1 diabetes in the United States was 7.9% in 2015, a value well above the target of 7% recommended by the American Diabetes Association for most adult patients. Further complicating matters, diabetic ketoacidosis (DKA) occurs at a rate of 10% per year in some age-groups (4). Overall, these data suggest a need for adjunctive therapies for type 1 diabetes that reduce the risk for hypoglycemia and weight gain. While β-cell dysfunction is clearly a therapeutic focus for all types of diabetes, multiple other pathways of hyperglycemia present opportunities for alternate treatment modalities that may assist in achieving glycemic targets (5). The ideal pharmacotherapy regimen for a patient with type 1 diabetes would not only target the β-cell dysfunction, but also decrease blood glucose through hyperglycemic pathways independent of β-cell …

OBJECTIVE: To study the impact of therapeutic interventions on pain analgesia and endogenous pain modulation in knee osteoarthritis (KOA). DESIGN: Systematic review and meta-analysis. METHODS: We searched for KOA randomized clinical trials and observational studies with data on therapeutic interventions comparing pain intensity, temporal summation (TS), and conditioned pain modulation (CPM) scores relative to control. These data were pooled as Hedge’s g. To study the relationship between pain intensity and TS/CPM, we performed metaregression with 10,000 Monte-Carlo permutations. RESULTS: We reviewed 11 studies (559 participants). On studying all the interventions together, we found no significant changes in pain modulation, TS, or CPM. Our findings show that this lack of difference is likely because surgical and nonsurgical interventions resulted in contrary effects. Metaregression significantly correlated pain reduction with normalization of TS and CPM. CONCLUSIONS: We demonstrate an association between pain reduction and TS/CPM normalization. Though we cannot directly compare these interventions, the results allow us to draw hypotheses on potential practice schemas. Recovering defective endogenous pain modulation mechanisms may help establish long-term analgesia. However, to validate these paradigms as robust clinical biomarkers, further investigation into their mechanisms would be necessary. The registration number for this review is CRD42017072066.

6-Thiopurine (6TP) is a potent cytotoxic agent that is a clinically prescribed anti-metabolite employed in the treatment of numerous blood cancers since 1952. However, its reported severe toxicities limit its general usage in the clinic. We previously have undertaken investigations into identifying the mode of toxicity for 6TP, and have found that the oxidative metabolites of 6TP, specifically 6-thiouric acid (6TU), is responsible for the in vitro inhibition of UDP-glucose dehydrogenase (UDPGDH) in a UV-vis method. In this method, inhibition was quantified through the quantification of NADH production, however, purines absorb at the same wavelength and thereby can interfere with the NADH detection. Herein, we report a HPLC method that allows for direct quantification of UDP-glucuronic acid, product from UDPGDH, for the assessment of inhibition towards UDPGDH with no interference from purines. In this method it was revealed that 6TP possesses a greater inhibitory properties than previously observed; 111 vs. 288 μM. Building upon the data collected from a previously performed rat hepatocyte study, which correlated our in vitro to in vivo inhibition theories about UDPGDH, we have developed a bio-mimic in vitro assay to aid in the inhibitory assessment of 6TP and analogs. In our efforts to expand the use of 6TP, and analogs constructed, our laboratory has undertaken a screening campaign to identify small molecule potentiators that work in synergy with 6TP in other types of cancers. Three chalcone-based compounds have been discovered through our total synthesis campaign of uvaretin, and it has been found that 11c has strong synergism with 6TP in the pancreatic cancer cell line MIA PaCa-2. Through the work presented herein, we reveal new methods to assess toxicity of 6TP and future analogs and new small molecules that work in synergy to expand the therapeutic applications of this neglected cytotoxic agent.

Visual Abstract, Highlights • SAN disease is prevalent in hypertension and heart failure and can be induced by chronic Ang II treatment in mice. • Ang II caused SAN disease in mice in association with impaired electrical conduction, reduction in the hyperpolarization-activated current (If) in SAN myocytes, and increased SAN fibrosis. • Ang II-induced SAN disease was worsened in mice lacking NPR-C in association with enhanced SAN fibrosis. • Mice co-treated with Ang II and an NPR-C agonist (cANF) were protected from SAN disease. • NPR-C may represent a new target to protect against Ang II-induced SAN disease., Summary Sinoatrial node (SAN) disease mechanisms are poorly understood, and therapeutic options are limited. Natriuretic peptide(s) (NP) are cardioprotective hormones whose effects can be mediated partly by the NP receptor C (NPR-C). We investigated the role of NPR-C in angiotensin II (Ang II)-mediated SAN disease in mice. Ang II caused SAN disease due to impaired electrical activity in SAN myocytes and increased SAN fibrosis. Strikingly, Ang II treatment in NPR-C−/− mice worsened SAN disease, whereas co-treatment of wild-type mice with Ang II and a selective NPR-C agonist (cANF) prevented SAN dysfunction. NPR-C may represent a new target to protect against the development of Ang II-induced SAN disease.

Introduction\udStudies of prevalence and the demographic profile of type 1 diabetes are challenging because of the relative rarity of the condition, however, these outcomes can be determined using routine healthcare data repositories. Understanding the epidemiology of type 1 diabetes allows for targeted interventions and care of this life-affecting condition.\ud\ud\udObjectives\udTo describe the prevalence, incidence and demographics of persons with type 1 diabetes diagnosed in Wales, UK, using the Secure Anonymised Information Linkage (SAIL) Databank.\ud\ud\udMethods\udData derived from primary and secondary care throughout Wales available in the SAIL Databank were used to identify people with type 1 diabetes to determine the prevalence and incidence of type 1 diabetes over a 10 year period (2008–18) and describe the demographic and clinical characteristics of this population by age, socioeconomic deprivation and settlement type. The seasonal variation in incidence rates was also examined.\ud\ud\udResults\udThe prevalence of type 1 diabetes in 2018 was 0.32% in the whole population, being greater in men compared to women (0.35% vs 0.28% respectively); highest in those aged 15-29 years (0.52%) and living in the most socioeconomically deprived areas (0.38%). The incidence of type 1 diabetes over 10 years was 14.0 cases/100,000 people/year for the whole population of Wales. It was highest in children aged 0-14 years (33.6 cases/100,000 people/year) and areas of high socioeconomic deprivation (16.8 cases/100,000 people/year) and least in those aged 45-60 years (6.5 cases/100,000 people/year) and in areas of low socioeconomic deprivation (11.63 cases/100,000 people/year). A seasonal trend in the diagnoses of type 1 diabetes was observed with higher incidence in winter months.\ud\ud\udConclusion\udThis nation-wide retrospective epidemiological study using routine data revealed that the incidence of type 1 diabetes in Wales was greatest in those aged 0-14 years with a higher incidence and prevalence in the most deprived areas. These findings illustrate the need for health-related policies targeted at high deprivation areas to include type 1 diabetes in their remit.

Purpose To assess rural-urban differences in participation rates of diabetes self-management education and associated factors among Medicare beneficiaries with type 2 diabetes (T2DM). Methods Data were from the 2016 to 2018 Medicare Current Beneficiary Survey (MCBS). Participation in diabetes self-management education was self-reported. The study sample included 3,799 beneficiaries aged 65 years and older with self-reported T2DM. Logistic regression was used to assess the association of participation in diabetes self-management education and residential location. Sampling weights embedded in the MCBS were incorporated into all analyses. Findings Overall, the participation rate of diabetes self-management education was 46.8% (95% CI: 44.4%-49.2%). The rate was 40.3% for beneficiaries in rural areas, 48.0% for suburban areas, and 47.3% for urban areas. About 31% of beneficiaries newly diagnosed with diabetes did not participate within the past year. Controlling for other covariates, beneficiaries in rural areas were less likely to have participated in diabetes self-management education (AOR = 0.73, 95% CI: 0.55-0.95) than those living in urban areas. Asian Americans were less likely to have participated (AOR = 0.49, 95% CI: 0.28-0.84) than Whites. Those who were older, with lower education, and lower income levels were less likely to have participated (P Conclusions Recent MCBS data indicate that more than half of Medicare beneficiaries with T2DM did not participate in diabetes self-management education, and the participation rate in rural areas was 7 percentage points lower than that ​in urban areas. The study findings highlight challenges to maximize the benefits of participating in diabetes self-management education, particularly in rural areas.

Parkinson disease (PD) and other related diseases with α-synuclein pathology are associated with a long prodromal or preclinical stage of disease. Predictive models based on diagnosis of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) make it possible to identify people in the prodromal stage of synucleinopathy who have a high probability of future disease and provide an opportunity to implement neuroprotective therapies. However, rehabilitation providers may be unaware of iRBD and the motor abnormalities that indicate early motor system dysfunction related to α-synuclein pathology. Furthermore, there is no existing rehabilitation framework to guide early interventions for people with iRBD. The purpose of this work is to (1) review extrapyramidal signs of motor system dysfunction in people with iRBD and (2) propose a framework for early protective or preventive therapies in prodromal synucleinopathy using iRBD as a predictive marker. Longitudinal and cross-sectional studies indicate that the earliest emerging motor deficits in iRBD are bradykinesia, deficits performing activities of daily living, and abnormalities in speech, gait, and posture. These deficits may emerge up to 12 years before a diagnosis of synucleinopathy. The proposed rehabilitation framework for iRBD includes early exercise-based interventions of aerobic exercise, progressive resistance training, and multimodal exercise with rehabilitation consultations to address exercise prescription, progression, and monitoring. This rehabilitation framework may be used to implement neuroprotective, multidisciplinary, and proactive clinical care in people with a high likelihood of conversion to PD, dementia with Lewy bodies, or multiple systems atrophy.

Financial support provided by the Craig H. Neilsen Foundation.© Copyright 2020, Paralyzed Veterans of AmericaThese guidelines have been prepared based on scientific and professional information ava...

The impact of universal varicella vaccination on herpes zoster (HZ) risk in unvaccinated and vaccinated children, and its long-term influence on HZ epidemiology, remains unknown. We conducted a retrospective cohort study using population-based administrative health data for children born between 1993 and 2018 (n = 924,124). We calculated age-specific cumulative HZ incidence rates by vaccination status for cohorts born before (1993–1999) and after (2000–2018) programme implementation; results were used to calculate relative risk of HZ by age group, vaccination status and vaccine availability period. Annual HZ incidence rates were calculated for 1993–2018. HZ risk was higher among unvaccinated children compared to vaccinated children across age groups; 64% higher before universal vaccination (RR: 0.36, 95% CI: 0.33, 0.39), and 32% higher after universal vaccination (RR: 0.68, 95% CI: 0.64, 0.73). Among unvaccinated children, HZ risk was 60% lower after vaccine programme implementation (RR: 0.40, 95% CI: 0.38, 0.43). Two-dose receipt corresponded with a 41% lower risk of HZ compared to one-dose receipt (RR: 0.59, 95% CI: 0.53, 0.65). Crude annual HZ incidence rates declined 64% after programme implementation, with decreases observed across age groups. Universal varicella vaccination programme implementation corresponds to decreased paediatric HZ incidence across age groups, in both vaccinated and unvaccinated individuals. Results from this study can be used to help inform varicella vaccination programme decision-making in other countries.

Primiparous female rabbits have high nutritional requirements and, while it is recommended that they are subjected to an extensive reproductive rhythm, this could lead to overweight, affecting reproductive outcomes. We hypothesised that restricting food intake during the less energetic period of gestation could improve reproductive outcome without impairing offspring viability. This study compares two groups of primiparous rabbit does in an extensive reproductive programme, one in which feed was restricted from Day 0 to Day 21 of gestation (R021), and another in which does were fed ad libitum (control) throughout pregnancy. The mother and offspring variables compared were (1) mother reproductive outcomes at the time points pre-implantation (Day 3 postartificial insemination [AI]), preterm (Day 28 post-AI) and birth; and (2) the prenatal offspring characteristic IGF system gene expression in foetal liver, liver fibrosis and foetus sex ratio, and postnatal factor viability and growth at birth, and survival and growth until weaning. Feed restriction did not affect the conception rate, embryo survival, or the number of morulae and blastocysts recovered at Day 3 post-AI. Preterm placenta size and efficiency were similar in the two groups. However, both implantation rate (P < 0.001) and the number of foetuses (P = 0.05) were higher in the R021 mothers than controls, while there was no difference in foetal viability. Foetal size and weight, the weights of most organs, organ weight/BW ratios and sex ratio were unaffected by feed restriction; these variables were only affected by uterine position (P < 0.05). Conversely, in the R021 does, foetal liver IGBP1 and IGF2 gene expression were dysregulated despite no liver fibrosis and a normal liver structure. No effects of restricted feed intake were produced on maternal fertility, prolificacy, or offspring birth weight, but control females weaned more kits. Litter weight and mortality rate during the lactation period were also unaffected. In conclusion, pre-implantation events and foetal development were unaffected by feed restriction. While some genes of the foetal hepatic IGF system were dysregulated during pregnancy, liver morphology appeared normal, and the growth of foetuses and kits until weaning was unmodified. This strategy of feed restriction in extensive reproductive rhythms seems to have no significant adverse effects on dam reproductive outcome or offspring growth and viability until weaning.

Neonatal HNT in the pharynx is a rare cause of respiratory distress and poor feeding in the newborn, but must be differentiated from teratoma, encephalocele, and nasal glioma. While surgical resection is the preferred treatment modality, we posit there is a role for sclerosis of the glial heterotopic cyst if complete surgical excision is not possible or carries risk of high morbidity. Here, we present a case of a 7-day-old neonate presenting with acute respiratory distress found to have a nasopharyngeal/oropharyngeal mass ultimately treated with sclerotherapy at 9 months of age.