Search

AMP deaminase 1 (AMPD1) deficiency has been associated with premature muscle fatigue and reduced work capacity, but this finding has been inconsistent. Herein, we report that although AMPD1 knockdown in mouse skeletal muscle does not change maximal isometric force, it negatively impacts muscle function by slowing contraction and relaxation kinetics in EDL muscle but not SOL muscle. Furthermore, AMPD1 knockdown differentially affects the [AMP]/AMPK responses to fatiguing contractions in an intensity-dependent manner in EDL muscle.

Pre-drinking behaviour has grown in prevalence and generates harm for pre-drinkers and others. In this article, we answer three research questions: (i) Where and when do pre-drinkers obtain their alcohol?; (ii) What is the difference in the level of intoxication of pre-drinkers versus non-pre-drinkers, and how does this difference vary over the course of a night?; and (iii) Is the level of intoxication of pre-drinkers related to where and when they obtain their alcohol?We obtained data from 469 respondents using a street-intercept survey conducted in Hamilton, New Zealand in 2019. Data were analysed by cross-tabulation, linear regression and plotting the average intoxication level in the night-time economy over time.The majority of pre-drinkers purchase their alcohol for pre-drinking on the day of consumption. Half of the same-day purchasers purchase before 6 pm. The average level of intoxication increases over the course of the night, and is unambiguously higher for pre-drinkers than non-pre-drinkers. The level of intoxication does not differ based on the source or timing of pre-drinking purchases. The main motivation for pre-drinking was price, especially among women.Pre-drinking is a contributor to intoxication in the night-time economy, but most drinkers purchase their alcohol for pre-drinking before 7 pm. Further research is required to understand whether trading hours restrictions for off-premises alcohol suppliers will affect the most harmful drinking patterns. Price interventions to reduce the price differential between on-licenced and off-licence alcohol outlets offer the greatest potential to reduce pre-drinking and associated harm.

Purpose To compare visual acuity (VA) and OCT outcomes in patients with idiopathic macular telangiectasia (IMT) type 2 who underwent pars plana vitrectomy (PPV) surgery for full-thickness macular holes (FTMHs) versus those who elected to be medically managed (MM) without surgery. Design Comparative retrospective case series. Participants Patients with IMT type 2 and FTMH. Methods We reviewed records within an 11-year period and collected data on VA, OCT changes, development of choroidal neovascularization, and length of follow-up. The VA measurements were standardized from Snellen to logarithm of the minimum angle of resolution units for statistical analysis. Two-sample t tests were used to analyze VA data. OCT changes were assessed by a single masked retinal specialist. Results There were 12 eyes in the PPV group and 26 eyes in the MM group. There was no statistically significant VA improvement in either group between initial VA recording and last follow-up. The PPV group had no significant change in VA between the preoperative visit and the visits at 3 or 12 months. OCT scans improved by 1 step in 10 patients in the PPV group. None of the patients in the MM group had OCT improvement. Choroidal neovascularization developed in 1 eye in the PPV group and 5 eyes in the MM group. Conclusions There was no significant change in VA in patients who opted to have PPV to treat their IMT type 2 and FTMH compared with those who did not undergo surgery. OCT scans improved by qualitative judgment in patients who underwent surgery compared with those who opted for medical management.

INTRODUCTION Pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) are severe but highly treatable postinfectious inflammatory brain conditions. Despite published diagnostic and treatment guidelines for this condition, there are long delays in obtaining appropriate care. The reasons for these delays are poorly understood. We sought to identify health care system barriers to timely treatment by examining cases of PANDAS/PANS occurring in children of health care professionals. METHOD We recruited families via e-mail request through the PANDAS Physicians Network. Participating parents completed a structured questionnaire and provided a written case description. RESULTS Eleven families completed data collection, representing a broad spectrum of disease (child disease onset age 4-15, 7 males/4 females, mild to severe). Parents included 11 physicians, 2 mental health professionals, 2 nurses, and a PharmD. Nine cases (82%) had "very delayed" diagnosis and treatment (>4 weeks after onset). The most commonly encountered causes for treatment delay were clinician lack of awareness (82%), clinician skepticism (82%), overdependence on diagnostic testing (91%), and out-of-pocket expenses >$100 US (82%). Other common challenges included difficulties finding a provider to spearhead care (64%), psychological misdiagnosis (55%), and children's suppression of behaviors during assessments (55%). CONCLUSIONS We found numerous barriers to treatment of PANDAS/PANS among children of health care providers. Our findings suggest that even among the medically sophisticated, PANDAS/PANS diagnosis and treatment remains challenging. Improvement in PANDAS/PANS education of clinicians who may encounter children with this disorder is 1 key step toward addressing our identified barriers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Despite improvements in treatment, people with type 1 diabetes continue to have increased cardiovascular disease (CVD) risk. Glycemic control does not fully explain this excess CVD risk, so a greater understanding of other risk factors is needed.The authors review the relationship between glycemia and CVD risk in adults with type 1 diabetes and summarize evidence regarding other factors that may explain risk beyond glycemia. Insulin resistance, weight gain, sex differences, genetics, inflammation, emerging markers of risk, including lipid subclasses and epigenetic modifications, and future directions are discussed. As glycemic control improves, an increased focus on other CVD risk factors is warranted in type 1 diabetes. Novel markers and precision medicine approaches may improve CVD prediction, but a lack of type 1 diabetes-specific guidelines for lipids, blood pressure, and physical activity are likely impediments to optimal CVD prevention in this high-risk population.

Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.

Functional changes in the brain during ageing can alter learning and memory, gait and balance – in some cases leading to early cognitive decline, disability or injurious falls among older adults. Dietary interventions with strawberry (SB) have been associated with improvements in neuronal, psychomotor and cognitive functions in rodent models of ageing. We hypothesised that dietary supplementation with SB would improve mobility and cognition among older adults. In this study, twenty-two men and fifteen women, between the ages of 60 and 75 years, were recruited into a randomised, double-blind, placebo-controlled trial in which they consumed either freeze-dried SB (24 g/d, equivalent to two cups of fresh SB) or a SB placebo for 90 d. Participants completed a battery of balance, gait and cognitive tests at baseline and again at 45 and 90 d of intervention. Significant supplement group by study visit interactions were observed on tests of learning and memory. Participants in the SB group showed significantly shorter latencies in a virtual spatial navigation task (P = 0·020, ηp2 = 0·106) and increased word recognition in the California Verbal Learning test (P = 0·014, ηp2 = 0·159) across study visits relative to controls. However, no improvement in gait or balance was observed. These findings show that the addition of SB to the diets of healthy, older adults can improve some aspects of cognition, but not gait or balance, although more studies with a larger sample size and longer follow-up are needed to confirm this finding.

Blueberries (BB) contain an array of bioactive phenolic compounds that may play a protective role against various age-related diseases. Here we explored the metabolic fate of BB phenolics and their relationship to cognitive function after chronic (90 days) supplementation of freeze-dried BB (24 g d-1, equivalent to 1 cup of fresh BB) or control in a randomized, double-blind, parallel study with 38 healthy older adults (60-75 years). Blood samples were collected at fasting (t = 0 h) and 2 h after a breakfast meal on days 0 (no treatment), 45, and 90, and a battery of cognitive tests was also conducted on these days. Hippuric acid, phloroglucinaldehyde, syringic acid, ferulic acid-glucuronide, cyanidin-3-O-galactoside, cyanidin-3-O-glucoside, malvidin-3-O-galactoside, malvidin-3-O-glucoside, peonidin-3-O-xyloside, peonidin glucuronide, and petunidin-3-O-glucoside concentrations were significantly altered after 90 days of BB consumption compared to control. Stepwise regression was used to assess the relationship between significantly altered concentrations of plasma phenolics and observed improvements in cognition. Among participants in the BB group, changes in switch errors on the task-switching test (TST) from day 0 to 90 were associated with changes in postprandial levels of plasma ferulic acid-glucuronide, syringic acid, and malvidin-3-galactoside (R2 = 0.521, p < 0.05). Changes in repetition errors on the California Verbal Learning Test (CVLT-II) from day 0 to 90 were associated with changes in postprandial levels of ferulic acid-glucuronide, syringic acid, and hippuric acid (R2 = 0.807, p < 0.001). These findings demonstrate that the addition of easily achievable quantities of BB to the diets of older adults significantly alters levels of circulating phenolic compounds which are related to improvements in cognition.

Background: The importance of leisure sedentary behavior (LSB) change in diabetes prevention efforts is not well known. This study examines the relationships between changes in self-reported LSB and the primary intervention goals (weight and moderate-intensity to vigorous-intensity physical activity [MVPA]) during a community-based translation of the Diabetes Prevention Program (the Group Lifestyle Balance Program). Methods: A total of 322 adults at risk for type 2 diabetes were recruited from 3 community centers, a worksite, and military site. Community and worksite participants were randomized to immediate or delayed-delivery (control) intervention. All military site participants (n = 99) received immediate intervention. Logistic and linear generalized estimating equations were used to determine associations between LSB changes and weight-related outcomes and MVPA. Results: Results were obtained for 259 (80.4%) participants. The LSB decreased after 6 and 12 months (mean [95% confidence interval]: −25.7 [−38.6 to −12.8] and −16.1 [−28.2 to −3.9] min/d; both P P = .042; adjusted model including MVPA), but LSB was not related to changes in reported MVPA minutes or MVPA goal achievement. Conclusion: Within the context of existing lifestyle intervention programs, reducing sedentary behavior has the potential to contribute to weight loss separately from reported MVPA improvement.

Background Group lifestyle sessions with phone maintenance could improve weight, health, and function in vulnerable older adults. Methods Community-dwelling adults (N = 322) with body mass index (BMI, kg/m2) ≥27 and additional risk factors received 12 one-hour in-person behavioral weight management group sessions then were randomized to 8 half-hour telephone sessions (n = 162) or newsletter control (n = 160) from 4 to 12 months with no treatment contact thereafter. Primary outcome was 0- to 12-month weight change. Cardiometabolic, short physical performance battery (SPPB), and self-reported activity changes were assessed at 12 and 24 months. Results At baseline, the mean (SD) age was 71.2 (4.3) and BMI was 33.8 (5.1). Participants were 77% women, 13% Black, 85% retired, averaging 4 medical conditions, and taking blood pressure (67.4%) and lipid-lowering (51.6%) medications. At 12 months, a greater proportion of the phone group (66.0%) achieved ≥5% weight loss compared with newsletter control (53.2%; p = .02). Mean (95% CI) weight loss was greater for phone (−6.6 kg [−7.5, −5.8]) than newsletter (−5.1 kg [−7.2, −3.0]); p = .01. Modest lipid, glucose, and blood pressure improvements were found, but did not differ significantly between groups. Small SPPB and activity improvements were maintained at 12 and 24 months in both groups. Conclusions Brief phone contacts compared to newsletters enhanced weight loss maintenance among older high-risk adults at 1 year, but not cardiometabolic outcomes. Modest functional improvements were observed in both. Lower-intensity maintenance contacts (phone or newsletter) for weight, health, and physical function in older adults warrant further study. Clinical Trials Registration Number NCT03192475

Pharmaceutical marketing campaigns and biomedical discourses tend to oppose two types of sexual enhancement medication (SEM) use. While "therapeutic" use is associated with older heterosexual men in committed relationships, "recreational" use is associated with young gay men, and with the context of casual sex. However, little is known about the real objectives of older men (especially older gay men) who use SEM or the contexts in which they use such drugs. Furthermore, SEM conveys representations of masculinity and sexuality that focus on performance and youth, and the influence of these representations on SEM users remains unexplored. Based on semi-structured interviews conducted, in French, in 2015-2016, with 27 Canadian men (12 heterosexual, 15 gay) aged 65 to 84 years, we examined the context in which older men used such medication and the reasons why they used it, and we explored how older men's notions of sexuality, masculinity, and aging influenced their experiences with SEM use. Our participants' narratives focused on three themes: exploring sexual possibilities/improving one's sex life, restoring sexual capacities, and masculinity and aging. This study improves our understanding of older men's use of SEM and contributes to the deconstruction of normative models of older men's masculinity and sexuality.

Burnout within health care is prevalent, and its effects are detrimental to patient outcomes, organizations, and individuals. Effects stemming from burnout include anxiety, depression, excessive alcohol and drug use, cardiovascular problems, time off work, and worse patient outcomes. Published data have suggested up to 50% of health care workers experience burnout and 79% of respiratory therapists (RTs) experience burnout. Leadership has been cited as a key driver of burnout among RTs. We aimed to identify factors associated with a positive or negative leadership perception.A post hoc analysis of an institutional review board-approved survey to evaluate RT burnout, administered via REDCap by convenience sample to 26 health care centers (3,124 potential respondents) from January 17-March 15, 2021, was performed to identify factors associated with a positive view of leadership. Survey questions included validated tools to measure leadership, burnout, staffing, COVID-19 exposure, and demographics. Data analysis was descriptive, and logistic regression was performed to evaluate factors associated with leadership perception.Of 1,080 respondents, 710 (66%) had a positive view of leadership. Univariate analysis revealed those with a positive view of leadership were more likely to be working with adequate staffing, were rarely unable to complete all work, were less likely to be burned out, disagreed that people in this work environment were burned out, were less likely to miss work for any reason, more likely to be in a leadership position, worked fewer hours in intensive care, worked in a center affiliated with a medical school, worked day shift, were less likely to care for adult patients, and were more likely to be male. Logistic regression revealed providing care to patients with COVID-19 (odds ratio [OR] 5.8-10.5,Most RTs had a positive view of their leadership. A negative leadership score was associated with higher burnout and missing work. This relationship requires further investigation to evaluate if changes in leadership practices can improve employee well-being and reduce burnout.

Exposure to ozone is a well-documented risk factor for negative physical health outcomes but has been considered less frequently in the context of socioemotional health. We examined whether levels of neighborhood ozone predicted trajectories of depressive symptoms over a four-year period in 213 adolescents (ages 9-13 years at baseline; 57% female; 53% of minority race/ethnicity). Participants self-reported depressive and other types of psychopathology symptoms up to 3 times, and their home addresses were used to compute ozone levels in their census tract. Possible confounding variables, including personal, family, and neighborhood characteristics, were also assessed. We found that higher ozone predicted steeper increases in depressive symptoms across adolescent development, a pattern that was not observed for other forms of psychopathology symptoms. These findings underscore the importance of considering ozone exposure in understanding trajectories of depressive symptoms across adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Illicit drug use has been found to increase the risks of male barroom aggression (MBA). Personality traits such as dispositional aggressiveness have been associated with illicit substance use and aggressive behaviour, along with social normative masculinity factors. The present study assessed the relationships between illicit drug use, key personality (trait aggression, impulsivity, narcissism) and masculinity (conformity to masculine norms, male honour) variables with physical MBA perpetration and victimisation among male Australian construction workers.A purposive, high-risk sample of male construction workers aged 18-69 years (n = 476, MParticipants reported high rates of both physical MBA perpetration (21%; n = 100) and victimisation (31.1%; n = 148) as well as any illicit drug use (33.61%; n = 160). Logistic regressions revealed the use of amphetamine-type stimulants (methamphetamine, ecstasy) was associated with violence perpetration, even after accounting for high-intensity drinking (HID) which was the strongest predictor of MBA involvement. Trait variables (Trait Physical aggressiveness, narcissism) and the masculine norm CMNI Violence were also risk factors for MBA perpetration while CMNI Playboy was protective against MBA.The use of amphetamine-type stimulants is a risk-factor for MBA perpetration, as are key personality traits such as aggressiveness and narcissism. Most aspects of masculinity, including male honour, were either unrelated to or protective against involvement in physical violence in bars, clubs or pubs.

A useful model for determining the mechanisms by which actin and actin binding proteins control cellular architecture is the

The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition., PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Variation in development time can affect life-history traits that contribute to fitness. In Gryllus vocalis, a non-diapausing cricket with variable development time, we used a path analysis approach to determine the causative relationships between parental age, offspring development time and offspring life-history traits. Our best-supported path model included both the effects of parental age and offspring development time on offspring morphological traits. This result suggests that offspring traits are influenced by both variation in acquisition of resources and trade-offs between traits. We found that crickets with longer development times became larger adults with better phenoloxidase-based immunity. This is consistent with the hypothesis that crickets must make a trade-off between developing quickly to avoid predation before reproduction and attaining better immunity and a larger adult body size that provides advantages in male-male competition, mate choice and female fecundity. Slower-developing crickets were also more likely to be short-winged (unable to disperse by flight). Parental age has opposing direct and indirect effects on the body size of daughters, but when both the direct and indirect effects of parental age are taken into account, younger parents had smaller sons and daughters. This pattern may be attributable to a parental trade-off between the number and size of eggs produced with younger parents producing more eggs with fewer resources per egg. The relationships between variables in the life-history traits of sons and daughters were similar, suggesting that parental age and development time had similar causative effects on male and female life-history traits.

Background The Diabetes Prevention Program (DPP) behavioral lifestyle intervention was effective among a diverse sample of adults with prediabetes. Demonstrated effectiveness in translated versions of the DPP lifestyle intervention (such as Group Lifestyle Balance, DPP-GLB) led to widescale usage with national program oversight and reimbursement. However, little is known about the success of these DPP-translation programs across subgroups of sociodemographic factors. This current effort investigated potential disparities in DPP-translation program primary goal achievement (physical activity and weight) by key sociodemographic factors. Methods Data were combined from two 12-month community-based DPP-GLB trials among overweight/obese individuals with prediabetes and/or metabolic syndrome. We evaluated change in weight (kilograms and percent) and activity (MET-hrs/week) and goal achievement (yes/no; ≥5% weight loss and 150 min per week activity) after 6 and 12 months of intervention within and across subgroups of race/ethnicity (non-Hispanic white, non-Hispanic black), employment status, education, income, and gender. Results Among 240 participants (85%) with complete data, most sociodemographic subgroups demonstrated significant weight loss. However, non-Hispanic white lost more weight at both 6 and 12 months compared to non-Hispanic black participants [median weight loss (IQR), 6 months: 5.7% (2.7–9.0) vs. 1.5% (1.2–7.5) p = .01 and 12 months: 4.8% (1.1–9.6) vs. 1.1% (− 2.0–3.7) p = .01, respectively]. In addition, a larger percentage of non-Hispanic white demonstrated a 5% weight loss at 6 and 12 months. Employment was significantly related to 12-month weight loss, with retired participants being the most successful. Men, participants with graduate degrees, and those with higher income were most likely to meet the activity goal at baseline and 12 months. Differences in physical activity goal achievement across gender, education, and income groups were significant at baseline, attenuated after 6 months, then re-emerged at 12 months. Conclusions The DPP-GLB was effective in promoting weight loss and helped to alleviate disparities in physical activity levels after 6 months. Despite overall program success, differences in weight loss achievement by race/ethnicity were found and disparities in activity re-emerged after 12 months of intervention. These results support the need for intervention modification providing more tailored approaches to marginalized groups to maximize the achievement and maintenance of DPP-GLB behavioral goals. Trial registration NCT01050205, NCT02467881.

Early life stress (ELS) may accelerate frontoamygdala development related to socioemotional processing, serving as a potential source of resilience. Whether this circuit is associated with other proposed measures of accelerated development is unknown. In a sample of young adolescents, we examined the relations among ELS, frontoamygdala circuitry during viewing of emotional faces, cellular aging as measured by telomere shortening, and pubertal tempo. We found that greater cumulative severity of ELS was associated with stronger negative coupling between bilateral centromedial amygdala and the ventromedial prefrontal cortex, a pattern that may reflect more mature connectivity. More negative frontoamygdala coupling (for distinct amygdala subdivisions) was associated with slower telomere shortening and pubertal tempo over 2 years. These potentially protective associations of negative frontoamygdala connectivity were most pronounced in adolescents who had been exposed to higher ELS. Our findings provide support for the formulation that ELS accelerates maturation of frontoamygdala connectivity and provide novel evidence that this neural circuitry confers protection against accelerated biological aging, particularly for adolescents who have experienced higher ELS. Although negative frontoamygdala connectivity may be an adaptation to ELS, frontoamygdala connectivity, cellular aging, and pubertal tempo do not appear to be measures of the same developmental process.

Background Bereaved children often struggle in the school environment and school personnel often feel inadequately prepared to support them. This pilot study explored the experiences and opinions of school staff regarding approaches to addressing the needs of bereaved students in the classroom. Methods Teachers/school personnel (N = 29) completed written open-ended questions about their experiences with bereaved students and opinions regarding a bereavement-focused accommodation (ie, 504) plan. Responses were summarized using qualitative content analysis. Results Most participants (93%) reported interacting with bereaved students and: (1) providing emotional support; (2) making classroom accommodations; (3) collaborating with the family/community; and (4) referring the student for counseling. Many (72%) expressed interest in a templated bereavement plan (21% did not respond; 7% said no) with education/resources for school personnel and suggested accommodations for students. Conclusions Teachers encountering grieving students would welcome a templated bereavement plan to help meet students' needs. Such a plan would allow staff to become more knowledgeable about grief and provide guidance for developing specific strategies to accommodate grieving students both emotionally and academically.

Introduction The delivery of emergency medical services is primarily performed by emergency medical technicians and paramedics in the United States. More recently, nurses and physicians have become more involved in the delivery of emergency medical services. Advanced placement paramedic education bridging programs have been developed to prepare the workforce, but the success of these programs is unknown. This study evaluated the demographics and performance of nonemergency medical services health care professionals who attended an advanced placement paramedic education program at a Midwestern university. Methods This was a retrospective evaluation of student data from 2007 to 2017. Descriptive statistics were used to tabulate demographics, program performance, and individual performance in the National Paramedic Certification Examination. Results The program admitted 305 students; registered nurses (95%) were the majority of students. Of the 305 admitted students, 271 (88.9%) fulfilled all program requirements and were eligible to take the National Registry of Emergency Medical Technicians paramedic certification examination. Of these 271 eligible students, 201 (74.2%) took the National Paramedic Certification Examination. A total of 195 (97%) obtained certification at the first test attempt, whereas 200 (99.5%) obtained certification within 3 attempts. Of the 200 who passed the test, 175 (88%) successfully demonstrated entry-level competency in paramedic-level psychomotor testing. Discussion The advanced placement paramedic program evaluated in this study had high rates of successful program completion, as well as high first-time and cumulative passing rates for the National Paramedic Certification Examination. Further research is needed to identify the best practices in determining student requirements and the methodologies in delivering advanced placement paramedic education bridging programs.

Hanson, NJ, Scheadler, CM, Katsavelis, D, and Miller, MG. Validity of the Wattbike 3-minute aerobic test: measurement and estimation of V[Combining Dot Above]O2max. J Strength Cond Res XX(X): 000-000, 2019-The Wattbike includes a 3-minute aerobic test (3mAT) along with an estimation of V[Combining Dot Above]O2max. The estimation equation that is used is from a previous study using a different protocol and sedentary subjects. The purpose of this study was to determine whether (a) the 3mAT is able to elicit V[Combining Dot Above]O2max, and (b) whether this estimation is accurate. Thirteen cyclists (10 men; age: 29.2 ± 10.0 years, height 178.7 ± 8.3 cm, and mass 75.1 ± 12.5 kg) with a range of experience volunteered for this study. At the first visit, a self-paced V[Combining Dot Above]O2max (SPV) test was performed to obtain the "true" V[Combining Dot Above]O2max. At the second session, subjects completed the 3mAT. Primary dependent variables included maximal values of oxygen consumption (V[Combining Dot Above]O2), carbon dioxide production (V[Combining Dot Above]CO2), heart rate (HR), ventilation (VE), and respiratory exchange ratio (RER). A repeated-measures analysis of variance showed no difference (p = 0.367) between V[Combining Dot Above]O2max values (3mAT estimation: 54.3 ± 9.3 ml·kg·min, 3mAT measured: 52.5 ± 8.7, SPV: 54.0 ± 9.7). Paired-samples t-tests showed that HR (p = 0.027) was higher in the SPV (184.7 ± 10.6 vs. 180.9 ± 6.3 b·min), whereas RER and V[Combining Dot Above]CO2 were both higher in the 3mAT (1.29 ± 0.10 vs. 1.19 ± 0.06 and 4.92 ± 1.01 vs. 4.62 ± 0.98, respectively; both p < 0.05). The intraclass correlation between the V[Combining Dot Above]O2max measured from the SPV and 3mAT was 0.96 (95% CI: 0.88-0.99, p < 0.001), and between the 3mAT measured and estimated values was 0.91 (95% CI: 0.71-0.97 p < 0.001). If an athlete has access to a Wattbike, they can complete the 3mAT, receive their V[Combining Dot Above]O2max estimation, and be confident of its accuracy.

Electroencephalography research surrounding maximal exercise testing has been limited to male subjects. Additionally, studies have used open-looped protocols, meaning individuals do not know the exercise endpoint. Closed-loop protocols are often shown to result in optimal performance as self-pacing is permitted. The purpose of this study was to compare brain activity during open- and closed-loop maximal exercise protocols, and to determine if any sex differences are present. Twenty-seven subjects (12 males, ages 22.0 ± 2.5 years) participated in this study. A pre-assembled EEG sensor strip was used to collect brain activity from specific electrodes (F3/F4: dorsolateral prefrontal cortex, or dlPFC; and C3/Cz/C4: motor cortex, or MC). Alpha (8–12 Hz) and beta (12–30 Hz) frequency bands were analyzed. Subjects completed two maximal exercise tests on a cycle ergometer, separated by at least 48 h: a traditional, open-loop graded exercise test (GXT) and a closed-loop self-paced VO2max (SPV) test. Mixed model ANOVAs were performed to compare power spectral density (PSD) between test protocols and sexes. A significant interaction of time and sex was shown in the dlPFC for males, during the GXT only (p = 001), where a peak was reached and then a decrease was shown. A continuous increase was shown in the SPV. Sex differences in brain activity during exercise could be associated with inhibitory control, which is a function of the dlPFC. Knowledge of an exercise endpoint could be influential towards cessation of exercise and changes in cortical brain activity.

Aim To assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship. Methods Data were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992–94, received a partial mouth periodontal exam, and who were followed for up to 19 years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4 mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models. Results During 19 years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HR = 1.12, CI = 1.01–1.23) and Hard CAD (HR = 1.30, CI = 1.11–1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HR = 1.25, CI = 1.03–1.50) and Hard CAD (HR = 1.85, CI = 1.17–2.93) only among smokers. Conclusion PD was a significant predictor of CAD and Hard CAD among current smokers with T1D.

OBJECTIVE: Exposure to high levels of fine particle air pollution (PM(2.5)) is associated with adolescent pathophysiology. It is unclear, however, if PM(2.5) is associated with physiology within psychosocial contexts, such as social stress, and whether some adolescents are particularly vulnerable to PM(2.5) -related adverse effects. This study examined the association between PM(2.5) and autonomic reactivity to social stress in adolescents and tested whether symptoms of anxiety and depression moderated this association. METHODS: Adolescents from Northern California (n=144) participated in a modified Trier Social Stress Test (TSST) while providing high-frequency heart rate variability (HRV) and skin conductance level (SCL) data. PM(2.5) data were recorded from CalEnviroScreen. Adolescents reported on their own symptoms of anxiety and depression using the Youth Self-Report, which has been used in prior studies and has good psychometric properties (Cronbach’s alpha in this sample was 0.86). RESULTS: Adolescents residing in neighborhoods characterized by higher concentrations of PM(2.5) demonstrated greater autonomic reactivity (i.e., indexed by lower HRV and higher SCL) (β=.27; b=0.44, p=.001, 95% CI [0.19, 0.68]) in response to social stress; this association was not accounted for by socioeconomic factors. In addition, adolescents who reported more severe anxiety and depression symptoms showed the strongest association between PM(2.5) and autonomic reactivity to social stress (β=.53; b=0.86, p

Thioredoxin reductase-1 (TrxR1)-, glutathione reductase (Gsr)-, and Nrf2 transcription factor-driven antioxidant systems form an integrated network that combats potentially carcinogenic oxidative damage yet also protects cancer cells from oxidative death. Here we show that although unchallenged wild-type (WT), TrxR1-null, or Gsr-null mouse livers exhibited similarly low DNA damage indices, these were 100-fold higher in unchallenged TrxR1/Gsr–double-null livers. Notwithstanding, spontaneous cancer rates remained surprisingly low in TrxR1/Gsr-null livers. All genotypes, including TrxR1/Gsr-null, were susceptible to N -diethylnitrosamine (DEN)-induced liver cancer, indicating that loss of these antioxidant systems did not prevent cancer cell survival. Interestingly, however, following DEN treatment, TrxR1-null livers developed threefold fewer tumors compared with WT livers. Disruption of TrxR1 in a marked subset of DEN-initiated cancer cells had no effect on their subsequent contributions to tumors, suggesting that TrxR1-disruption does not affect cancer progression under normal care, but does decrease the frequency of DEN-induced cancer initiation. Consistent with this idea, TrxR1-null livers showed altered basal and DEN-exposed metabolomic profiles compared with WT livers. To examine how oxidative stress influenced cancer progression, we compared DEN-induced cancer malignancy under chronically low oxidative stress (TrxR1-null, standard care) vs. elevated oxidative stress (TrxR1/Gsr-null livers, standard care or phenobarbital-exposed TrxR1-null livers). In both cases, elevated oxidative stress was correlated with significantly increased malignancy. Finally, although TrxR1-null and TrxR1/Gsr-null livers showed strong Nrf2 activity in noncancerous hepatocytes, there was no correlation between malignancy and Nrf2 expression within tumors across genotypes. We conclude that TrxR1, Gsr, Nrf2, and oxidative stress are major determinants of liver cancer but in a complex, context-dependent manner.

BACKGROUND: Asthma is a common reason for admissions to the pediatric intensive care unit (PICU). Since June 2014, our institution has used a pediatric asthma clinical pathway for all patients, including those in PICU. The pathway promotes respiratory therapist– driven bronchodilator weaning based on the Modified Pulmonary Index Score (MPIS). This pathway was associated with decreased hospital length of stay (LOS) for all pediatric asthma patients; however, the effect on PICU patients was unclear. We hypothesized that the implementation of a pediatric asthma pathway would reduce hospital LOS for asthmatic patients admitted to the PICU. METHODS: We retrospectively reviewed the medical records of all pediatric asthma subjects 2–17 y old admitted to our PICU before and after pathway initiation. Primary outcome was hospital LOS. Secondary outcomes were PICU LOS and time on continuous albuterol. Data were analyzed using the chi-square test for categorical data, the t test for normally distributed data, and the Mann-Whitney test for nonparametric data. RESULTS: A total of 203 eligible subjects (49 in the pre-pathway group, 154 in the post group) were enrolled. There were no differences between groups for age, weight, gender, home medications, cause of exacerbation, medical history, or route of admission. There were significant decreases in median (interquartile range) hospital LOS (4.4 [2.9 – 6.6] d vs 2.7 [1.6 – 4.0] d, P CONCLUSIONS: The implementation of an asthma pathway was associated with decreased hospital LOS, PICU LOS, and time on continuous albuterol. There was also an increase in the use of high-flow nasal cannula and noninvasive ventilation after the implementation of this clinical pathway.

Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial.The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes.As of July 1, 2021, 5,076 subjects had been randomized.The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

Background:Parents who receive a diagnosis of a severe, life-threatening CHD for their foetus or neonate face a complex and stressful decision between termination, palliative care, or surgery. Understanding how parents make this initial treatment decision is critical for developing interventions to improve counselling for these families.Methods:We conducted focus groups in four academic medical centres across the United States of America with a purposive sample of parents who chose termination, palliative care, or surgery for their foetus or neonate diagnosed with severe CHD.Results:Ten focus groups were conducted with 56 parents (Mage = 34 years; 80% female; 89% White). Results were constructed around three domains: decision-making approaches; values and beliefs; and decision-making challenges. Parents discussed varying approaches to making the decision, ranging from relying on their “gut feeling” to desiring statistics and probabilities. Religious and spiritual beliefs often guided the decision to not terminate the pregnancy. Quality of life was an important consideration, including how each option would impact the child (e.g., pain or discomfort, cognitive and physical abilities) and their family (e.g., care for other children, marriage, and career). Parents reported inconsistent communication of options by clinicians and challenges related to time constraints for making a decision and difficulty in processing information when distressed.Conclusion:This study offers important insights that can be used to design interventions to improve decision support and family-centred care in clinical practice.

This study investigated whether parents and kindergarten children show concurrent and time-lagged physiological synchrony during dyadic interaction. Further, we tested whether parent-child behavioral co-regulation was associated with concurrent and time-lagged synchrony, and whether synchrony varied by the type of interaction task. Participants were 94 children (Mage = 5.6 years, 56% female) and their parents. We simultaneously measured parent and child respiratory sinus arrhythmia (RSA) during four dyadic interaction tasks: free play, clean up, problem-solving, and puzzle teaching. We found that synchrony varied by task. Concurrent synchrony occurred only during the puzzle teaching task, such that parent and child RSA were significantly and positively associated with each other simultaneously. Time-lagged synchrony occurred only during the problem-solving task, such that parent RSA was positively associated with child RSA 30 seconds later, and child RSA was negatively associated with parent RSA 30 seconds later. Although behavioral co-regulation and physiological synchrony have been conceptualized as markers of responsive parent-child interactions, our study finds no evidence that physiological synchrony is associated with between-dyad differences in behavioral co-regulation.

Purpose The purpose of this study was to examine how maintenance session attendance and 6-month weight loss (WL) goal achievement impacted 12-month 5% WL success in older adults participating in a community-based Diabetes Prevention Program (DPP) lifestyle intervention. Methods Data were combined from 2 community trials that delivered the 12-month DPP-based Group Lifestyle Balance (GLB) to overweight/obese adults (mean age = 62 years, 76% women) with prediabetes and/or metabolic syndrome. Included participants (n = 238) attended ≥4 core sessions (months 0-6) and had complete data on maintenance attendance (≥4 of 6 sessions during months 7-12) and 6- and 12-month WL (5% WL goal, yes/no). Multivariate logistic regression was used to estimate the odds of 12-month 5% WL associated with maintenance attendance and 6-month WL. Associations between age (Medicare-eligible ≥65 vs Results Both attending ≥4 maintenance sessions and meeting the 6-month 5% WL goal increased the odds of meeting the 12-month 5% WL goal. For those not meeting the 6-month WL goal, maintenance session attendance did not improve odds of 12-month WL success. Medicare-eligible adults ≥65 years were more likely to meet the 12-month WL goal (odds ratio = 3.03, 95% CI, 1.58-5.81) versus Conclusions The results of this study provide important information regarding participant attendance and WL for providers offering DPP-based lifestyle intervention programs across the country who are seeking Medicare reimbursement. Understanding Medicare reimbursement-defined success will allow these providers to focus on and develop strategies to enhance program effectiveness and sustainability.

Study objective Emergency departments (EDs) often serve vulnerable populations who may lack primary care and have suffered disproportionate COVID-19 pandemic effects. Comparing patients having and lacking a regular source of medical care and other ED patient characteristics, we assessed COVID-19 vaccine hesitancy, reasons for not wanting the vaccine, perceived access to vaccine sites, and willingness to get the vaccine as part of ED care. Methods This was a cross-sectional survey conducted from December 10, 2020, to March 7, 2021, at 15 safety net US EDs. Primary outcomes were COVID-19 vaccine hesitancy, reasons for vaccine hesitancy, and sites (including EDs) for potential COVID-19 vaccine receipt. Results Of 2,575 patients approached, 2,301 (89.4%) participated. Of the 18.4% of respondents who lacked a regular source of medical care, 65% used the ED as their usual source of health care. The overall rate of vaccine hesitancy was 39%; the range among the 15 sites was 28% to 58%. Respondents who lacked a regular source of medical care were more commonly vaccine hesitant than those who had a regular source of medical care (47% versus 38%, 9% difference, 95% confidence interval 4% to 14%). Other characteristics associated with greater vaccine hesitancy were younger age, female sex, Black race, Latinx ethnicity, and not having received an influenza vaccine in the past 5 years. Of the 61% who would accept a COVID-19 vaccine, 21% stated that they lacked a primary physician or clinic at which to receive it; the vast majority (95%) of these respondents would accept the COVID-19 vaccine as part of their care in the ED. Conclusion ED patients who lack a regular source of medical care are particularly hesitant regarding COVID-19 vaccination. Most COVID-19 vaccine acceptors would accept it as part of their care in the ED. EDs may play pivotal roles in COVID-19 vaccine messaging and delivery to highly vulnerable populations.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

COVID-19 pathology involves dysregulation of diverse molecular, cellular, and physiological processes. To expedite integrated and collaborative COVID-19 research, we completed multi-omics analysis of hospitalized COVID-19 patients, including matched analysis of the whole-blood transcriptome, plasma proteomics with two complementary platforms, cytokine profiling, plasma and red blood cell metabolomics, deep immune cell phenotyping by mass cytometry, and clinical data annotation. We refer to this multidimensional dataset as the COVIDome. We then created the COVIDome Explorer, an online researcher portal where the data can be analyzed and visualized in real time. We illustrate herein the use of the COVIDome dataset through a multi-omics analysis of biosignatures associated with C-reactive protein (CRP), an established marker of poor prognosis in COVID-19, revealing associations between CRP levels and damage-associated molecular patterns, depletion of protective serpins, and mitochondrial metabolism dysregulation. We expect that the COVIDome Explorer will rapidly accelerate data sharing, hypothesis testing, and discoveries worldwide., Graphical Abstract, Sullivan et al. describe the development of a multidimensional dataset for the study of COVID-19 known as the COVIDome, which includes diverse clinical, transcriptome, proteome, metabolome, and immune cell datasets. A researcher portal known as the COVIDome Explorer was created to enable global data access and analysis.

AIMS We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (

Social anxiety disorder (SAD) is commonly diagnosed during adolescence and is associated with psychological stress reactivity and heightened physiological arousal. No study, however, has systematically examined which aspects of autonomic nervous system function mediate likely links between stress sensitivity and social anxiety symptoms in adolescents. Here, we assessed 163 adolescents (90 females; 12.29 ± 1.39 years) with respect to life stress and social anxiety symptoms, and measured respiratory sinus arrhythmia (RSA) and skin conductance levels (SCL) during a psychosocial stress paradigm. We operationalized stress sensitivity as the residual variance in subjective stress severity after accounting for objective severity and changes in autonomic regulation using standardized change scores in RSA and SCL. In females only, stress sensitivity and social anxiety symptoms were significantly correlated with each other (p < .001) and with autonomic regulation during both reactivity and recovery (all ps < 0.04). Further, sympathetic nervous system dominance during recovery specifically mediated associations between stress sensitivity and social anxiety symptoms (B = 1.06, 95% CI: 0.02–2.64). In contrast, in males, stress sensitivity, autonomic regulation during reactivity or recovery, and social anxiety symptoms were not significantly associated (all ps > 0.1). We interpret these results in the context of psychobiological models of SAD and discuss implications for interventions targeting autonomic processes.

Summary Background Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. Methods ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov , NCT03037385 , and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. Findings Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion–positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48–89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46–73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52–100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. Interpretation Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Funding Blueprint Medicines.

Compared to others, individuals living in communities of socioeconomic disadvantage experience more atherosclerotic cardiovascular disease (CVD) and a greater extent of preclinical atherosclerosis. Although the mechanisms underlying these associations remain unclear, it is widely hypothesized that alterations in normative cortisol release from the Hypothalamic Pituitary Adrenal (HPA) axis may play a role in linking lower community socioeconomic position (C-SEP) to CVD risk. The current study examined this hypothesis in relation to a marker of preclinical atherosclerosis among 488 healthy midlife adults (30–54 years, Mean age= 43, 52% Female, 81% White). All participants were employed and without clinical CVD. C-SEP was estimated from census tract data, and atherosclerosis was measured as intima-medial thickness of the carotid arteries (cIMT) by duplex ultrasonography. Four indicators of HPA activity [cortisol at awakening and the cortisol awakening response (CAR), rate of diurnal decline in cortisol (diurnal slope), and total output expressed as area under the curve (AUC)] were derived from salivary cortisol measurements obtained from 5 samples on each of 3 working days. Path analyses were used to examine associations of C-SEP with cIMT and HPA activity and to test whether individual differences in HPA activity could account for any association of C-SEP with cIMT using bootstrapping (5000 iterations). All models were adjusted for age, sex, race, and composite measures of both individual-level socioeconomic position (income, education, occupation), and cardiometabolic risk (systolic and diastolic blood pressure, waist circumference, fasting lipids and glucose). Lower C-SEP was related to both greater cIMT (b = −0.004, p = .021) and a flatter diurnal slope of cortisol (b = −0.001, p = .039). An indirect effect showed attenuated diurnal slope to partially mediate the relationship between C-SEP and cIMT (95% CI = −0.0018 to −0.0001), and a residual direct effect of C-SEP on cIMT remained significant (95% CI = −0.0097 to −0.004). These results suggest that low C-SEP associations with preclinical atherosclerosis may be due in part to correlated variation in adrenocortical activity.

Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (Protein coding variants in the hydroxysteroid 17

Buxton, JD, Prins, PJ, Miller, MG, Moreno, A, Welton, GL, Atwell, AD, Talampas, TR, and Elsey, GE. The effects of a novel quadrupedal movement training program on functional movement, range of motion, muscular strength, and endurance. J Strength Cond Res 36(8): 2186-2193, 2022-Quadrupedal movement training (QMT) is a form of bodyweight training incorporating animal poses, transitions, and crawling patterns to reportedly improve fitness. This type of training may improve multiple facets of fitness, unfortunately, little evidence exists to support commercial claims and guide practitioners in the best use of QMT. Therefore, the purpose of this study was to assess the impact of a commercially available QMT program on functional movement, dynamic balance, range of motion, and upper body strength and endurance. Forty-two active college-age (19.76 ± 2.10 years) subjects (males = 19, females = 23) were randomly assigned to a QMT ( n = 21) or control (CON) ( n = 21) group for 8 weeks. Quadrupedal movement training consisted of 60-minute classes performed 2×·wk -1 in addition to regular physical activity. Active range of motion, Functional Movement Screen (FMS), Y-Balance Test (YBT), handgrip strength, and push-up endurance were assessed before and after the intervention. The QMT group showed significantly greater improvements than the CON group in FMS composite score (1.62 ± 1.53 vs. 0.33 ± 1.15, p = 0.004) and FMS advanced movements (0.81 ± 0.87 vs. 0.01 ± 0.71, p = 0.002) and fundamental stability (0.57 ± 0.75 vs. 0.05 ± 0.50, p = 0.011), along with hip flexion, hip lateral rotation, and shoulder extension ( p0.05). No significant differences between groups were observed for dynamic balance or upper body strength and endurance. Our results indicate that QMT can improve FMS scores and various active joint ranges of motion. Quadrupedal movement training is a viable alternative form of training to improve whole-body stabilization and flexibility.

Minimally invasive glaucoma surgery (MIGS) is increasingly performed at the time of cataract extraction. Understanding the demographic and clinical characteristics of patients undergoing MIGS procedures may provide insight into patient selection. This study evaluates racial-ethnic and other differences in the use of MIGS in persons with cataract and open-angle glaucoma (OAG).Retrospective cohort study using Intelligent Research in Sight (IRIS) Registry data.Patients aged ≥ 40 years with a diagnosis of OAG and no history of MIGS or cataract surgery who were undergoing cataract extraction, with or without MIGS, during 2013 to 2017 in the United States.Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).Variables assessed include age, sex, race-ethnicity, disease severity, insurance type, census region, comorbidity, and cup-to-disc ratio (CDR).The odds of MIGS use was greater among patients who were aged ≥ 60 years (OR, 1.10 [95% CI, 1.05-1.16]); Black (OR, 1.11 [CI, 1.07-1.15]) compared with White; a Medicare recipient (OR, 1.12 [CI, 1.10-1.15]) versus privately insured; or in the Midwest (OR, 1.32 [CI, 1.28-1.36]) or Northeast (OR, 1.26 [CI, 1.22-1.30]) compared with the South. Having moderate rather than mild glaucoma (OR, 1.07 [CI, 1.04-1.11]) and a higher CDR (OR for 0.5 to 0.8 vs.0.5, 1.24 [CI, 1.21-1.26]; OR for0.8 to 1.0 vs.0.5, 1.27 [CI, 1.23-1.32]) were also each associated with increased odds of MIGS use. Use of MIGS was less likely in women (OR, 0.96 [CI, 0.94-0.98]); patients taking 5 to 7 glaucoma medications (OR, 0.94 [CI, 0.90-0.99]) compared with 1 to 2 medications; and patients with severe, compared with mild, glaucoma (OR, 0.64 [CI, 0.61-0.67]).This analysis highlights the importance of capturing race-ethnicity data and other pertinent patient characteristics in electronic health records to provide insight into practice patterns. Such data can be used to assess the long-term performance of MIGS and other procedures in various patient populations.

Objective Assess the effectiveness of a multifaceted stewardship intervention to reduce frequency and duration of inappropriate antibiotic use for emergency department (ED) patients with skin and soft tissue infections (SSTI). We hypothesized the antibiotic stewardship program would reduce antibiotic duration and improve guideline adherence in discharged SSTI patients. Design Nonrandomized controlled trial. Setting Academic EDs (intervention site and control site). Patients or participants Attending physicians and nurse practitioners at participating EDs. Intervention(s) Education regarding guideline-based treatment of SSTI, tests of antimicrobial treatment of SSTI, implementation of a clinical treatment algorithm and order set in the electronic health record, and ED clinicians' audit and feedback. Results We examined 583 SSTIs. At the intervention site, clinician adherence to guidelines improved from 41% to 51% (aOR = 2.13 [95% CI: 1.20–3.79]). At the control site, there were no changes in adherence during the “intervention” period (aOR = 1.17 [0.65–2.12]). The between-site comparison of these during vs. pre-intervention odds ratios was not different (aOR = 1.82 [0.79–4.21]). Antibiotic duration decreased by 26% at the intervention site during the intervention compared to pre-intervention (Adjusted Geometric Mean Ratio [95% CI] = 0.74 [0.66–0.84]). Adherence was inversely associated with SSTI severity (severe vs mild; adjusted OR 0.42 [0.20–0.89]) and purulence (0.32 [0.21–0.47]). Mean antibiotic prescription duration was 1.95 days shorter (95% CI: 1.54–2.33) in the time period following the intervention than pre-intervention period. Conclusions A multifaceted intervention resulted in modest improvement in adherence to guidelines compared to a control site, driven by treatment duration reductions.

Felid semen has historically been frozen using an egg yolk-based cryopreservation medium. However, the use of egg introduces several potential concerns, such as variability in composition, microbial contamination, and regulatory issues. In the present study, our aim was to compare a chemically-defined, soy-based medium (SOY) to a commercial egg yolk-based medium (TEY) for the cryopreservation of sperm in four imperiled small cat species. Semen was collected from adult male cats (n = 6 black-footed cats; n = 6 sand cats; n = 4 fishing cats; and n = 7 Pallas’ cats) via electroejaculation, split into two aliquots, and cryopreserved in SOY or TEY. Frozen-thawed samples were evaluated for sperm motility and rate of progressive motility (up to 24 h post-thaw) and acrosome status (0 and 6 h). No difference in post-thaw traits were observed between treatments in all four species. Heterologous IVF using oocytes collected laparoscopically from domestic cats demonstrated no difference among freezing treatments in percentage of mature oocytes that cleaved or the mean number of blastomeres at 48 h post-insemination. More spermatozoa frozen with SOY were bound to the zona pellucida in the sand cat (P = 0.018), but no treatment effect was observed in the other three species. These findings collectively demonstrate that SOY may be a preferable alternative to TEY for sperm cryopreservation in these four wild felid species.

Background Early pubertal maturation has been posited to be a biopsychosocial risk factor for the onset of internalizing psychopathology in adolescence; further, early-maturing youths exhibit heightened reactivity to stressful events. School closures and enforced social distancing, as well as health and financial uncertainties, during the COVID-19 pandemic are expected to adversely affect mental health in youths, particularly adolescents who are already at risk for experiencing emotional difficulties. The executive control network (ECN) supports cognitive processes required to successfully navigate novel challenges and regulate emotions in stressful contexts. Methods We examined whether functional coherence of the ECN, measured using resting-state functional magnetic resonance imaging 5 years before the pandemic (T1), is a neurobiological marker of resilience to increases in the severity of internalizing symptoms during COVID-19 in adolescents who were in more advanced stages of puberty at T1 relative to their same-age peers (N = 85, 49 female). Results On average, participants reported an increase in symptoms from the 3 months before pandemic to the 2 most recent weeks during the pandemic. We found that early-maturing youths exhibited greater increases in internalizing symptoms during the pandemic if their ECN coherence was low; in contrast, relative pubertal stage was not associated with changes in internalizing symptoms in adolescents with higher ECN coherence at T1. Conclusions These findings highlight the role of the functional architecture of the brain that supports executive functioning in protecting against risk factors that may exacerbate symptoms of internalizing psychopathology during periods of stress and uncertainty.

The SPOT GRADE (SG), a Surface Bleeding Severity Scale, is a unique visual method for assessing bleeding severity based on quantitative determinations of blood flow. This study assessed the reliability of the SG scale in a clinical setting and collected initial data on the safety and efficacy of HEMOBLAST Bellows (HB), a hemostatic agent, in abdominal and orthopedic operations. Twenty-seven patients were enrolled across 3 centers and received the investigational device. Bleeding severity and hemostasis were independently assessed by 2 surgical investigators at baseline and at 3, 6, and 10 minutes after application of HB and compared for agreement. The mean paired κ statistic for assignment of SG scores was .7754. The mean paired κ statistics for determining eligibility for participation in the trial based on bleeding severity and the mean paired κ statistics determining the presence of hemostasis were .9301 and .9301, respectively. The proportion of patients achieving hemostasis within 3, 6, and 10 minutes of HB application were 50.0%, 79.2%, and 91.7%, respectively. There were no unanticipated adverse device effects and one possible serious adverse device effect, as determined by the Independent Data Monitoring Committee (IDMC). The reliability of the SG scale was validated in a clinical setting. Initial data on the safety and efficacy of HB in abdominal and orthopedic operations were collected, and there were no concerns raised by the investigators or the IDMC.

Background: The experience of starting and growing a pediatric palliative care program (PPCP) has changed over the last 10 years as rapid increases of patient volume have amplified challenges relat...

Attachment plays a key role in how children process information about the self and others. Here, we examined the neural bases of interindividual differences in attachment in late childhood and tested whether social cognition-related neural activity varies as function of age. In a small sample of 8-year-old to 12-year-old children (n = 21/19), we used functional magnetic resonance imaging to measure neural responses during social feedback processing and self–other distinction. Attachment was assessed using child self-report. The social feedback processing task presented smiling and angry faces either confirming or disconfirming written information about participant performance on a perceptual game. In addition to observing main effects of facial emotion and performance, an increase in age was related to a shift from negative (i.e., angry faces/bad performance) to positive (i.e., smiling faces/good performance) information processing in the left amygdala/hippocampus, bilateral fusiform face area, bilateral anterior temporal pole (ATP), and left anterior insula. There were no effects of attachment on social feedback processing. The self–other distinction task presented digital morphs between children’s own faces and faces of their mother or stranger females. We observed differential activation in face processing and mentalizing regions in response to self and mother faces versus morphed faces. Furthermore, left ATP activity was associated with attachment anxiety such that greater attachment anxiety was related to a shift from heightened processing of self and mother faces to morphed faces. There were no effects of age on self–other distinction. We discuss our preliminary findings in the context of attachment theory and previous work on social evaluation and self–other processing. Electronic supplementary material The online version of this article (10.3758/s13415-020-00781-w) contains supplementary material, which is available to authorized users.

AIMS/HYPOTHESIS: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association’s cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA(1c), BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. METHODS: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0–7) was defined as the sum of all metrics within the ideal range, and a total metric score (0–14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores. RESULTS: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA(1c) demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p=0.01), and each unit increase in total metric score was associated with a 17% lower risk (p

Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.