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Following anabolic stimuli (mechanical loading and/or amino acid provision), the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of protein synthesis, translocates toward the cell periphery. However, it is unknown if mTORC1-mediated phosphorylation events occur in these peripheral regions or before translocation (i.e., in central regions). We therefore aimed to determine the cellular location of a mTORC1-mediated phosphorylation event, RPS6Ser240/244, in human skeletal muscle following anabolic stimuli. Fourteen young, healthy males either ingested a protein-carbohydrate beverage (0.25 g/kg protein and 0.75 g/kg carbohydrate) alone [ n = 7; 23 ± 5 yr; 76.8 ± 3.6 kg; and 13.6 ± 3.8% body fat (BF), FED] or following a whole body resistance exercise bout ( n = 7; 22 ± 2 yr; 78.1 ± 3.6 kg; and 12.2 ± 4.9%BF, EXFED). Vastus lateralis muscle biopsies were obtained at rest (PRE) and 120 and 300 min following anabolic stimuli. RPS6Ser240/244 phosphorylation measured by immunofluorescent staining or immunoblot was positively correlated ( r = 0.76, P < 0.001). Peripheral staining intensity of p-RPS6Ser240/244 increased above PRE in both FED and EXFED at 120 min (∼54% and ∼138%, respectively, P < 0.05) but was greater in EXFED at both poststimuli time points ( P < 0.05). The peripheral-to-central ratio of p-RPS6240/244 staining displayed a similar pattern, even when corrected for total RPS6 distribution, suggesting RPS6 phosphorylation occurs to a greater extent in the periphery of fibers. Moreover, p-RPS6Ser240/244 intensity within paxillin-positive regions, a marker of focal adhesion complexes, was elevated at 120 min irrespective of stimulus ( P = 0.006) before returning to PRE at 300 min. These data confirm that RPS6Ser240/244 phosphorylation occurs in the region of human muscle fibers to which mTOR translocates following anabolic stimuli and identifies focal adhesion complexes as a potential site of mTORC1 regulation in vivo.

This study assessed the feasibility of a phase II randomized controlled trial of high-intensity interval training (HIIT), resistance training (RT), and usual care (UC) in men with prostate cancer (PCa) on active surveillance and evaluated changes in clinically relevant outcomes. Eighteen men undergoing active surveillance for PCa were randomized to HIIT (n = 5), RT (n = 7), or UC (n = 6). Exercise participants attended 2 supervised sessions weekly and were instructed to complete 1 home-based session weekly for 8 weeks. UC participants were provided with physical activity guidelines. Feasibility was met for attendance, compliance, and retention, but not recruitment. HIIT increased leg press (mean: +8.2 kg, 95% CI 1.1 to 15.3) from baseline to 8 weeks. RT increased seated row (mean: +11.7 kg, 95% CI 6.1 to 17.3), chest press (mean: +10.4 kg, 95% CI 5.3 to 15.5), leg press (mean: +13.1 kg, 95% CI 5.9 to 20.3), serum insulin-like binding protein-3 (IGFBP-3) (mean: +400.0 ng/mL, 95% CI 94.5 to 705.5), and decreased interferon-γ (mean: −3.1 pg/mL, 95% CI −5.7 to −0.4). No changes were observed in the UC group. HIIT and RT may be effective strategies for improving muscle strength; however, only RT may increase serum IGFBP-3. Strategies that can enhance recruitment in men on active surveillance are important prior to conducting a phase II trial. Trial registration number: ClinicalTrials.gov number NCT04266262. Novelty: High-intensity interval training or resistance training are feasible during active surveillance for prostate cancer. Resistance training may suppress the tumour-promoting effects of insulin-like growth factor-I (IGF-I) via increased expression of IGFBP-3.

BACKGROUND Reproductive tract infections are hypothesized to influence uterine fibroid development, yet few studies have investigated the common condition of bacterial vaginosis (BV). The literature is currently limited to data using self-report of BV. METHODS We conducted a nested case-control study of 200 women (100 cases and 100 controls) from a large study of 23- to 35-year-old African American women, 1310 of whom were fibroid-free and prospectively followed up for 5 years to identify incident fibroids with standardized ultrasound examinations. We used quantitative polymerase chain reaction, an objective molecular method, to assess 9 BV-associated and 4 Lactobacillus species from vaginal swab specimens. We used hierarchical logistic regression to compute odds ratios and 95% confidence intervals to examine associations between bacterial species (both individually and grouped as (1) "optimal" Lactobacillus and (2) BV-associated species) with fibroid incidence and number. We also examined vaginal imbalance (quantitatively more BV-associated bacteria than optimal Lactobacilli). RESULTS Contrary to our hypothesis, we found no increase in fibroid incidence or number among women with more BV-associated bacteria. High imbalance (only BV-associated bacteria, no optimal Lactobacillus bacteria) was actually inversely associated with fibroid incidence (odds ratio, 0.38; 95% confidence interval, 0.17-0.81). CONCLUSIONS This is the first study of ultrasound-detected incident fibroids and molecular vaginal bacterial assessment. We found no evidence that BV-associated bacteria increase the risk of fibroid incidence or number.

This study aimed to determine the influence of footwear condition, foot-strike pattern and step frequency on running spatiotemporal parameters and lower-body stiffness during treadmill running. Thirty-one amateur endurance runners performed a two-session protocol (shod and barefoot). Each session consisted of two trials at 12 km · h-1 over 5 minutes altering step frequency every minute (150, 160, 170, 180 and 190 spm). First, participants were instructed to land with the heel first; after completion, the same protocol was repeated landing with the forefoot first. Repeated measures ANOVAs showed significant differences for footwear condition, foot-strike pattern and step frequency for each variable: percent contact time, percent flight time, vertical stiffness and leg stiffness (all p

In Ceara, Brazil, seasonal influenza transmission begins before national annual vaccination campaigns commence. To assess the perinatal consequences of this misalignment, we tracked severe acute respiratory infection (SARI), influenza, and influenza immunizations during 2013-2018. Among 3,297 SARI cases, 145 (4.4%) occurred in pregnant women. Statewide vaccination coverage was >80%; however, national vaccination campaigns began during or after peak influenza season. Thirty to forty weeks after peak influenza season, birthweights decreased by 40 g, and rates of prematurity increased from 10.7% to 15.5%. We identified 61 children born to mothers with SARI during pregnancy; they weighed 10% less at birth and were more likely to be premature than 122 newborn controls. Mistiming of influenza vaccination campaigns adversely effects perinatal outcomes in Ceara. Because Ceara is the presumptive starting point for north-to-south seasonal influenza transmission in Brazil, earlier national immunization campaigns would provide greater protection for pregnant women and their fetuses in Ceara and beyond.

Purpose of review The practice of time-restricted feeding (TRF) has received fervent interest in recent years as a strategy to mitigate obesity and metabolic disease. We sought to review the implications of TRF for skeletal muscle health and function in aging. Recent findings TRF has high adherence and can promote body weight loss in older populations. Body weight reductions favor fat mass in the young, however, there is also the potential for undesirable losses in lean mass. There is currently no evidence to support TRF for skeletal muscle function and metabolism in older persons, and only tentative findings in the young. With a narrow eating window of 6-8 h and a prolonged fasting period to minimize daily insulin exposure, TRF may contradict recommended dietary practices for optimizing skeletal muscle anabolism in older people. Summary TRF might represent a promising intervention to address obesity and its associated metabolic diseases, however, at present there is insufficient evidence for optimizing skeletal muscle mass or health in older individuals. Further research is needed to: (1) ascertain the impact of TRF on body composition, skeletal muscle anabolism, and autophagy in aging, and; (2) delineate the potentially myoprotective roles of dietary protein and exercise within the framework of TRF in older persons.

It is established that protein requirements are elevated in athletes to support their training and post-exercise recovery and adaptation, especially within skeletal muscle. However, research on the requirements for this macronutrient has been performed almost exclusively in younger athletes, which may complicate their translation to the growing population of Master athletes (i.e. > 35 years old). In contrast to older (> 65 years) untrained adults who typically demonstrate anabolic resistance to dietary protein as a primary mediator of the ‘normal’ age-related loss of muscle mass and strength, Master athletes are generally considered successful models of aging as evidenced by possessing similar body composition, muscle mass, and aerobic fitness as untrained adults more than half their age. The primary physiology changes considered to underpin the anabolic resistance of aging are precipitated or exacerbated by physical inactivity, which has led to higher protein recommendations to stimulate muscle protein synthesis in older untrained compared to younger untrained adults. This review puts forth the argument that Master athletes have similar muscle characteristics, physiological responses to exercise, and protein metabolism as young athletes and, therefore, are unlikely to have protein requirements that are different from their young contemporaries. Recommendations for protein amount, type, and pattern will be discussed for Master athletes to enhance their recovery from and adaptation to resistance and endurance training.

Key points The ingestion of protein potentiates the stimulation of myofibrillar protein synthesis rates after an acute bout of resistance exercise. Protein supplementation (eating above the protein Recommended Dietary Allowance) during resistance training has been shown to maximize lean mass and strength gains in healthy young and older adults. Here, we assessed contractile, oxidative, and structural protein synthesis in skeletal muscle in response to a moderate or higher protein diet during the early adaptive phase of resistance training in middle-aged adults. We report that the stimulation of myofibrillar, mitochondrial, or collagen protein synthesis rates during 0-3 weeks of resistance training is not further enhanced by a higher protein diet. These results show that moderate protein diets are sufficient to support the skeletal muscle adaptive response during the early phase of a resistance training program. Abstract Protein ingestion augments muscle protein synthesis (MPS) rates acutely after resistance exercise and can offset age-related loss in muscle mass. Skeletal muscle contains a variety of protein pools, such as myofibrillar (contractile), mitochondrial (substrate oxidation), and collagen (structural support) proteins, and the sensitivity to nutrition and exercise seems to be dependent on the major protein fraction studied. However, it is unknown how free-living conditions of dietary protein density with habitual resistance exercise mediates muscle protein subfraction synthesis. Therefore, we investigated the effect of moderate (MOD: 1.06 ± 0.22 g·kg-1 ·d-1 ) or high (HIGH: 1.55 ± 0.25 g·kg-1 ·d-1 ) protein intake on daily MPS rates within the myofibrillar (MyoPS), mitochondrial (MitoPS), and collagen (CPS) protein fractions in middle-aged men and women (n = 20, 47 ± 1 y, BMI 28 ± 1 kg·m-2 ) during the early phase (0-3 wks) of a dietary counseling-controlled resistance training program. Participants were loaded with deuterated water, followed by daily maintenance doses throughout the intervention. Muscle biopsies were collected at baseline and after weeks 1, 2, and 3. MyoPS in the HIGH condition remained constant (P = 1.000), but MOD decreased over time (P = 0.023). MitoPS decreased after 0-3 wks when compared to 0-1 wks (P = 0.010) with no effects of protein intake (P = 0.827). A similar decline with no difference between groups (P = 0.323) was also observed for CPS (P = 0.007). Our results demonstrated that additional protein intake above moderate amounts does not potentiate the stimulation of longer-term MPS responses during the early stage of resistance training adaptations in middle-aged adults. This article is protected by copyright. All rights reserved.

The rate of strokes in Africa, particularly among lower socio-economic classes, is increasing. The impact on long-term, informal caregivers of stroke patients is not known, as most research has focused on acute and discharge care. This study reports on the findings from a study of in-depth qualitative interviews with 20 caregivers to family members with stroke diagnoses in Lome, Togo. Findings show that social, structural, and relational forces greatly impact the lives of informal caregivers. This study offers an understanding of the caregivers’ challenges through an intersectional framework which can be used to inform socio-economic, emotional, and health system supports for caregivers.

Background Docetaxel (DOC) and abiraterone (ABI) in the upfront setting have separately improved clinical outcomes for metastatic hormone-sensitive prostate cancer (mHSPC), but there are no studies comparing drug efficacies or the influence of racial disparities. Materials and Methods We performed a retrospective multicenter review from Winship Cancer Institute at Emory University and Georgia Cancer Center for Excellence at Grady Memorial Hospital (2014–2020) for patients with mHSPC treated with either upfront DOC or ABI. Outcomes evaluated were overall survival (OS), progression-free survival (PFS), and prostate-specific antigen complete response (PSA CR). Results A total of 168 patients were included, consisting of 92 (54.8%) Black patients and 76 (45.2%) non-Black patients (69 White and 7 Asian or Hispanic). Ninety-four (56%) received DOC and 74 (44%) received ABI. Median follow-up time was 22.8 months with data last reviewed June 2020. For OS, there was no significant difference between ABI versus DOC and Black versus non-Black patients. For PFS, DOC was associated with hazard ratio (HR) 1.7 compared with ABI for all patients based on univariate association and HR 2.27 compared with ABI for Black patients on multivariable analysis. For PSA CR, Black patients were less likely to have a CR (odds ratio [OR] = 0.27). Conclusion ABI and DOC have similar OS with a trend toward better PFS for ABI in a cohort composed of 54% Black patients. Racial disparities were observed as prolonged PFS for Black patients treated with ABI, more so compared with all patients, and less PSA CR for Black patients. A prospective trial comparing available upfront therapies in a diverse racial population is needed to help guide clinical decision-making in the era of novel treatment options. Implications for Practice Overall survival is similar for abiraterone and docetaxel when used as upfront therapy in metastatic hormone-sensitive prostate cancer in a cohort composed of 54% Black patients. There is a trend towards improved progression-free survival for abiraterone in all patients and Black patients. Non-Black patients were more likely to achieve prostate-specific antigen (PSA) complete response regardless of upfront therapy.

Objective: To examine stakeholder perspectives on food insecurity and associated challenges to healthy eating among American Indian and Alaska Native (AI/AN) adults with type 2 diabetes (T2D). Methods: Focus groups and interviews were conducted with purposively selected stakeholders: AI/ANs with T2D, their family members, healthcare administrators, nutrition and diabetes educators, and national content experts on AI/AN health. Two coders analyzed transcripts using the constant-comparison method. Results: Key themes included (1) rural- and urban-dwelling AI/ANs experience different primary food security and associated challenges; (2) factors contributing to food insecurity extend beyond cost of healthy food; and (3) barriers to consuming fresh, healthy food include cost, preparation time, limited cooking knowledge, and challenges with gardening. Discussion: Resources for AI/ANs with T2D who experience food insecurity and associated challenges to healthy eating should be tailored based on urban versus rural location and should address cost and other barriers to consumption of fresh fruits and vegetables.

Introduction: The underutilization of kidney transplant as the preferred treatment for end-stage kidney disease is influenced by a lack of knowledge, poor attitudes, and various socio-demographic characteristics. Negative attitudes toward renal transplant disengage patients from the evaluation process and often hinder their likelihood of receiving a transplant. Purpose: Determine whether a standardized educational session successfully improves knowledge and attitudes toward kidney transplant. Explore which socio-demographic variables are associated with more negative baseline attitude scores. Design: The program evaluation utilized a pre-test/post-test design to assess attitudes and knowledge toward renal transplant before and after an educational session. The pre- and post-surveys were distributed to a convenience sample of 341 and 115 patients, respectively, between the months of September and December 2019. Results: Exposure to a kidney transplant education program resulted in greater levels of knowledge ( P = 0.019, d = 0.334). Individuals with no college education were found to have more negative baseline attitudes toward renal transplantation ( P = 0.048, d = 0.382). Conclusion: More research is needed to explore how knowledge, attitudes, and certain socio-demographic characteristics impact a patient’s intention to pursue kidney transplant. Uncovering reasons as to why certain populations of individuals have more negative baseline attitudes toward kidney transplant may also provide clinicians and transplant programs with valuable information on how pre-transplant education can be tailored to meet the needs of specific populations.

Evidence shows that treatment by gynecologic oncologists (GOs) increases overall survival among women with ovarian cancer. However, specific strategies for institutions and community-based public health programs to promote treatment by GOs are lacking. To address this, we conducted a literature review to identify evidence-based and promising system- and environmental-change strategies for increasing treatment by GOs, in effort to ensure that all women with ovarian cancer receive the standard of care. We searched for English-language literature published from 2008 to 2018. We used PubMed, PubMed Central, OVID, and EBSCO for peer-reviewed literature and Google and Google Scholar for gray literature related to increasing receipt of care by GOs among ovarian cancer patients. Numerous suggested and proposed strategies that have potential to increase treatment by GOs were discussed in several articles. We grouped these approaches into five strategic categories: increasing knowledge/awareness of role and importance of GOs, improving models of care, improving payment structures, improving/increasing insurance coverage for GO care, and expanding or enhancing the GO workforce. We identified several strategies with the potential for increasing GO care among ovarian cancer patients, although currently there is little evidence regarding their effectiveness across US populations. Public health programs and entities that measure delivery of quality health care may pilot the strategies in their populations. Certain strategies may work better in certain environments and a combination of strategies may be necessary for any one entity to increase GO ovarian cancer care. Findings, lessons learned, and recommendations from implementation projects would inform community and public health practice.

Reproductive tract infections have long been hypothesized to be risk factors for development of uterine fibroids, but few studies have investigated the issue. In our 2016 cross-sectional analysis from the Study of Environment, Lifestyle and Fibroids (2010–2018), a large Detroit, Michigan, community-based cohort study of 23- to 35-year-old African-American women with ultrasound fibroid screening, we found no association between a very prevalent reproductive tract infection, herpes simplex virus type 2 (HSV-2), and fibroids. With prospective data from the cohort (ultrasounds performed every 20 months over 5 years), we examined HSV-2’s associations with fibroid incidence (among 1,208 women who were fibroid-free at baseline) and growth (among women with fibroids at baseline or diagnosed during the study). Using Cox proportional hazards models, we computed adjusted hazard ratios and 95% confidence intervals for fibroid incidence comparing HSV-2–seropositive women with HSV-2–seronegative women. The influence of HSV-2 infection on growth was assessed on the basis of the difference in fibroid size between successive ultrasounds (1,323 growth measures) using a linear mixed model, estimating the percent difference in growth scaled to 18 months. HSV-2 seropositivity was not associated with fibroid incidence (adjusted hazard ratio = 0.88, 95% confidence interval: 0.69, 1.12) or growth (estimated growth difference = 3.1%, 95% confidence interval: −5.8, 13.0). Women can be reassured that HSV-2 infection is unlikely to increase their risk of fibroid-related health problems, given these longitudinal measures.

Optimal carbohydrate and protein intakes are vital for modulating training adaptation, recovery, and exercise performance. However, the research base underpinning contemporary sport nutrition guidelines has largely been conducted in male populations with a lack of consensus on whether the menstrual phase and associated changes in sex hormones allow broad application of these principles to female athletes. The present review will summarise our current understanding of carbohydrate and protein requirements in female athletes across the menstrual cycle and provide a critical analysis on how they compare to male athletes. On the basis of current evidence, we consider it premature to conclude that female athletes require sex specific guidelines in relation to CHO or protein requirements provided energy needs are met. However, there is a need for further research using sport-specific competition and training related exercise protocols that rigorously control for prior exercise, CHO/energy intake, contraceptive use and phase of menstrual cycle. Our overarching recommendation is to use current recommendations as a basis for adopting an individualised approach that takes into account athlete specific training and competition goals whilst also considering personal symptoms associated with the menstrual cycle.

Avascular necrosis (AVN) after bunion surgery is an unfortunate complication which can be devastating and painful. We present a case report of gradual medializing transport of the second metatarsal with external fixation to repair a large bone defect caused by AVN affecting >50% of the first metatarsal. The procedure was performed on a 49-year-old female who suffered AVN after failed bunion surgery. At 12-month follow up, first ray position and length were maintained. With respect to the second ray, there were no clinically significant issues. The second digit was mildly elevated but there was no frank instability of the toe or of the Lisfranc complex. The patient was pain free and had returned to her desired daily activities.

Background Digits-in-noise (DIN) tests have become popular for hearing screening over the past 15 years. Several recent studies have highlighted the potential utility of DIN as a school-aged hearing test. However, age may influence test performance in children due to maturation. In addition, a new antiphasic stimulus paradigm has been introduced, allowing binaural intelligibility level difference (BILD) to be measured by using a combination of conventional diotic and antiphasic DIN. Purpose This study determined age-specific normative data for diotic and antiphasic DIN, and a derived measure, BILD, in children. A secondary aim evaluated the validity of DIN as a smartphone self-test in a subgroup of young children. Research Design A cross-sectional, quantitative design was used. Participants with confirmed normal audiometric hearing were tested with a diotic and antiphasic DIN. During the test, arrangements of three spoken digits were presented in noise via headphones at varying signal-to-noise ratio (SNR). Researchers entered each three-digit spoken sequence repeated by the participant on a smartphone keypad. Study Sample Overall, 621 (428 male and 193 female) normal hearing children (bilateral pure tone threshold of ≤ 20 dB hearing level at 1, 2, and 4 kHz) ranging between the ages of 6 and 13 years were recruited. A subgroup of 7-year-olds (n = 30), complying with the same selection criteria, was selected to determine the validity of self-testing. Data Collection and Analysis DIN testing was completed via headphones coupled to a smartphone. Diotic and antiphasic DIN speech recognition thresholds (SRTs) were analyzed and compared for each age group. BILD was calculated through subtraction of antiphasic from diotic SRTs. Multiple linear regressions were run to determine the effect of age on SRT and BILD. In addition, piecewise linear regressions were fit across different age groups. Wilcoxon signed-rank tests were used to determine differences between self- and facilitated tests. Results Age was a significant predictor, of both diotic and antiphasic DIN SRTs (p 0.05). Conclusions Increasing age was significantly associated with improved SRT and BILD using diotic and antiphasic DINs. DIN could be used as a smartphone self-test in young children from 7 years of age with appropriate quality control measures to avoid potential false positives.

Background Although resuscitation with IV fluids is the cornerstone of sepsis management, consensus regarding their association with improvement in clinical outcomes is lacking. Research Question Is there a difference in the incidence of respiratory failure in patients with sepsis who received guideline-recommended initial IV fluid bolus of 30 mL/kg or more conservative resuscitation of less than 30 mL/kg? Study Design and Methods This was a retrospective analysis of prospectively collected clinical data conducted at an academic medical center in Omaha, Nebraska. We abstracted data from 214 patients with sepsis admitted to a single academic medical center between June 2017 and June 2018. Patients were stratified by receipt of guideline-recommended fluid bolus. The primary outcome was respiratory failure defined as an increase in oxygen flow rate or more intense oxygenation and ventilation support; oxygen requirement and volume were measured at admission, 6 h, 12 h, 24 h, and at discharge. Subgroup analyses were conducted in high-risk patients with congestive heart failure (CHF) as well as those with chronic kidney disease (CKD). Results A total of 62 patients (29.0%) received appropriate bolus treatment. The overall rate of respiratory failure was not statistically different between patients who received appropriate bolus or did not (40.3% vs 36.8%; P = .634). Likewise, no differences were observed in time to respiratory failure (P = .645) or risk of respiratory failure (adjusted hazard ratio, 1.1 [95% CI, 0.7-1.7]; P = .774). Results were similar within the high-risk CHF and CKD subgroups. Interpretation In this single-center retrospective study, we found that by broadly defining respiratory failure as an increase in oxygen requirements, a conservative initial IV fluid resuscitation strategy did not correlate with decreased rates of hypoxemic respiratory failure.

Delayed diagnosis of scaphoid fractures can lead to long-term morbidity. While radiography is the preferred screening examination, there is a relative paucity of literature that examines fracture visibility in younger children, who have smaller ossification centers, an abundance of unossified cartilage and fractures that preferentially involve the distal scaphoid. To characterize acute scaphoid fractures in younger children on radiographs with observer agreement and with respect to fracture location. This institutional review board (IRB)-approved and Health Insurance Portability and Accountability Act (HIPAA)-compliant cross-sectional study included children (≤10 years of age) with acute scaphoid fractures (≤7 days), who underwent radiographic examinations at a tertiary children’s hospital between December 2008 and June 2019. Three readers (two pediatric radiologists and one orthopedic surgeon) reviewed each examination to determine fracture visibility on each radiographic view and fracture location. Kruskal-Wallis, Fisher exact and Cochran-Armitage tests were used to compare fracture visibility and location, and Kappa tests were used to calculate observer agreement. Twenty-eight children (15 boys, 13 girls; mean age: 9.5±0.6 years) with 10 (36%) distal corner, 11 (39%) distal body and 7 (25%) mid-body fractures, underwent 7 (25%) 4-view, 18 (64%) 3-view and 3 (11%) 2-view examinations. Twenty-six (93%) fractures were visible on at least one view with six (21%) fractures visible on all available views. No significant association was found between fracture visibility and fracture location (P=0.32). Observer agreement was substantial to almost perfect. Only 7% of these acute scaphoid fractures in younger children are inconspicuous on the initial radiographic examination.

Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gαq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive. Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition. Results: We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo. Conclusions: These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma. See related commentary by Neelature Sriramareddy and Smalley, p. 1217

OBJECTIVE: To describe the case of an 88-yearold male with rheumatoid arthritis who developed pulmonary manifestations. Treatment for his RA previously included various biologics, while at the time of pulmonary consultation included meloxicam, methotrexate, and abatacept. Following chest scans, bronchoscopy, needle biopsy, pulmonary function testing, and a thoracentesis, the diagnosis of pleural effusion and nodules associated with rheumatoid arthritis was determined. The patient was recommended to follow-up with the pulmonologist but was lost to follow-up because of nonpulmonary and nonrheumatoid arthritis complications. SETTINGS: Ambulatory clinic pharmacy practice, Community pharmacy, Consultant pharmacy practice. PRACTICE CONSIDERATIONS: Drugs used to treat rheumatoid arthritis may produce pulmonary toxicity similar to what is seen with the disease itself. Drug therapy may require modification if identified as an offending agent causing pulmonary manifestations. If fibrosing interstitial lung disease develops, the addition of nintedanib may need to be considered. CONCLUSION: In order for pharmacists to better assist providers and patients and improve therapeutic outcomes, it is important for pharmacists to understand that pulmonary manifestations are common in patients having rheumatoid arthritis as well as with drugs used to treat rheumatoid arthritis.

Talent of the practitioner is irrelevant if the person receiving support (or the person responsible for delivering support) does not follow through with the plan. This is true in applied behavior analysis (ABA), medicine, and allied health-care services. The cost of nonadherence and related nonoptimized interventions is a major contributor to the overall cost of health care, estimated at $290–528 billion annually in the United States (New England Healthcare Institute, 2009; Watanabe, McInnis, & Hirsch, 2018). Although a topic of research in medicine for over 60 years, no gold standard for the enhancement of adherence has been demonstrated in any single population, disease condition, or therapeutic approach (Nieuwlaat et al., 2014; Rudd, 1979). Given the broad applicability of behavior analysis as a framework for understanding human behavior, and the need to recognize and address the problem of nonadherence in ABA (Allen & Warzak, 2000) we propose a systematic behavioral model for adherence and the development of strategies to enhance follow-through with individualized support plans.

Breaking up prolonged sitting with intermittent walking breaks can improve glycemic control. Here, we demonstrated that interrupting prolonged sitting every 30 min with 1 min of repeated chair stands was as effective as 2-min treadmill walks for lowering postprandial insulinemia in healthy adults. Markers of contraction- and insulin-mediated muscle glucose uptake were unchanged. Repeated chair stands as a form of body-weight resistance activity may represent a cost- and space-efficient activity break for mitigating cardiometabolic-disease risk.

The global digital transformation enables computational audiology for advanced clinical applications that can reduce the global burden of hearing loss. In this article, we describe emerging hearing-related artificial intelligence applications and argue for their potential to improve access, precision, and efficiency of hearing health care services. Also, we raise awareness of risks that must be addressed to enable a safe digital transformation in audiology. We envision a future where computational audiology is implemented via interoperable systems using shared data and where health care providers adopt expanded roles within a network of distributed expertise. This effort should take place in a health care system where privacy, responsibility of each stakeholder, and patients' safety and autonomy are all guarded by design.

OBJECTIVES: The digits-in-noise test (DIN) is a popular self-test measure that has traditionally been used to screen for hearing loss by providing either a pass or refer result. Standard approaches either tested each ear monaurally or used a binaural diotic version where identical digits and noise were presented simultaneously to both ears. Recently, a dichotic, antiphasic version was developed, increasing sensitivity of the DIN to unilateral or asymmetric sensorineural hearing loss (SNHL) and conductive hearing loss (CHL). The purpose of this study was to determine predictors and normative ranges of the antiphasic and diotic DIN and to determine if a combination of diotic and antiphasic DIN could accurately categorize hearing into (1) normal, (2) bilateral SNHL, or (3) unilateral SNHL or CHL. DESIGN: The analytical sample consisted of 489 participants between the ages of 18 and 92 years with varying types, symmetry, and degrees of hearing loss. Degree and type of hearing loss were determined based on standard clinical four-frequency (0.5-4 kHz) pure-tone air and bone conduction threshold averages. The sample consisted of bilateral normal hearing (n = 293), bilateral SNHL (n = 172), unilateral SNHL (n = 42), and CHL (n = 32). All participants (n = 489) first completed an antiphasic DIN (digit stimuli 180° out-of-phase between ears), while 393 of the sample also completed a diotic DIN. Two procedures were assessed for their ability to categorize hearing into one of the three hearing groups. The first used a fixed antiphasic cutoff combined with a cutoff formed by a linear combination of antiphasic and diotic speech recognition threshold (SRT) or binaural intelligibility-level difference. RESULTS: Poorer ear pure-tone average was the strongest predictor of antiphasic DIN score, whereas better ear pure-tone average explained more of the variance in diotic SRT. The antiphasic DIN sensitivity and specificity was 90% and 84%, respectively, for detecting hearing loss, with outstanding area under the receiver operating characteristics values exceeding 0.93 to identify hearing loss in the poorer ear. The first fixed SRT cutoff procedure could categorize 75% of all participants correctly, while the second procedure increased correct categorization to 79%. False negative rates for both procedures were below 10%. CONCLUSIONS: A sequential antiphasic and diotic DIN could categorize hearing to a reasonable degree into three groups of (1) normal hearing; (2) bilateral SNHL; and (3) unilateral asymmetric SNHL or CHL. This type of approach could optimize care pathways using remote and contactless testing, by identifying unilateral SNHL and CHL as cases requiring medical referral. In contrast, bilateral SNHL cases could be referred directly to an audiologist, or nontraditional models like OTC hearing aids.

RAS mutant tumors have been largely refractory to therapies until now. Recent findings published in the New England Journal of Medicine show that sotorasib provides clinical benefit for KRAS p.G12C-mutated non-small-cell lung cancer (NSCLC) and provide mechanistic insights into acquired resistance to KRASG12C-specific inhibition.

Background Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine has proven highly effective in preventing HIV acquisition and is therefore offered to all participants in the control group as part of the standard of care package in many new HIV prevention studies. We propose a methodology for predicting HIV incidence in a hypothetical "placebo arm" for open-label studies or clinical trials with active control among African women. We apply the method to an open-label PrEP study, HIV Prevention Trials Network 082, which tested strategies to improve PrEP adherence in young African women all of whom were offered PrEP. Methods Our model predicted HIV infection risk for female study cohorts in sub-Saharan Africa using baseline behavioral risk factors and contemporary HIV prevalence and viral suppression in the local male population. The model was calibrated to HIV incidence in the Vaginal and Oral Interventions to Control the Epidemic study. Results Our model reproduced the annual HIV incidence of 3.2%-4.8% observed over 1 year of follow-up in the placebo groups of 4 completed clinical studies. We predicted an annual HIV incidence of 3.7% (95% confidence interval: 3.2 to 4.2) among HIV Prevention Trials Network 082 participants in the absence of PrEP and other risk reduction interventions. Conclusions We demonstrated the potential of the proposed methodology to provide HIV incidence predictions based on assessment of individual risk behaviors and community and time-specific HIV exposure risk using HIV treatment and viral suppression data. These estimates may serve as comparators in HIV prevention trials without a placebo group.

Iron is an essential micronutrient, and, in the case of bacteria, its availability is commonly a growth-limiting factor. However, correct functioning of cells requires that the labile pool of chelatable “free” iron be tightly regulated. Correct metalation of proteins requiring iron as a cofactor demands that such a readily accessible source of iron exist, but overaccumulation results in an oxidative burden that, if unchecked, would lead to cell death. The toxicity of iron stems from its potential to catalyze formation of reactive oxygen species that, in addition to causing damage to biological molecules, can also lead to the formation of reactive nitrogen species. To avoid iron-mediated oxidative stress, bacteria utilize iron-dependent global regulators to sense the iron status of the cell and regulate the expression of proteins involved in the acquisition, storage, and efflux of iron accordingly. Here, we survey the current understanding of the structure and mechanism of the important members of each of these classes of protein. Diversity in the details of iron homeostasis mechanisms reflect the differing nutritional stresses resulting from the wide variety of ecological niches that bacteria inhabit. However, in this review, we seek to highlight the similarities of iron homeostasis between different bacteria, while acknowledging important variations. In this way, we hope to illustrate how bacteria have evolved common approaches to overcome the dual problems of the insolubility and potential toxicity of iron.

Acumapimod, an investigational oral p38 mitogen-activated protein kinase inhibitor for treatment during severe acute exacerbations of chronic obstructive pulmonary disease, is metabolized primarily by cytochrome P450 3A4 (CYP3A4) and is a P-glycoprotein (P-gp) substrate. Concerns about drug-drug interactions (DDIs) have meant patients receiving drugs that inhibit CYP3A4 were ineligible for acumapimod trials. We report on how 2 acumapimod clinical DDI studies and a physiologically-based pharmacokinetic (PBPK) model assessing how co-administration of a weak (azithromycin) and strong (itraconazole) CYP3A4 inhibitor affected acumapimod systemic exposure, informed decision making and supported concomitant use of CYP3A4 and P-gp inhibitors. Studies MBCT102 and MBCT103, respectively, demonstrated that co-administration of azithromycin or itraconazole had no clinically meaningful impact on acumapimod pharmacokinetics. Findings were consistent with PBPK model results. Safety profiles were similar when acumapimod was co-administered with azithromycin or itraconazole. These studies highlight the value of PBPK modeling in drug development, and its potential to inform DDI investigations.

One important limitation for achieving therapeutic expression of human factor VIII (FVIII) in hemophilia A gene therapy is inefficient secretion of the FVIII protein. Substitution of five amino acids in the A1 domain of human FVIII with the corresponding porcine FVIII residues generated a secretion-enhanced human FVIII variant termed B-domain-deleted (BDD)-FVIII-X5 that resulted in 8-fold higher FVIII activity levels in the supernatant of an in vitro cell-based assay system than seen with unmodified human BDD-FVIII. Analysis of purified recombinant BDD-FVIII-X5 and BDD-FVIII revealed similar specific activities for both proteins, indicating that the effect of the X5 alteration is confined to increased FVIII secretion. Intravenous delivery in FVIII-deficient mice of liver-targeted adeno-associated virus (AAV) vectors designed to express BDD-FVIII-X5 or BDD-FVIII achieved substantially higher plasma FVIII activity levels for BDD-FVIII-X5, even when highly efficient codon-optimized F8 nucleotide sequences were employed. A comprehensive immunogenicity assessment using in vitro stimulation assays and various in vivo preclinical models of hemophilia A demonstrated that the BDD-FVIII-X5 variant does not exhibit an increased immunogenicity risk compared to BDD-FVIII. In conclusion, BDD-FVIII-X5 is an effective FVIII variant molecule that can be further developed for use in gene- and protein-based therapeutics for patients with hemophilia A., Graphical Abstract, Limited secretion of factor VIII remains a hurdle in hemophilia A gene therapy. Minimal alterations in human factor VIII resulted in the secretion-enhanced variant BDD-FVIII-X5 that improved expression yet retained normal specific activity and an immunogenicity profile similar to that of unmodified FVIII, supporting its further development as therapeutics for hemophilia A patients.

Perioperative pain management protocols have a significant impact on early surgical outcomes and recovery. We hypothesized that multimodal protocol including fascia iliaca compartment nerve block (MM-FICNB) would decrease the length of hospital stay (LOS) by facilitating earlier mobilization, without compromising analgesia, compared to a traditional lumbar epidural-based protocol (EP). Demographics/comorbidities, surgical/block characteristics and perioperative pain/mobilization data were collected from a prospectively recruited MM-FICNB group (N = 16) and a retrospective EP cohort (N = 16) who underwent PAO using similar surgical techniques, physical therapy/discharge criteria. Association of MM-FICNB group with LOS (primary outcome), postoperative pain, postoperative opioid requirements in morphine equivalent rates (MER) (mcg/kg/h) and time to complete physical therapy were tested using multivariable and survival regression. Patient and surgical characteristics were similar between groups. Median time for FICNB performance was significantly less than epidural (6 versus 15 min; P

Background Individuals often report concurrent social risk factors such as food insecurity, unstable housing, and transportation barriers. Comparing relative changes between pairs of social risk factors may identify those that are more resistant to change. Objective The objective of this study was to develop a method to describe relative changes in pairs of social risk factors. Research design This was a prospective cohort study. Subjects Participants in a randomized controlled trial of hypertension care in an Urban Indian Health Organization. Measures We measured 7 social risk factors (housing, transportation, food, clothing, health care, utilities, and debts) at enrollment, 6, and 12 months among 295 participants in the trial. We hypothesized that pairwise comparisons could identify social risk factors that were less likely to change over time. We used conditional odds ratios (ORs) with 95% confidence intervals (CIs) to rank each pair. Results Food, clothing, health care, utilities, and debts had more changes between 0 and 6 months relative to housing (OR=2.3, 3.4, 4.7, 3.5, and 3.4, respectively; all 95% CI excluded 1.0). These same social risk factors also had more changes between baseline and 6 months relative to transportation (OR=2.8, 3.4, 4.9, 4.7, and 4.1, respectively; all 95% CI excluded 1.0). Changes in housing and transportation risk factors were comparable (OR=0.7, 95% CI: 0.4-1.4). Relative changes between 6 and 12 months were similar. Conclusions Housing and transportation exhibited fewer relative changes than other social risk factors and might be more resistant to change. Awareness of the relationships between social risk factors can help define priorities for intervention.

There is conflicting evidence regarding the impact of hypothetical cumulative fatigue after performing too many endoscopic procedures on both polyp and adenoma detection rates (PDR, and ADR, respectively). The aim of this study is to evaluate the effect of successive endoscopic procedures on PDR and ADR. A retrospective cross-sectional study was undertaken among consecutive patients on whom colonoscopy and/or esophagogastroduodenoscopy were performed between January 2012 and August 2014. Data regarding polyp and adenoma detection, cecal intubation, and bowel cleansing quality as well as demographical data of subjects were extracted. Endoscopic procedures were classified according to the time slots of the procedures throughout the endoscopy session in three groups: from the 1st to 4th endoscopy study (round 1), from the 5th to the 8th study (round 2), above the 9th study (round 3). We compared PDR and ADR among rounds. Overall, 3388 patients were enrolled. Median age was 50 years (range 18–95) and 52.39% were female. There was a significant difference in terms of PDR among rounds (36.83%, 41.24%, and 43.38%, respectively, p = 0.007) and a non-significant numerical difference when ADR was compared (23.2%, 25.71%, and 26.78%, p = 0.07). On multivariate analysis, ADR was significantly associated with age (odds ratio [OR] 1.02 [1.01–1.03]), and male sex (OR 1.64 [1.38–1.94]). Theoretical endoscopist’s fatigue due to cumulative performance of endoscopies does not diminish colonoscopy quality. Both PDR and ADR seem to improve after endoscopist’s cumulative rounds of performed endoscopies. This could be due to a “warm-up” effect.

Background Mycoplasma genitalium is associated with adverse reproductive problems. However, prevalence estimates from studies that screen women not seeking care are rare. Studies have reported co-occurrence of M. genitalium with bacterial vaginosis (BV), but no prior study of specific BV-associated bacteria has been conducted in African Americans whose reproductive tract infection burden is high. Methods Using quantitative polymerase chain reaction, we screened vaginal swabs for M. genitalium, 9 BV-associated bacteria, and 4 Lactobacillus species from 200 participants drawn from a cohort of African Americans 23 to 35 years old. Sexual history, herpes serostatus, and Nugent score had been assessed. Prevalence of M. genitalium was computed. The associations of other vaginal bacteria with M. genitalium were examined with binomial regression. Results M. genitalium prevalence was 18%. Detection and quantity of 2 BV-associated bacteria were significantly associated with a higher prevalence of M. genitalium (Leptotrichia/Sneathia: detection prevalence ratio (PR) of 2.9 [95% confidence interval {CI}, 1.1-7.7] and quantity PR of 1.2 [95% CI, 1.0-1.3]; Megasphaera phylotype 1: detection PR of 2.2 [95% CI, 1.2-4.2] and quantity PR of 1.1 [95% CI, 1.0-1.2]). Increased quantity of L. iners was also positively associated with M. genitalium (PR, 1.3 [95% CI, 1.0-1.8]). Nugent ≥7, herpes serostatus, and lifetime number of sex partners were not associated with M. genitalium. Conclusions Specific BV-associated microbes and L. iners were associated with M. genitalium, but Nugent ≥7 was not. Studies are needed to confirm a high prevalence of M. genitalium in African Americans and to understand its interactions with other vaginal bacteria.

OBJECTIVE: The prevalence of unrecognized and late-diagnosed hearing loss is higher in low- and middle-income than in high-income countries, due in part to lack of access to hearing services. Because hearing screening is important for early identification of hearing loss, development of an accessible, self-screening test that can detect hearing loss reliably and quickly would provide significant benefits, especially for underserved populations. This study aimed to develop and validate a new version of the digits-in-noise (DIN) test for Persian speaking countries. DESIGN: Recordings of Persian digits 0–9 were binaurally presented in broadband speech-shaped noise. Using fitted speech intelligibility functions, digits were homogenized to achieve equal perceptual difficulty across stimuli. Evaluation was established by reference to existing English DIN tests. STUDY SAMPLE: Thirty Persian speaking young adults with normal hearing thresholds (≤ 20 dB HL, 0.25 – 8 kHz). RESULTS: Speech intelligibility functions produced a mean speech reception threshold (SRT) of −7.7 dB, corresponding closely to previously developed DIN tests. There was no significant difference between test-retest SRTs, indicating high reliability of the test. Our findings suggest that language-specific factors need to be considered for cross-language comparison of DIN-SRTs. CONCLUSIONS: This study introduces a convenient tool for future hearing screening in Persian speaking countries with limited access to audiology services.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogene...

Skeletal muscle is a highly plastic tissue capable of remodeling in response to a range of physiological stimuli, including nutrients and exercise. Historically, the lysosome has been considered an essentially catabolic organelle contributing to autophagy, phagocytosis, and exo-/endocytosis in skeletal muscle. However, recent evidence has emerged of several anabolic roles for the lysosome, including the requirement for autophagy in skeletal muscle mass maintenance, the discovery of the lysosome as an intracellular signaling hub for mechanistic target of rapamycin complex 1 (mTORC1) activation, and the importance of transcription factor EB/lysosomal biogenesis-related signaling in the regulation of mTORC1-mediated protein synthesis. We, therefore, propose that the lysosome is an understudied organelle with the potential to underpin the skeletal muscle adaptive response to anabolic stimuli. Within this review, we describe the molecular regulation of lysosome biogenesis and detail the emerging anabolic roles of the lysosome in skeletal muscle with particular emphasis on how these roles may mediate adaptations to chronic resistance exercise. Furthermore, given the well-established role of amino acids to support muscle protein remodeling, we describe how dietary proteins “labeled” with stable isotopes could provide a complementary research tool to better understand how lysosomal biogenesis, autophagy regulation, and/or mTORC1-lysosomal repositioning can mediate the intracellular usage of dietary amino acids in response to anabolic stimuli. Finally, we provide avenues for future research with the aim of elucidating how the regulation of this important organelle could mediate skeletal muscle anabolism.

Cerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in the early days of life. These inducible models thus have a relatively short period for drug administration. We developed an inducible CCM3 mouse model that develops CCMs after weaning and provides a longer period for potential therapeutic intervention. Using this new model, three recently proposed CCM therapies, fasudil, tempol, vitamin D(3), and a combination of the three drugs, failed to substantially reduce CCM formation when treatment was administered for five weeks, from postnatal day 21 (P21) to P56. We next restricted Ccm3 deletion to the brain vasculature and provided greater time (121 days) for CCMs to develop chronic hemorrhage, recapitulating the human lesions. We also developed the first model of acute CCM hemorrhage by injecting mice harboring CCMs with lipopolysaccharide. These efficient models will enable future drug studies to more precisely target clinically relevant features of CCM disease: CCM formation, chronic hemorrhage, and acute hemorrhage.

STUDY OBJECTIVES: Pediatric polysomnography can result in suboptimal patient and provider (physician and advanced practice provider) experiences. We embarked on a project aimed at increasing the proportion of maximal satisfaction survey scores by a minimum of 10% in 1 year without adding personnel or major expenses. METHODS: We used a Six Sigma framework, define, measure, analyze, improve, and control (DMAIC), to conduct our analysis. For measurement, we designed a project-specific survey that was given to caregivers of children who underwent PSG in February 2018 and repeated the survey after interventions in February 2019. Lean and Six Sigma quality improvement tools were used to define important processes that influence patient satisfaction, including: supplier, input, process, output, customer, and requirements (SIPOC-R); journey mapping; 1-2-4-All brainstorming; and views solicited from our center’s Patient and Family Advisory Council. We analyzed the relationships between identified processes and outcomes using usual descriptive statistics. We prioritized interventions using a Kano model and a quality function deployment (QFD) technique to rank priorities for interventions. Multiple opportunities to improve patient and family satisfaction before, during, and after a pediatric polysomnography were identified. Many were simple, one-step interventions and were implemented simultaneously. For those that required substantial training and/or scheduling changes, pilots were performed and plan, do, study, act (PDSA) cycles were used to check effectiveness. RESULTS: After implementation, top box scores rose 20%, from 51% (n = 47) in 2018 to 71% (n = 50) in 2019. CONCLUSIONS: Various quality improvement techniques employed in business, engineering, and manufacturing were used to identify and address areas of improvement in the pediatric polysomnography experience. CITATION: Baughn JM, Lechner HG, Herold DL, et al. Enhancing the patient and family experience during pediatric sleep studies. J Clin Sleep Med. 2020;16(7):1037–1043.

Rationale: Complement is crucial for host defense but may also drive dysregulated inflammation. There is limited understanding of alternative complement function, which can amplify all complement a...

The dendritic arbor of neurons constrains the pool of available synaptic partners and influences the electrical integration of synaptic currents. Despite these critical functions, our knowledge of the dendritic structure of cortical neurons during early postnatal development and how these dendritic structures are modified by visual experience is incomplete. Here, we present a large-scale dataset of 849 3D reconstructions of the basal arbor of pyramidal neurons collected across early postnatal development in visual cortex of mice of either sex. We found that the basal arbor grew substantially between postnatal day 7 (P7) and P30, undergoing a 45% increase in total length. However, the gross number of primary neurites and dendritic segments was largely determined by P7. Growth from P7 to P30 occurred primarily through extension of dendritic segments. Surprisingly, comparisons of dark-reared and typically reared mice revealed that a net gain of only 15% arbor length could be attributed to visual experience; most growth was independent of experience. To examine molecular contributions, we characterized the role of the activity-regulated small GTPase Rem2 in both arbor development and the maintenance of established basal arbors. We showed that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. Acute deletion of Rem2 reduced directionality of dendritic arbors. The data presented here establish a highly detailed, quantitative analysis of basal arbor development that we believe has high utility both in understanding circuit development as well as providing a framework for computationalists wishing to generate anatomically accurate neuronal models. SIGNIFICANCE STATEMENT Dendrites are the sites of the synaptic connections among neurons. Despite their importance for neural circuit function, only a little is known about the postnatal development of dendritic arbors of cortical pyramidal neurons and the influence of experience. Here we show that the number of primary basal dendritic arbors is already established before eye opening, and that these arbors primarily grow through lengthening of dendritic segments and not through addition of dendritic segments. Surprisingly, visual experience has a modest net impact on overall arbor length (15%). Experiments in KO animals revealed that the gene Rem2 is positive regulator of dendritic length and a negative regulator of dendritic segments.

Postexercise protein ingestion can elevate rates of myofibrillar protein synthesis (MyoPS), mTORC1 activity, and mTOR translocation/protein-protein interactions. However, it is unclear if leucine-enriched essential amino acids (LEAA) can similarly facilitate intracellular mTOR trafficking in humans after exercise. The purpose of this study was to determine the effect of postexercise LEAA (4 g total EAAs, 1.6 g leucine) on acute MyoPS and mTORC1 translocation and signaling. Recreationally active men performed lower-body resistance exercise (5 × 8–10 leg press and leg extension) to volitional failure. Following exercise participants consumed LEAA (n = 8) or an isocaloric carbohydrate drink (PLA; n = 10). MyoPS was measured over 1.5–4 h of recovery by oral pulse of l-[ring-(2)H(5)]-phenylalanine. Phosphorylation of proteins in the mTORC1 pathway were analyzed via immunoblotting and mTORC1-LAMP2/WGA/Rheb colocalization via immunofluorescence microscopy. There was no difference in MyoPS between groups (LEAA = 0.098 ± 0.01%/h; PL = 0.090 ± 0.01%/h; P > 0.05). Exercise increased (P < 0.05) rpS6(Ser240/244)(LEAA = 35.3-fold; PLA = 20.6-fold), mTOR(Ser2448)(LEAA = 1.8-fold; PLA = 1.2-fold) and 4EBP1(Thr37/46)(LEAA = 1.5-fold; PLA = 1.4-fold) phosphorylation irrespective of nutrition (P > 0.05). LAT1 and SNAT2 protein expression were not affected by exercise or nutrient ingestion. mTOR-LAMP2 colocalization was greater in LEAA preexercise and decreased following exercise and supplement ingestion (P < 0.05), yet was unchanged in PLA. mTOR-WGA (cell periphery marker) and mTOR-Rheb colocalization was greater in LEAA compared with PLA irrespective of time-point (P < 0.05). In conclusion, the postexercise consumption of 4 g of LEAA maintains mTOR in peripheral regions of muscle fibers, in closer proximity to its direct activator Rheb, during prolonged recovery independent of differences in MyoPS or mTORC1 signaling compared with PLA ingestion. This intracellular localization of mTOR may serve to “prime” the kinase for future anabolic stimuli. NEW & NOTEWORTHY This is the first study to investigate whether postexercise leucine-enriched amino acid (LEAA) ingestion elevates mTORC1 translocation and protein-protein interactions in human skeletal muscle. Here, we observed that although LEAA ingestion did not further elevate postexercise MyoPS or mTORC1 signaling compared with placebo, mTORC1 peripheral location and interaction with Rheb were maintained. This may serve to “prime” mTORC1 for subsequent anabolic stimuli.

OBJECTIVES: This study tested the hypothesis that undetected peripheral hearing impairment occurs in children with idiopathic listening difficulties (LiD), as reported by caregivers using the Evaluation of Children’s Listening and Processing Skills (ECLiPS) validated questionnaire, compared to children with typically developed (TD) listening abilities. DESIGN: Children with LiD aged 6–14 y.o. (n = 60, mean age = 9.9 yr.) and 54 typical age matched children were recruited from audiology clinical records and from IRB-approved advertisements at hospital locations and in the local and regional area. Both groups completed standard and extended high frequency pure tone audiometry, wideband absorbance tympanometry and middle ear muscle reflexes, distortion product and chirp transient evoked otoacoustic emissions. Univariate and multivariate mixed models and multiple regression analysis were used to examine group differences and continuous performance, as well as the influence of demographic factors and pressure equalization (PE) tube history. RESULTS: There were no significant group differences between the LiD and TD groups for any of the auditory measures tested. However, analyses across all children showed that extended high frequency hearing thresholds, wideband tympanometry, contralateral middle ear muscle reflexes, distortion product and transient evoked otoacoustic emissions were related to a history of PE tube surgery. The physiologic measures were also associated with extended high frequency hearing loss, secondary to PE tube history. CONCLUSIONS: Overall, the results of this study in a sample of children with validated LiD compared to a TD group matched for age and sex showed no significant differences in peripheral function using highly sensitive auditory measures. Histories of PE tube surgery were significantly related to EHF hearing and to a range of physiologic measures in the combined sample.

To systematically investigate age-dependent changes in scaphoid fracture prevalence and fracture patterns on radiographs in children under 15 years of age. This retrospective study included children with scaphoid fractures, who underwent radiographic examinations between May 1, 2009, and August 31, 2019. Blinded to outcome, all radiographs were reviewed to determine fracture visibility on initial radiographs; to characterize fracture location (distal corner, distal, mid, and proximal body) and orientation (horizontal oblique, transverse, and vertical oblique); and to identify the presence or absence of gap, displacement, and concomitant fractures. Demographic information and information on weight and height were collected. Mann-Whitney U, Kruskal-Wallis rank sum, chi-square, and post hoc tests were used to investigate associations between age, fracture characteristics, and BMI percentile. The study included 180 children (134 boys and 46 girls; 12.3 ± 1.4 years) with 59 (33%) distal corner, 42 (23%) distal, 76 (42%) mid, and 3 (2%) proximal body fractures. Younger children were more likely to present with distal corner and distal body fractures while older children with mid and proximal body fractures (p = 0.035). No association was found between age and fracture visibility (p = 0.246), fracture orientation (p = 0.752), presence of gap (p = 0.130), displacement (p = 0.403), or concomitant fractures (p = 0.588). Younger children with scaphoid fractures were more likely to be obese (n = 117; p = 0.038). Scaphoid fractures of the distal corner and distal body were significantly more common in younger children, who are more likely to be obese.

Since the appearance of the E-Cigarette in the early 2000s, its industry, popularity, and prevalence have risen dramatically. In the past, E-Cigarette use with the vaping of nicotine or cannabis products had been associated with a few reported cases of lung injury. However, in 2019, thousands of cases of E-Cigarette or vaping product use-associated lung injury (EVALI) were reported in the United States. Evidence linked this outbreak with vaping of tetrahydrocannabinol (THC). We report two confirmed cases of EVALI and their associated clinical, radiologic, and pathologic features. This report supports the growing body of information regarding EVALI. It also discusses various substances, particularly vitamin E acetate, which has been suggested as a causative agent.

Interactive voice response and text message (IVR‐T) technology may improve hypertension control in under‐resourced settings. We conducted a randomized clinical trial to determine whether an IVR‐T intervention would improve blood pressure (BP), medication adherence and visit keeping among adults with hypertension from multiple racial and ethnic groups in primary care at an Urban Indian Health Organization in Albuquerque, New Mexico. Two hundred and ninety‐five participants were randomly assigned to IVR‐T (N = 148) or to usual care (N = 147). The IVR‐T arm received reminders for clinic visits, messages to reschedule missed clinic visits, monthly medication refill reminders, weekly motivational messages, and a blood pressure cuff. The usual care arm received no messages. The primary outcome was change in systolic BP (SBP) between baseline and 12 months. Secondary outcomes included change in SBP between baseline and 6 months, change in diastolic BP (DBP) at 6 and 12 months, self‐reported adherence at 6 months, and the proportion of missed primary care clinic appointments. The intervention did not affect SBP or DBP at 6 or 12 months. The 12‐month change in SBP/DBP was 1.66/1.10 mm Hg in usual care and 0.23/1.34 mm Hg in the intervention group (P values = .57 and .88, respectively). Self‐reported medication adherence improved comparably in both groups, and there was no difference in percentage of kept visits. Several features of study design, clinic operations, and data transfer were barriers to demonstrating effectiveness.