High fat, high sucrose diet promotes increased expression of ACE2 receptor in the SIV-infected host: implications for SARS-CoV-2 infection.

Introduction: People with pre-existing conditions, including metabolic comorbidities, are at greater risk for complications of SARS-CoV-2 infection and expression of machinery required for viral entry into host cells may be a contributing factor. This study tested the hypothesis that high fat, high sucrose diet (HFSD) and alcohol use increase expression of angiotensin converting enzyme 2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) in tissues isolated from simian immunodeficiency virus (SIV) infected macaques, the most clinically relevant model for the study of HIV. Methods: Biospecimens obtained from a longitudinal study of SIV-infected, antiretroviral therapy (ART)-treated female rhesus macaques (Macaca mulatta) were used to determine whether HFSD and chronic binge alcohol (CBA) increased ACE2 and TMPRSS2 protein and gene expression. Macaques (n = 10) were assigned to HFSD or standard diet (SD) for 3 months before CBA or vehicle administration. Three months later, macaques were infected with SIV; ART was initiated 2.5 months thereafter. Tissue samples including lung, pancreas, and kidney were collected at study endpoint (12 months post-SIV infection). Results: Protein expression of ACE2 in the lung, whole pancreas, and pancreatic islets was significantly greater in HFSD- than SD-fed macaques with no significant differences in protein expression of TMPRSS2 or mRNA expression of ACE2 or TMPRSS2. CBA did not significantly alter any measures. Discussion: The increased ACE2 receptor expression observed in lung and pancreas of SIV-infected HFSD-fed female rhesus macaques aligns with reports that diet may increase susceptibility to COVID-19. These data provide direct evidence for a link between dietary quality and cellular adaptations that may increase the risk for SARS-CoV-2 infection.

Injectable peptide-glycosaminoglycan hydrogels for soft tissue repair: in vitro assessment for nucleus augmentation.

We report the development of peptide-glycosaminoglycan hydrogels as injectable biomaterials for load-bearing soft tissue repair. The hydrogels are injectable as a liquid for clinical delivery, rapidly form a gel in situ, and mimic the osmotic swelling behaviour of natural tissue. We used a new in vitro model to demonstrate their application as a nucleus augmentation material for the treatment of intervertebral disc degeneration. Our study compared a complex lab gel preparation method to a simple clinical benchtop process. We showed pH differences did not significantly affect gel formation, and temperature variations had no impact on gel performance. Rheological results demonstrated consistency after benchtop mixing or needle injection. In our in vitro disc degeneration model, we established that peptide augmentation could restore the native biomechanical properties. This suggests the feasibility of minimally invasive peptide-GAG gel delivery, maintaining consistent properties across temperature and needle sizes while restoring disc height and stiffness in vitro.

Sense of Belonging Among Medical Students, Residents, and Fellows: Associations With Burnout, Recruitment Retention, and Learning Environment.

PURPOSE: This study examines sense of belonging (belongingness) in a large population of medical students, residents, and fellows and associations with learner burnout, organizational recruitment retention indicators, and potentially modifiable learning environment factors. METHOD: All medical students, residents, and fellows at Mayo Clinic sites were surveyed between October and November 2020 with items measuring sense of belonging in 3 contexts (school or program, organization, and surrounding community), burnout (2 Maslach Burnout Inventory items), recruitment retention indicators (likelihood of recommending the organization and accepting a job offer), potentially modifiable learning environment factors, and demographic factors (age, gender, race and ethnicity, LGBTQ+ identification, disability, and socioeconomic background). RESULTS: Of 2,257 learners surveyed, 1,261 (56%) responded. The number of learners reporting a somewhat or very strong sense of belonging was highest in the school or program (994 of 1,227 [81%]) followed by the organization (957 of 1,222 [78%]) and surrounding community (728 of 1,203 [61%]). In adjusted analyses, learners with very strong organization belongingness had lower odds of burnout (odds ratio [OR], 0.05; 95% CI, 0.02-0.12) and higher odds of being likely to recommend the organization (OR, 505.23; 95% CI, 121.54-2,100.18) and accept a job offer (OR, 38.68; 95% CI, 15.72-95.15; all P < .001). School or program and community belongingness were also strongly associated with these outcomes. In multivariable analyses, social support remained associated with higher odds of belongingness in school or program, organization, and surrounding community, favorable ratings of faculty relationships and leadership representation with higher odds of school or program and organization belongingness, and favorable ratings of diversity, equity, and inclusion learning climate with higher odds of community belongingness. CONCLUSIONS: Belongingness among medical students, residents, and fellows varies across contexts, strongly correlates with learner burnout and organizational recruitment retention indicators, and is associated with multiple potentially modifiable learning environment factors.

Survival of Infants Born at 22 to 25 Weeks' Gestation Receiving Care in the NICU: 2020-2022.

OBJECTIVE: To provide contemporary data on infants inborn at 22 to 25 weeks' gestation and receiving care at level 3 and 4 neonatal intensive care units in the United States. METHODS: Vermont Oxford Network members submitted data on infants born at 22 to 25 weeks' gestation at a hospital with a level 3 or 4 NICU from 2020 to 2022. The primary outcome was survival to hospital discharge. Secondary outcomes included survival without severe complications, length of stay, and technology dependence. RESULTS: Overall, 22 953 infants at 636 US hospitals were included. Postnatal life support increased from 68.0% at 22 weeks to 99.8% at 25 weeks. The proportion of infants born at 22 weeks receiving postnatal life support increased from 61.6% in 2020 to 73.7% in 2022. For all infants, survival ranged from 24.9% at 22 weeks to 82.0% at 25 weeks. Among infants receiving postnatal life support, survival ranged from 35.4% at 22 weeks to 82.0% at 25 weeks. Survival without severe complications ranged from 6.3% at 22 weeks to 43.2% at 25 weeks. Median length of stay ranged from 160 days at 22 weeks to 110 days at 25 weeks. Among survivors, infants born at 22 weeks had higher rates of technology dependence at discharge home than infants born at later gestational ages. CONCLUSIONS: Survival ranged from 24.9% at 22 weeks to 82.1% at 25 weeks, with low proportions of infants surviving without complications, prolonged lengths of hospital stay, and frequent technology dependence at all gestational ages.

Short-term risk of fracture is increased by deficits in cortical and trabecular bone microarchitecture independent of DXA BMD and FRAX: bone microarchitecture international consortium (BoMIC) prospective cohorts.

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height and weight, and then additionally adjusted for femoral neck (FN) aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 to -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, failure load and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

Identifying individuals at risk for short-term fracture (within 2-years) is essential to offer prompt treatment. We examined bone microarchitecture at arm and lower leg for prediction of short-term fractures in 7327 older adults, independent of the common clinical practice measures ­ DXA-BMD and FRAX. After adjusting for other factors, we found that measures of failure load, cortical and trabecular bone microarchitecture and density predicted short-term risk of fracture beyond the usual clinical measures of DXA and FRAX. These measures of bone that indicate deficits in microarchitecture may be a useful adjunct to traditional assessment of fracture risk in older adults.

Reports of Burnout Among Historically Marginalized and Female Graduating Medical Students During the COVID-19 Pandemic.

PURPOSE: To examine graduating medical student reports of burnout by sex, race and ethnicity, and sexual orientation and explore trends within intersectional demographic groups from 2019-2021 in a national sample. METHOD: The authors obtained medical student responses to the 2019-2021 Association of American Medical Colleges (AAMC) Graduation Questionnaires (GQs) linked to data from other AAMC sources. The dataset included year of GQ completion, responses to a modified Oldenburg Burnout Inventory (exhaustion subscale range: 0-24; disengagement subscale range: 0-15), and demographics previously shown to relate to the risk of burnout in medical students, residents, or physicians. Multivariable linear regression analysis was performed to evaluate independent associations between demographics and burnout. RESULTS: Overall response rate was 80.7%. After controlling for other factors, mean exhaustion scores were higher among Asian (parameter estimate [PE] 0.38, 95% confidence interval [CI] 0.21, 0.54), bisexual (PE 0.97, 95% CI 0.76, 1.17), and gay or lesbian (PE 0.55, 95% CI 0.35, 0.75) students than those who did not identify with each of those respective groups. Mean disengagement scores were lower among female (PE -0.47, 95% CI -0.52, -0.42), Hispanic (PE -0.11, 95% CI -0.22, -0.01), and White (PE -0.10, 95% CI -0.19, 0.00) students and higher among Asian (PE 0.17, 95% CI 0.07, 0.27), Black or African American (PE 0.31, 95% CI 0.18, 0.44), bisexual (PE 0.54, 95% CI 0.41, 0.66), and gay or lesbian (PE 0.23, 95% CI 0.11, 0.35) students than those who did not identify with each of those respective groups. From 2019-2021, mean exhaustion and disengagement scores were relatively stable or improved across nearly all intersectional groups. CONCLUSIONS: Male, Asian, Black or African American, and sexual minority students had a higher risk of burnout, while female, Hispanic, White, and heterosexual or straight students had a lower risk of burnout.

Toward Physiological Detection of a "Just-Right" Challenge Level for Motor Learning in Immersive Virtual Reality: Protocol for a Cross-Sectional Study.

BACKGROUND: Motor learning, a primary goal of pediatric rehabilitation, is facilitated when tasks are presented at a "just-right" challenge level-at the edge of the child's current abilities, yet attainable enough to motivate the child in persistent efforts for success. Immersive virtual reality (VR) may be ideally suited for "just-right" task challenges because it enables precise adjustments of task parameters in motivating environments. Rehabilitation-specific VR tasks often use dynamic difficulty algorithms based on task performance to personalize task difficulty. However, these approaches do not consider relevant cognitive processes that could also impact "just-right" challenges, such as attention and engagement. Objective physiological measurement of these cognitive processes using wearable sensors could support their integration within "just-right" challenge detection and prediction algorithms. As a first step, it is important to explore relationships between objectively and subjectively measured psychophysiological states at progressively challenging task difficulty levels. OBJECTIVE: This study aims to (1) evaluate the performance of wearable sensors in a novel movement-based motor learning immersive VR task; (2) evaluate changes in physiological data at 3 task difficulty levels; and (3) explore the relationship between physiological data, task performance, and self-reported cognitive processes at each task difficulty level. METHODS: This study uses the within-participant experimental design. Typically developing children and youth aged 8-16 years will be recruited to take part in a single 90-minute data collection session. Physiological sensors include electrodermal activity, heart rate, electroencephalography, and eye-tracking. After collecting physiological data at rest, participants will play a seated unimanual immersive VR task involving bouncing a virtual ball on a virtual racket. They will first play for 3 minutes at a predefined medium level of difficulty to determine their baseline ability level and then at a personalized choice of 3 progressive difficulty levels of 3 minutes each. Following each 3-minute session, participants will complete a short Likert-scale questionnaire evaluating engagement, attention, cognitive workload, physical effort, self-efficacy, and motivation. Data loss and data quality will be calculated for each sensor. Repeated-measures ANOVAs will evaluate changes in physiological response at each difficulty level. Correlation analyses will determine individual relationships between task performance, physiological data, and self-reported data at each difficulty level. RESULTS: Research ethics board approval has been obtained, and data collection is underway. Data collection was conducted on December 12, 2023, and April 12, 2024, with a total of 15 typically developing children. Data analysis has been completed, and results are expected to be published in the fall of 2024. CONCLUSIONS: Wearable sensors may provide insights into the physiological effects of immersive VR task interaction at progressive difficulty levels in children and youth. Understanding the relationship between physiological and self-reported cognitive processes is a first step in better identifying and predicting "just-right" task challenges during immersive VR motor learning interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55730.

Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

SLC35A2 modulates paramyxovirus fusion events during infection.

Paramyxoviruses are significant human and animal pathogens that include mumps virus (MuV), Newcastle disease virus (NDV) and the murine parainfluenza virus Sendai (SeV). Despite their importance, few host factors implicated in paramyxovirus infection are known. Using a recombinant SeV expressing destabilized GFP (rSeVCdseGFP) in a loss-of-function CRISPR screen, we identified the CMP-sialic acid transporter (CST) gene SLC35A1 and the UDP-galactose transporter (UGT) gene SLC35A2 as essential for paramyxovirus infection. SLC35A1 knockout (KO) cells showed significantly reduced binding and infection of SeV, NDV and MuV due to the lack of cell surface sialic acids, which act as their receptors. However, SLC35A2 KO cells revealed unknown critical roles for this factor in virus-cell and cell-to-cell fusion events during infection with different paramyxoviruses. While the UGT was essential for virus-cell fusion during SeV entry to the cell, it was not required for NDV or MuV entry. Importantly, the UGT promoted the formation of larger syncytia during MuV infection, suggesting a role in cell-to-cell virus spread. Our findings demonstrate that paramyxoviruses can bind to or enter A549 cells in the absence of canonical galactose-bound sialic-acid decorations and show that the UGT facilitates paramyxovirus fusion processes involved in entry and spread.

Kidney Health Monitoring in Neonatal Intensive Care Unit Graduates: A Modified Delphi Consensus Statement.

Importance: Kidney disease is common in infants admitted to the neonatal intensive care unit (NICU). Despite the risk of chronic kidney disease (CKD) in infants discharged from the NICU, neither evidence- nor expert-based recommendations exist to guide clinical care after discharge. Objective: To develop recommendations for risk stratification and kidney health monitoring among infants after discharge from the NICU. Evidence Review: At the National Institute of Health-supported Consensus Workshop to Address Kidney Health in Neonatal Intensive Care Unit Graduates meeting conducted in February 2024, a panel of 51 neonatal nephrology experts focused on 3 at-risk groups: (1) preterm infants, (2) critically ill infants with acute kidney injury (AKI), and (3) infants with critical cardiac disease. Using established modified Delphi processes, workgroups derived consensus recommendations. Findings: In this modified Delphi consensus statement, the panel developed 10 consensus recommendations, identified gaps in knowledge, and prioritized areas of future research. Principal suggestions include risk stratification at time of hospital discharge, family and clinician education and counseling for subsequent kidney health follow-up, and blood pressure assessment as part of outpatient care. Conclusions and Relevance: Preterm infants, critically ill infants with AKI, and infants with critical cardiac disease are at increased risk of CKD. We recommend (1) risk assessment at the time of discharge, (2) clinician and family education, and (3) kidney health assessments based on the degree of risk. Future work should focus on improved risk stratification, identification of early kidney dysfunction, and development of interventions to improve long-term kidney health.

Addressing Susceptibility to Non-Prescription Substances for Weight Loss Among Immigrant Hispanic College Students: A Pilot Study.

Non-prescription weight loss substances, such as supplements and herbal remedies, can be harmful. Hispanic immigrant students may be highly susceptible to these substances, especially those advertised on social media. This study was a feasibility/acceptability pilot trial of an intervention to reduce this susceptibility. Latino or Hispanic immigrant students aged 18-35 were randomized to receive either a single-session, culturally tailored online intervention (Redes Sociales Para la Salud), or a dose-matched intervention focused on general support for immigrant students (Immigrant Support). Following the intervention, participants answered quantitative and open-ended questions about intervention satisfaction, and completed measures of susceptibility to non-prescription weight loss substances. Participants additionally completed measures of social media use and social norm perceptions. Fifty-five participants enrolled in the study, and 32 had primary outcome data. Participants were majority female (62.5%) and graduate students (81.3%) with a mean BMI of 24.6 ± 3.5 kg/m2. Ratings of intervention satisfaction were moderate (3.5-3.7 out of 5). In open-ended questions, participants identified areas of high satisfaction (cultural appropriateness, learning new information) and suggested improvements (increase interactivity, improve presentation appearance). Considering signal of an effect, participant ratings indicated that susceptibility to non-prescription weight loss substances was lower after Redes Sociales Para la Salud compared to the control intervention. In exploratory analyses, susceptibility to non-prescription weight loss substances was positively associated with extent of social media use (r = 0.41-0.46) and social norms about use of these substances (r = 0.38). With additional refinement, the Redes Sociales Para la Salud has promise for addressing susceptibility to non-prescription weight loss substances.

Branched-Chain and Aromatic Amino Acids, Type 2 Diabetes, and Cardiometabolic Risk Factors among Puerto Rican Adults.

(1) Background: Branched-chain and aromatic amino acids (BCAAs/AAAs) have been considered as markers of type 2 diabetes (T2D); however, studies on associations between these metabolites and T2D and cardiometabolic traits in Hispanic populations are limited. The aim of this study was to examine the associations between baseline BCAAs (isoleucine, leucine, valine)/AAAs (phenylalanine, tyrosine) and prevalent and incident T2D, as well as baseline and longitudinal (2 year) changes in cardiometabolic traits (measures of glycemia, dyslipidemia, inflammation, and obesity) in two large cohorts of adults of Puerto Rican descent. (2) Methods: We included participants of the Boston Puerto Rican Health Study (BPRHS, n = 670) and San Juan Overweight Adult Longitudinal study (SOALS, n = 999) with available baseline metabolite and covariate data. T2D diagnosis was defined based on American Diabetes Association criteria. Multivariable logistic (for baseline T2D), Poisson (for incident T2D), and linear (for cardiometabolic traits) regression models were used; cohort-specific results were combined in the meta-analysis and adjusted for multiple comparisons. (3) Results: Higher baseline BCAAs were associated with higher odds of prevalent T2D (OR1SD BCAA score = 1.46, 95% CI: 1.34-1.59, p < 0.0001) and higher risk of incident T2D (IRR1SD BCAA score = 1.24, 95% CI: 1.13-1.37, p < 0.0001). In multivariable longitudinal analysis, higher leucine and valine concentrations were associated with 2-year increase in insulin (beta 1SD leucine = 0.37 mcU/mL, 95% CI: 0.11-0.63, p < 0.05; beta 1SD valine = 0.43 mcU/mL, 95% CI: 0.17-0.68, p < 0.01). Tyrosine was a significant predictor of incident T2D (IRR = 1.31, 95% CI: 1.09-1.58, p < 0.05), as well as 2 year increases in HOMA-IR (beta 1SD tyrosine = 0.13, 95% CI: 0.04-0.22, p < 0.05) and insulin concentrations (beta 1SD tyrosine = 0.37 mcU/mL, 95% CI: 0.12-0.61, p < 0.05). (4) Conclusions: Our results confirmed the associations between BCAAs and prevalent and incident T2D, as well as concurrent measures of glycemia, dyslipidemia, and obesity, previously reported in predominantly White and Asian populations. Baseline leucine, valine, and tyrosine were predictors of 2 year increases in insulin, whereas tyrosine was a significant predictor of deteriorating insulin resistance over time. Our study suggests that BCAAs and tyrosine could serve as early markers of future glycemic changes in Puerto Ricans.

Primary care mental health integration to improve early treatment engagement for veterans who screen positive for depression.

OBJECTIVE: To examine the relationship between the penetration (or reach) of a national program aiming to integrate mental health clinicians into all primary care clinics (PC-MHI) and rates of guideline-concordant follow-up and treatment among clinic patients newly identified with depression in the Veterans Health Administration (VA). DATA SOURCES/STUDY SETTING: 15,155 screen-positive patients 607,730 patients with 2-item Patient Health Questionnaire scores in 82 primary care clinics, 2015-2019. STUDY DESIGN: In this retrospective cohort study, we used established depression care quality measures to assess primary care patients who (a) newly screened positive (score ≥3) and (b) were identified with depression by clinicians via diagnosis and/or medication (n = 15,155; 15,650 patient-years). Timely follow-up included ≥3 mental health, ≥3 psychotherapy, or ≥3 primary care visits for depression. Minimally appropriate treatment included ≥4 mental health visits, ≥3 psychotherapy, or ≥60 days of medication. In multivariate regressions, we examined whether higher rates of PC-MHI penetration in clinic (proportion of total primary care patients in a clinic who saw any PC-MHI clinician) were associated with greater depression care quality among cohort patients, adjusting for year, healthcare system, and patient and clinic characteristics. DATA COLLECTION/EXTRACTION METHODS: Electronic health record data from 82 VA clinics across three states. PRINCIPAL FINDINGS: A median of 9% of all primary care patients were seen by any PC-MHI clinician annually. In fully adjusted models, greater PC-MHI penetration was associated with timely depression follow-up within 84 days (∆P = 0.5; SE = 0.1; p < 0.001) and 180 days (∆P = 0.3; SE = 0.1; p = 0.01) of a positive depression screen. Completion of at least minimal treatment within 12 months was high (77%), on average, and not associated with PC-MHI penetration. CONCLUSIONS: Greater PC-MHI program penetration was associated with early depression treatment engagement at 84-/180-days among clinic patients newly identified with depression, with no effect on already high rates of completion of minimally sufficient treatment within the year.

Dietary protein in the ICU in relation to health outcomes.

PURPOSE OF REVIEW: Critical care nutrition guidelines recommend provision of higher protein doses than recommended in health. These recommendations have been predominately based on lower quality evidence and physiological rationale that greater protein doses may attenuate the significant muscle loss observed in critically ill patients. This review discusses the mechanistic action of protein in the critically ill, details results from recent trials on health outcomes, discusses considerations for interpretation of trial results, and provides an overview of future directions. RECENT FINDINGS: Two recent large clinical trials have investigated different protein doses and the effect on clinical outcome. Important findings revealed potential harm in certain sub-groups of patients. This harm must be balanced with the potential for beneficial effects on muscle mass and physical function given that two recent systematic reviews with meta-analyses demonstrated attenuation of muscle loss with higher protein doses. Utilizing biological markers such as urea: creatinine ratio or urea levels may prove useful in monitoring harm from higher protein doses. SUMMARY: Future research should focus on prospectively investigating biological signatures of harm as well as taking into the consideration elements that will likely enhance the effectiveness of protein dose.

Patellofemoral Instability in Pediatric and Adolescent Athletes: A Review of Risk Factors and Treatments.

Pediatric patellar instability can impair function and restrict activity participation. If left untreated, it can lead to a degenerative knee. The incidence of patellar dislocations is highest in adolescents between 10 and 17 years of age; more than half of all first-time patellar dislocations occur during sports. This article reviews the evidence of risk factors for traumatic patellar instability, surgical interventions, and return-to-sport (RTS) considerations for pediatric and adolescent athletes. Anatomic risk factors for patellar instability in pediatric and adolescent patients include trochlear dysplasia, elevated tibial tuberosity-trochlear groove (TT-TG) distance, patella alta, genu valgum, femoral anteversion and tibial torsion, and hyperlaxity.

In vitro assessment of the Kirpa Kit™ modified manual single lumen alternating micro-batch (mSLAMB) dialysis device.

BACKGROUND: Access to pediatric dialysis is challenged in low-resource settings due to high costs, scarcity of equipment, and the lack of qualified personnel availability. We demonstrated the manual single lumen alternating micro-batch (mSLAMB) device can remove small solutes in vitro without the need for electricity, batteries, or pumps. We developed a new version (Kirpa Kit™) to address some of the technical limitations of mSLAMB. Here, we compare the in vitro clearance performance and ease of use of the Kirpa Kit™ with that of prior mSLAMB configurations. METHODS: A mixture of expired packed red blood cells, 0.9% NaCl, urea, and heparin was used to test the efficiency of two mSLAMB configurations and the Kirpa Kit™ in removing potassium and urea. Clearance was evaluated by measuring percent reduction after 25-min sessions with each device. A survey was used to evaluate the ease of use of each configuration. RESULTS: The Kirpa Kit™ achieved a median urea reduction of 82.4% and potassium reduction of 82.1%, which were higher than those achieved with the best-performing mSLAMB configuration (urea 71.9%, potassium 75.4%). The Kirpa Kit™ was easier to use with a shorter perceived time of use than the mSLAMB. CONCLUSIONS: The Kirpa Kit™, evolution of mSLAMB, is easy to use and may have improved efficacy, making it an optimal candidate for in vivo testing.

Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). OBJECTIVES: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. METHODS: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. MEASUREMENTS AND MAIN RESULTS: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFß1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. CONCLUSIONS: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.

Using a simplified Downes score to predict the receipt of surfactant in a highly resourced setting.

OBJECTIVE: The Downes score is a neonatal examination scoring tool frequently used to guide initiation of CPAP, but its ability to predict the need for surfactant has not been assessed. We assessed the extent to which the Downes score predicts the receipt of surfactant. STUDY DESIGN: We calculated a simplified Downes score from nursing admission data for infants (≤ 2000 grams, and ≥ 25 weeks' gestation) admitted on CPAP to a highly resourced level III NICU, to assess the predictive value for the receipt of surfactant. RESULTS: Fifty-three (31.5%) out of 168 infants admitted on CPAP received surfactant. A simplified Downes score of ≥ 4 predicted the receipt of surfactant with 90.6% sensitivity, 52.2% specificity, 46.6% positive predictive value, 92.3% negative predictive value, and 64.3% accuracy. CONCLUSION: The high sensitivity and negative predictive value suggest utility for using the Downes score to help guide clinical decision making regarding surfactant therapy.