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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.

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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.

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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.

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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.

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BACKGROUND: Continuous kidney replacement therapy (CKRT) is often used for acute kidney injury (AKI) or fluid overload (FO) in children ≤ 10 kg. Intensive care unit (ICU) mortality in children ≤ 10 kg reported by the prospective pediatric CRRT (ppCRRT, 2001-2003) registry was 57%. We aimed to evaluate characteristics associated with ICU mortality using a contemporary registry. METHODS: The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) registry is a retrospective, multinational, observational study of children and young adults aged 0-25 years receiving CKRT (2015-2021) for AKI or FO. This analysis included patients ≤ 10 kg at hospital admission. PRIMARY AND SECONDARY OUTCOMES: ICU mortality and major adverse kidney events at 90 days (MAKE-90) defined as death, persistent kidney dysfunction, or dialysis within 90 days, respectively. RESULTS: A total of 210 patients were included (median age 0.53 years (IQR, 0.1, 0.9)). ICU mortality was 46.5%. MAKE-90 occurred in 150/207 (72%). CKRT was initiated at a median 3 days (IQR 1, 9) after ICU admission and lasted a median 6 days (IQR 3, 16). On multivariable analysis, pediatric logistic organ dysfunction score (PELOD-2) at CKRT initiation was associated with increased odds of ICU mortality (aOR 2.64, 95% CI 1.68-4.16), and increased odds of MAKE-90 (aOR 2.2, 95% CI 1.31-3.69). Absence of comorbidity was associated with lower MAKE-90 (aOR 0.29, 95%CI 0.13-0.65). CONCLUSIONS: We report on a contemporary cohort of children ≤ 10 kg treated with CKRT for acute kidney injury and/or fluid overload. ICU mortality is decreased compared to ppCRRT. The extended risk of death and morbidity at 90 days highlights the importance of close follow-up.

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Purpose: Hemi-epiphysiodesis procedures in skeletally immature patients are commonly done to correct genu valgum over time. This study seeks to demonstrate the average rate of deformity correction for genu valgum using hinged tension band plates, while examining different age groups and sex-related differences. Methods: A retrospective chart review of patients who underwent hemi-epiphysiodesis with hinged tension band plates for valgus knee deformity from 2012 to 2022 by one pediatric orthopaedic surgeon was performed. Expected time of growth remaining was calculated as the difference between age of skeletal maturity and bone age at time of surgery. The mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, mechanical femoral tibia angle, screw divergence angle, and hinge angle were measured immediately after implant placement and prior to implant removal. Results: 54 skeletally immature patients were treated for pathologic genu valgum. The mean age at time of surgery was 12.5 ± 1.9 years. The radiographic measurement of the valgus deformity between the beginning and end of treatment showed significant correction (p = 0.002). The lower limb axis of the younger cohort corrected significantly faster (7.5 ± 4.6°/year) than the older cohort (5.3 ± 2.8°/year) (p = 0.030). The mechanical lateral distal femoral angle correction rate was also significantly different between the two cohorts (7.0 ± 4.7°/year vs. 4.8 ± 2.8°/year, respectively (p = 0.002)). The group with greater expected time of growth remaining demonstrated a significantly faster rate of correction than the group with less than 2 years of growth remaining (p < 0.001). Conclusion: This study reaffirms the finding that timing is essential when performing temporary hemi-epiphysiodesis for valgus knee deformity in skeletally immature patients.

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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.

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(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.

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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.

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In diderm bacteria, the Lol pathway canonically mediates the periplasmic transport of lipoproteins from the inner membrane (IM) to the outer membrane (OM) and therefore plays an essential role in bacterial envelope homeostasis. After extrusion of modified lipoproteins from the IM via the LolCDE complex, the periplasmic chaperone LolA carries lipoproteins through the periplasm and transfers them to the OM lipoprotein insertase LolB, itself a lipoprotein with a LolA-like fold. Yet, LolB homologs appear restricted to γ-proteobacteria and are missing from spirochetes like the tick-borne Lyme disease pathogen Borrelia burgdorferi, suggesting a different hand-off mechanism at the OM. Here, we solved the crystal structure of the B. burgdorferi LolA homolog BB0346 (LolABb) at 1.9 Å resolution. We identified multiple structural deviations in comparative analyses to other solved LolA structures, particularly a unique LolB-like protruding loop domain. LolABb failed to complement an Escherichia coli lolA knockout, even after codon optimization, signal I peptide adaptation, and a C-terminal chimerization which had allowed for complementation with an α-proteobacterial LolA. Analysis of a conditional B. burgdorferi lolA knockout strain indicated that LolABb was essential for growth. Intriguingly, protein localization assays indicated that initial depletion of LolABb led to an emerging mislocalization of both IM and periplasmic OM lipoproteins, but not surface lipoproteins. Together, these findings further support the presence of two separate primary secretion pathways for periplasmic and surface OM lipoproteins in B. burgdorferi and suggest that the distinct structural features of LolABb allow it to function in a unique LolB-deficient lipoprotein sorting system.

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Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20-1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including L-valine and uric acid, potentially mediating the haem iron-T2D relationship, highlighting their pivotal role in T2D pathogenesis.

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Alcohol misuse in people with HIV (PWH) and chronic binge alcohol (CBA) administration in simian immunodeficiency virus (SIV)-infected macaques are associated with increased physical frailty and impaired functional skeletal muscle mass, respectively. Previous studies by our group demonstrate that muscle-enriched microRNAs (myomiRs) are differentially expressed in skeletal muscle (SKM) from CBA-administered SIV-infected male macaques and their altered expression contributes to impaired differentiation of SKM stem cells, or myoblasts. MicroRNAs can be transported in extracellular vesicles (EVs) to mediate numerous cellular responses through intercellular communication. The current study tested the hypothesis that EV-mediated delivery of miR-206 can ameliorate CBA-mediated decreased myoblast differentiation. Myoblasts were isolated from SKM of female SIV-infected, antiretroviral therapy-treated macaques that received either CBA (2.5g/kg/day, CBA/SIV) or water (VEH/SIV) for 14.5 months. Myotube and myotube derived EV myomiR expression, including miR-206, was lower in the CBA/SIV group. Overexpression of miR-206 decreased histone deacetylase 4 (HDAC4) and paired box 7 (PAX7) expression in myotubes and increased fusion index, a differentiation index, in CBA/SIV-derived myotubes. Similarly, EV-mediated delivery of miR-206 increased both fusion index and myotube density of CBA/SIV-derived myoblasts. These results support the potential therapeutic utility of EVs in delivering myomiRs to improve SKM stem cell differentiation.

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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.

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BACKGROUND: A welcoming environment may influence patient care experiences, and it may be particularly relevant for underrepresented groups, such as women veterans at Veterans Health Administration (VA) facilities where they represent only 8-10% of patients. Challenges to ensuring a welcoming environment for women veterans may include unwelcome comments from male veterans and staff or volunteers and feeling unsafe inside or outside VA facilities. We assessed associations between reports of gender-related environment of care problems and patient-reported outcomes. PROCEDURES: We merged national patient-reported outcomes from women veterans (n = 4,961) using Consumer Assessment of Health Plans & Systems Patient Centered Medical Home (CAHPS-PCMH) survey composite measures with Women Veteran Program Managers' reports of gender-related environment of care problems (n = 127, 2016-2017) at VA facilities. We performed multilevel bivariate logistic regressions to assess associations between Women Veteran Program Managers' reports of large/extreme problems and likelihood of women veterans' optimal ratings of primary care experiences (access, coordination, comprehensiveness, provider communication, and overall rating of primary care provider). We adjusted for patient-, site-, and area-level characteristics, and clustering of patients within VA facilities, and we applied design weights to address nonresponse bias in the patient data. Response rates were 40% for women veterans and 90% for Women Veteran Program Managers. MAIN FINDINGS: Few (<15%) Women Veteran Program Managers reported large/extreme environment of care problems. Women veterans obtaining care at those sites were less likely to rate provider communication and comprehensiveness (psychosocial health assessed) as optimal. PRINCIPAL CONCLUSIONS: Ensuring a welcoming environment may improve women veterans' primary care experiences.

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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.

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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.

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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.

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BACKGROUND: Patellofemoral instability is associated with chondral injuries to the patella, trochlea, and lateral femoral condyle. Although studies have demonstrated an association between patellar dislocations and chondral injuries, the influence of the number of dislocations on chondrosis is not established. PURPOSE: To elucidate the precise association between the number of patellar dislocation events and the severity of chondral injuries in a multicenter cohort study at the time of patellar stabilization procedures. STUDY DESIGN: Cross-sectional study; Level of evidence, 2. METHODS: A prospective multicenter cohort study (JUPITER [Justifying Patellar Instability Treatment by Early Results]) database was queried for cases of primary patellofemoral instability procedures from December 2016 to September 2022. Cartilage lesions were classified using the International Cartilage Repair Society (ICRS) classification system during an arthroscopic or open evaluation (direct visualization), with grades 2 to 4 considered abnormal. The number of dislocations was categorized as 1, 2-5, and >5. Categorical variables were compared with the chi-square test, and binary logistic regression was performed to identify predictors of the presence of chondral lesions. RESULTS: A total of 938 knees (mean age, 16.2 ± 3.8 years; 61.4% female) were included, with 580 (61.8%) demonstrating a chondral injury. The most affected region was the patella (n = 498 [53.1%]), followed by the lateral femoral condyle (n = 117 [12.5%]) and trochlea (n = 109 [11.6%]). There were no differences in the presence (P = .17) or grade (P = .63) of patellar lesions by the number of dislocations. Patients with >5 dislocations more frequently had trochlear chondral lesions (19.8%) compared with those with fewer dislocations (1, 7.6%; 2-5, 11.0%; P < .001). More dislocations were also associated with a higher proportion of ICRS grade 2 to 4 trochlear lesions (>5, 15.3%; 2-5, 10.0%; 1, 6.9%; P = .015). Combined patellar and trochlear lesions were also more common in those with >5 dislocations (P = .001). In multivariable regression, >5 dislocations was the only variable predictive of a trochlear lesion (odds ratio, 3.03 [95% CI, 1.65-5.58]; P < .001). CONCLUSION: This large prospective cohort study demonstrated that recurrent patellar dislocations can lead to more severe chondral damage in specific locations in the knee. More than 5 dislocations was associated with a >3-fold increase in the incidence and severity of trochlear chondral injuries. There were no differences in the presence or grade of patellar lesions by the number of dislocations. These findings should caution surgeons regarding prolonged nonoperative treatment.

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Two anhydrous polymorphs of the novel antiviral medicine nirmatrelvir were discovered during the development of Paxlovid, Pfizer's oral Covid-19 treatment. A comprehensive experimental and computational approach was necessary to distinguish the two closely related polymorphs, herein identified as Forms 1 and 4. This approach paired experimental methods, including powder X-ray diffraction and single-crystal X-ray diffraction, solid-state experimental methods, thermal analysis, solid-state nuclear magnetic resonance and Raman spectroscopy with computational investigations comprising crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations of the polymorphic transition. Forms 1 and 4 were ultimately determined to be enantiotropically related polymorphs with Form 1 being the stable form above the transition temperature of ∼17 °C and designated as the nominated form for drug development. The work described in this paper shows the importance of using highly specialized orthogonal approaches to elucidate the subtle differences in structure and properties of similar solid-state forms. This synergistic approach allowed for unprecedented speed in bringing Paxlovid to patients in record time amidst the pandemic.

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