Safety and Pharmacokinetics of Casirivimab and Imdevimab (CAS+IMD) in Pediatric Outpatients With COVID-19.

The safety of casirivimab+imdevimab (CAS+IMD) (anti-SARS-CoV-2 monoclonal antibodies [mAbs]) in pediatric outpatients with COVID-19 was evaluated in a randomized, phase 1/2/3 trial. Consistent with adults, CAS+IMD was generally well tolerated with low drug-induced immunogenicity rates. The findings support development of next-generation anti-SARS-CoV-2 mAbs for at-risk pediatric patients.

Assessing the safety and pharmacokinetics of casirivimab and imdevimab (CAS+IMD) in a cohort of pregnant outpatients with COVID-19: results from an adaptive, multicentre, randomised, double-blind, phase 1/2/3 study.

OBJECTIVE: Pregnant women with COVID-19 are at elevated risk for severe outcomes, but clinical data on management of these patients are limited. Monoclonal antibodies, such as casirivimab plus imdevimab (CAS+IMD), have proven effective in treating non-pregnant adults with COVID-19, prompting further evaluation in pregnant women. METHODS: A phase 3 portion of an adaptive, multicentre, randomised, double-blind, placebo-controlled trial evaluated the safety, clinical outcomes, pharmacokinetics and immunogenicity of CAS+IMD (1200 mg or 2400 mg) in the treatment of pregnant outpatients with COVID-19 (NCT04425629). Participants were enrolled between December 2020 and November 2021, prior to the emergence of Omicron-lineage variants against which CAS+IMD is not active. Safety was evaluated in randomised participants who received study drug (n=80); clinical outcomes were evaluated in all randomised participants (n=82). Only two pregnant participants received placebo, limiting conclusions regarding treatment effect. Infants born to pregnant participants were followed for developmental outcomes ≤1 year of age. RESULTS: In pregnant participants, CAS+IMD was well tolerated, with no grade ≥2 hypersensitivity or infusion-related reactions reported. There were no participant deaths, and only one COVID-19-related medically attended visit. Although two pregnancies (3%) reported issues in the fetus/neonate, they were confounded by maternal history or considered to be due to an alternate aetiology. No adverse developmental outcomes in infants ≤1 year of age were considered related to in utero exposure to the study drug. CAS+IMD 1200 mg and 2400 mg rapidly and similarly reduced viral loads, with a dose-proportional increase in concentrations of CAS+IMD in serum. Pharmacokinetics were consistent with that reported in the general population. Immunogenicity incidence was low. CONCLUSION: CAS+IMD treatment of pregnant outpatients with COVID-19 showed similar safety, clinical outcomes and pharmacokinetic profiles to that observed in non-pregnant adults. There was no evidence of an impact on developmental outcomes in infants ≤1 year of age. TRIAL REGISTRATION NUMBER: NCT04425629.

CYpHER: catalytic extracellular targeted protein degradation with high potency and durable effect.

Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.

A Two Step Validation of the Performance-Based IISCA: A Trauma-Informed Functional Analysis Model.

Functional analyses often involve extended exposure to evocative events and problem behavior, which potentially places the client at risk of retraumatization. The performance-based, interview-informed synthesized contingency analysis (IISCA) is a brief analysis that is conducted in a single session and applies a trauma-assumed framework in the development of the assessment procedures (e.g., measures of calm, reinforcing precursors to avoid escalation and physical management). We conducted 12 applications of the performance-based IISCA in the United States and Brazil and (1) compared the results to a subset of 7 applications who also experienced the original IISCA and (2) incorporated a function-based treatment informed by the performance-based IISCA in a further subset of 5 of those 12 applications. The results support the use of the performance-based IISCA in that this variation of the IISCA corresponded with the original IISCA and informed effective treatment of problem behavior. Supplementary Information: The online version contains supplementary material available at 10.1007/s40617-023-00792-2.

Integration of Group A Streptococcus Rapid Tests with the Open Fluidic CandyCollect Device.

The CandyCollect device is a lollipop-inspired open fluidic oral sampling device designed to provide a comfortable user sampling experience. We demonstrate that the CandyCollect device can be coupled with a rapid antigen detection test (RADT) kit designed for Group A Streptococcus (GAS). Through in vitro experiments with pooled saliva spiked with Streptococcus pyogenes we tested various reagents and elution volumes to optimize the RADT readout from CandyCollect device samples. The resulting optimized protocol uses the kit-provided reagents and lateral flow assay (LFA) while replacing the kit's pharyngeal swab with the CandyCollect device, reducing the elution solution volume, and substituting the tube used for elution to accommodate the CandyCollect device. Positive test results were detected by eye with bacterial concentrations as low as the manufacturer's "minimal detection limit" - 1.5×105 CFU/mL. LFA strips were also scanned and quantified with image analysis software to determine the signal-to-baseline ratio (SBR) and categorize positive test results without human bias. We tested our optimized protocol for integrating CandyCollect and RADT using CandyCollect clinical samples from pediatric patients (n=6) who were previously diagnosed with GAS pharyngitis via pharyngeal swabs tested with RADT as part of their clinical care. The LFA results of these CandyCollect devices and interspersed negative controls were determined by independent observers, with positive results obtained in four of the six participants on at least one LFA replicate. Taken together, our results show that CandyCollect devices from children with GAS pharyngitis can be tested using LFA rapid tests.

Risk factors for central line-associated bloodstream infection in the pediatric intensive care setting despite standard prevention measures.

OBJECTIVE: Identify risk factors for central line-associated bloodstream infections (CLABSI) in pediatric intensive care settings in an era with high focus on prevention measures. DESIGN: Matched, case-control study. SETTING: Quaternary children's hospital. PATIENTS: Cases had a CLABSI during an intensive care unit (ICU) stay between January 1, 2015 and December 31, 2020. Controls were matched 4:1 by ICU and admission date and did not develop a CLABSI. METHODS: Multivariable, mixed-effects logistic regression. RESULTS: 129 cases were matched to 516 controls. Central venous catheter (CVC) maintenance bundle compliance was >70%. Independent CLABSI risk factors included administration of continuous non-opioid sedative (adjusted odds ratio (aOR) 2.96, 95% CI [1.16, 7.52], P = 0.023), number of days with one or more CVC in place (aOR 1.42 per 10 days [1.16, 1.74], P = 0.001), and the combination of a chronic CVC with administration of parenteral nutrition (aOR 4.82 [1.38, 16.9], P = 0.014). Variables independently associated with lower odds of CLABSI included CVC location in an upper extremity (aOR 0.16 [0.05, 0.55], P = 0.004); non-tunneled CVC (aOR 0.17 [0.04, 0.63], P = 0.008); presence of an endotracheal tube (aOR 0.21 [0.08, 0.6], P = 0.004), Foley catheter (aOR 0.3 [0.13, 0.68], P = 0.004); transport to radiology (aOR 0.31 [0.1, 0.94], P = 0.039); continuous neuromuscular blockade (aOR 0.29 [0.1, 0.86], P = 0.025); and administration of histamine H2 blocking medications (aOR 0.17 [0.06, 0.48], P = 0.001). CONCLUSIONS: Pediatric intensive care patients with chronic CVCs receiving parenteral nutrition, those on non-opioid sedative infusions, and those with more central line days are at increased risk for CLABSI despite current prevention measures.

Public safety personnel's perceptions of mental health training: an assessment of the Emotional Resilience Skills Training.

Public safety personnel (PSP) work experiences necessitate diverse and frequent exposures to potentially psychologically traumatic events (PPTEs) and other occupational stressors, which may explain the higher prevalence of mental health disorders and suicidal ideation among PSP relative to the general population. Consequently, PSP require emotional coping skills and evidence-informed mental health training to navigate arduous situations. The Emotional Resilience Skills Training (ERST) is a pilot 13-week mental health training program led by a peer and based on the robustly evidenced Unified Protocol for the Transdiagnostic Treatment of Mental Disorders. The study assessed whether PSP: perceived the ERST as improving their mental health or their management of stressors; applied the associated knowledge and skills; and would recommend ESRT to other PSP. Data were collected using a self-report survey and focus groups. A total of 197 PSP (58% male) completed a self-report survey and 72 PSP (33% female) participated in a sector-specific focus group to assess the ERST. The results indicate that PSP perceived ERST as helpful when applied. Almost all participants would recommend the training to other PSP. PSP expressed the ongoing need for mental health skills and knowledge, but also identified mental health training gaps during early-career training and stages.

CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner.

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.

Open Suprascapular Nerve Decompression at the Spinoglenoid Notch.

Suprascapular nerve (SSN) entrapment is a rare but significant cause of posterior shoulder pain and weakness. Compression of the nerve at the level of the spinoglenoid notch leads to weakness and atrophy of the infraspinatus. A detailed history and physical examination along with appropriate workup are paramount to arrive at this diagnosis. Surgical decompression is indicated in cases refractory to conservative management. In this Technical Note, we describe our technique for open decompression of the SSN at the spinoglenoid notch. This approach permits direct visualization of the SSN and allows for a safe, reliable, and thorough decompression.

Estimated and in vivo measurements of bite force demonstrate exceptionally large bite forces in parrots (Psittaciformes).

Jaw morphology and function determine the range of dietary items that an organism can consume. Bite force is a function of the force exerted by the jaw musculature and applied via the skeleton. Bite force has been studied in a wide range of taxa using various methods, including direct measurement, or calculation from skulls or jaw musculature. Data for parrots (Psittaciformes), considered to have strong bites, are rare. This study calculated bite force for a range of parrot species of differing sizes using a novel method that relied on forces calculated using the area of jaw muscles measured in situ and their masses. The values for bite force were also recorded in vivo using force transducers, allowing for a validation of the dissection-based models. The analysis investigated allometric relationships between measures of body size and calculated bite force. Additionally, the study examined whether a measure of a muscle scar could be a useful proxy to estimate bite force in parrots. Bite force was positively allometric relative to body and skull mass, with macaws having the strongest bite recorded to date for a bird. Calculated values for bite force were not statistically different from measured values. Muscle scars from the adductor muscle attachment on the mandible can be used to accurately predict bite force in parrots. These results have implications for how parrots process hard food items and how bite forces are estimated in other taxa using morphological characteristics of the jaw musculature.

Psychosocial outcomes with the Omnipod® 5 Automated Insulin Delivery System in caregivers of very young children with type 1 diabetes.

AIM: Automated insulin delivery (AID) systems have demonstrated improved glycaemic outcomes in people with type 1 diabetes (T1D), yet limited data exist on these systems in very young children and their impact on caregivers. We evaluated psychosocial outcomes following use of the tubeless Omnipod® 5 AID System in caregivers of very young children. MATERIALS AND METHODS: This 3-month single-arm, multicentre, pivotal clinical trial enrolled 80 children aged 2.0-5.9 years with T1D to use the Omnipod 5 AID System. Caregivers completed questionnaires assessing psychosocial outcomes-diabetes distress (Problem Areas in Diabetes), hypoglycaemia confidence (Hypoglycemia Confidence Scale), well-being (World Health Organization 5 Well-Being Index), sleep quality (Pittsburgh Sleep Quality Index), insulin delivery satisfaction (Insulin Delivery Satisfaction Survey) and system usability (System Usability Scale) at baseline with standard therapy and after 3 months of AID use. RESULTS: Following 3 months of Omnipod 5 use, caregivers experienced significant improvements across all measures, including diabetes-related psychosocial outcomes (Problem Areas in Diabetes; p < 0.0001, Hypoglycemia Confidence Scale; p < 0.01), well-being (World Health Organization 5 Well-Being Index; p < 0.0001) and perceived system usability (System Usability Scale; p < 0.0001). Significant improvements were seen in the Pittsburgh Sleep Quality Index total score and the overall sleep quality, sleep duration and efficiency subscales (all p < 0.05). Insulin Delivery Satisfaction Survey scores improved on all subscales (greater satisfaction, reduced burden and reduced inconvenience; all p < 0.0001). CONCLUSIONS: Caregivers face unique challenges when managing T1D in very young children. While glycaemic metrics have unquestioned importance, these results evaluating psychosocial outcomes reveal additional meaningful benefits and suggest that the Omnipod 5 AID System alleviates some of the burdens caregivers face with diabetes management.

Exploratory Factor Analysis of a Patient-Facing PCBH Adherence Measure: The PPAQ-Patient.

Model adherence indicates the degree to which a program or intervention is delivered as intended. In integrated primary care, where mental health services are embedded into primary care clinics, appraisal of model adherence provides insight into whether these services align with key features of this unique practice environment (e.g., brief, interdisciplinary care). To date, such evaluations have emphasized system and provider factors. This study is a preliminary evaluation of whether a novel patient-facing measure, the Primary Care Behavioral Health Provider Adherence Questionnaire-Patient Version (PPAQ-Patient), can provide insight into adherence to the Primary Care Behavioral Health (PCBH) model of integrated primary care. Survey data were collected from 281 veterans who received PCBH care. Exploratory factor analyses evaluated the data structure. Results suggest that 19 items spanning three temporally-referenced subscales may feasibly capture patient perspectives on PCBH adherence at various stages of treatment. Future work is needed to refine the measure.

Smaller Left Ventricular Size But Preserved Function in Adolescents and Adults Born Preterm.

BACKGROUND: Prematurely born adults have increased risk for cardiovascular disease. There are limited cardiac data on US-born preterm individuals. We aimed to determine whether adolescents and adults born prematurely have altered left ventricular (LV) structure and function, and to interrogate diastolic function using isometric handgrip exercise. METHODS AND RESULTS: Adolescents and adults born moderately to extremely preterm (≤32 weeks gestation or <1500 g birth weight) were recruited from the Parkland Health Neonatal Intensive Care Unit Registry. Full-term participants were recruited from the local area. Study procedures included anthropometrics and vitals, handgrip testing, and echocardiography performed at rest and during isometric handgrip exercise. Data were reported as mean±SD. The study enrolled 107 preterm and 48 term participants. Preterm participants (gestational age: 29.5±2.5 weeks) were shorter with higher body mass index (P<0.001) compared with term participants. Preterm participants exhibited smaller LV end-diastolic volume index (50.8±10.1 versus 56.9±10.0 mL/m2, P<0.001), LV stroke volume index (29.6±6.0 versus 34.1±6.5 mL/m2, P<0.001), and LV mass index (67.2±13.1 versus 73.3±14.2 g/m2, P=0.002) compared with term individuals. Preterm participants also had subclinical reductions in LV peak systolic tissue velocity and peak early diastolic tissue velocity lateral at rest. Isometric handgrip exercise promoted a reduction in diastolic function and an increase in hemodynamic measures, but changes during isometric handgrip exercise were similar between groups. CONCLUSIONS: Adolescents and adults born preterm exhibit overall normal cardiac function despite smaller cardiac volumes and mass compared with individuals born full term. Effects are most pronounced at the lowest gestational ages.

Stem Life: A Framework for Understanding the Prebiotic-Biotic Transition.

Abiogenesis is frequently envisioned as a linear, ladder-like progression of increasingly complex chemical systems, eventually leading to the ancestors of extant cellular life. This "pre-cladistics" view is in stark contrast to the well-accepted principles of organismal evolutionary biology, as informed by paleontology and phylogenetics. Applying this perspective to origins, I explore the paradigm of "Stem Life," which embeds abiogenesis within a broader continuity of diversification and extinction of both hereditary lineages and chemical systems. In this new paradigm, extant life's ancestral lineage emerged alongside and was dependent upon many other complex prebiotic chemical systems, as part of a diverse and fecund prebiosphere. Drawing from several natural history analogies, I show how this shift in perspective enriches our understanding of Origins and directly informs debates on defining Life, the emergence of the Last Universal Common Ancestor (LUCA), and the implications of prebiotic chemical experiments.

Endoscopic Retrolabyrinthine Craniotomy for Exposure of the Trigeminal Nerve Root Entry Zone: Volumetric Analysis of Anatomic Exposure in the Cadaver.

BACKGROUND AND OBJECTIVES: Exposure of the root entry zone (REZ) of the trigeminal nerve (TN) for microvascular decompression is commonly obtained with a retrosigmoid approach, with or without endoscopic assistance. We hypothesized that adequate exposure of the TN REZ could be obtained through an endoscopic retrolabyrinthine (RL) approach. We aim to quantify exposure of the REZ of the TN using endoscopic RL approach, with and without drilling of the suprameatal tubercle of the internal auditory canal. METHODS: Surgical dissection was performed bilaterally on 3 embalmed cadaveric human heads at the anatomy laboratory of the House Institute. Heads were scanned for volumetric analysis using 3D Slicer software both before and after dissection. Extent of exposure was quantified in 2 ways: first, by assessment of the surgeon's ability to visualize 16 predetermined anatomic landmarks with the endoscope and second, we estimated the "working" area by placing fiducials under the fully endoscopic view and calculating the resultant 3D volume. RESULTS: Using the standard endoscopic RL approach, an average of 13.8 landmarks (range 12-16) was visualized. The estimated working volume exposed by the RL on each side of each head varied from 189.28 to 527.85 mm3. Drilling of the suprameatal tubercle provided both increases in landmark visualization and, on average, an additional 55 mm3 of working volume. CONCLUSION: The endoscopic RL approach is a viable alternative to the standard retrosigmoid approach. Potential advantages of the RL include a more lateral trajectory that minimizes the need for cerebellar retraction and a shorter working distance and shallower angle to the cerebellopontine angle. Potential disadvantages include longer surgery time, increased technical difficulty of exposure, and potential for cerebrospinal fluid leak and or hearing loss.

Trends in Payments for Facility and Surgeon Professional Fees for Shoulder Surgeries Performed at Ambulatory Surgery Centers.

BACKGROUND: It has previously been demonstrated that utilization of ambulatory surgery centers (ASCs) results in cost savings and improved outcomes. Despite these benefits, Medicare reimbursement for professional fees at ASCs are decreasing over time. In this study, we sought to analyze the discrepancy between facility fee and professional fee reimbursements for ASCs by Medicare for common shoulder procedures over time. We hypothesized that professional fees for shoulder procedures would decrease over the study period while facility fees kept pace with inflation. METHODS: Current Procedural Terminology (CPT) codes were used to identify shoulder specific procedures approved for ASCs by Centers for Medicare and Medicaid Services (CMS). Procedures were grouped into arthroscopic and open categories. Publicly available data from CMS was accessed via the Medicare Physician Fee Schedule Lookup Tool and used to determine professional fee payments from 2018-2024. Additionally, Medicare ASC Payment Rates files were accessed to determine facility fee reimbursements to ASCs from 2018-2024. Descriptive statistics were used to calculate means and percent change over time. Compound annual growth rates (CAGR) were calculated and discrepancies in inflation were corrected for using the Consumer Price Index. The Benjamini and Hochberg method was used to correct P values in the setting of multiple comparisons. RESULTS: A total of 33 common shoulder procedures were included for analysis (10 arthroscopic codes and 23 open codes). Reimbursements for facility fees have remained significantly higher than corresponding professional fees for both open and arthroscopic procedures (p<0.01). On average, facility fee reimbursements for common shoulder surgeries have risen on an annual basis in a manner consistent with inflation (p=0.838). However, professional fees for these procedures have experienced a nearly uniform decline over the study period both nominally and in inflation-adjusted dollars (p=0.064 and p=0.005, respectively). CONCLUSION: Facility fee payments for outpatient approved shoulder surgeries have matched or outpaced inflation. Over the same time period, professional fee reimbursements for surgeons are consistently decreasing, both in absolute and inflation-adjusted dollars. Reform to the physician fee schedule is necessary to ensure that Medicare patients retain access to high-quality physician care.

The very early evolution of biological complexity.

All extant life is descended from a common ancestor, which, despite being very ancient, appears to have been a complex cellular organism. A new study by Moody et al. shows that this ancestor was not only a complex cell, but also lived within a microbial ecology likely inhabited by other complex cells.

Low prevalence of testing for apolipoprotein B and lipoprotein (a) in the real world.

Objective: Apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]) are predictors of cardiovascular disease (CVD) risk; therefore, current recommendations for CVD risk assessment and management advocate that patients receive testing for ApoB and Lp(a) in addition to the standard lipid panel. However, US guidelines around ApoB and Lp(a) testing have evolved over time and vary slightly by expert committee. The objective of this analysis was to estimate the number of insured individuals in the USA who received any component of a lipid test, or ApoB and/or Lp(a) testing, during 2019. Methods: We conducted a cross-sectional analysis to estimate the prevalence of any component of a lipid test, ApoB, and/or Lp(a) in the USA using four different claim data sources (including Medicaid, Medicare, and commercially insured enrollees). Prevalence estimates were age-, sex-, payor-, and region-standardized to the 2019 US Annual Social and Economic Supplement of the Current Population Survey. We also described the clinical profile of patients who received lipid testing between 2019 and 2021 (cohort analysis) in Optum claims database. Enrollees were grouped into four non-mutually exclusive cohorts based on their completion of any component of the lipid panel, ApoB, Lp(a), or ApoB and Lp(a). Results: In the prevalence cohort, over a third (38 %) of insured adults in the USA underwent testing for any component of a lipid panel in 2019. This proportion was higher for individuals aged ≥65 years compared to younger adults (62% vs 31 %). The proportion of ApoB and Lp(a) testing represented only <1 % of testing for any component of a lipid panel. In the cohort analysis, we found that lipid testing increased with age and comorbidities. Conclusion: These data should be considered by guideline-issuing agencies and organizations to develop education campaigns encouraging more frequent use of tests beyond the standard lipid panel.

NR2F2 Reactivation in Early-life Adipocyte Stem-like Cells Rescues Adipocyte Mitochondrial Oxidation.

In humans, perinatal exposure to an elevated omega-6 (n6) relative to omega-3 (n3) Fatty Acid (FA) ratio is associated with the likelihood of childhood obesity. In mice, we show perinatal exposure to excessive n6-FA programs neonatal Adipocyte Stem-like cells (ASCs) to differentiate into adipocytes with lower mitochondrial nutrient oxidation and a propensity for nutrient storage. Omega-6 FA exposure reduced fatty acid oxidation (FAO) capacity, coinciding with impaired induction of beige adipocyte regulatory factors PPARγ, PGC1α, PRDM16, and UCP1. ASCs from n6-FA exposed pups formed adipocytes with increased lipogenic genes in vitro, consistent with an in vivo accelerated adipocyte hypertrophy, greater triacylglyceride accumulation, and increased % body fat. Conversely, n6-FA exposed pups had impaired whole animal 13C-palmitate oxidation. The metabolic nuclear receptor, NR2F2, was suppressed in ASCs by excess n6-FA intake preceding adipogenesis. ASC deletion of NR2F2, prior to adipogenesis, mimicked the reduced FAO capacity observed in ASCs from n6-FA exposed pups, suggesting that NR2F2 is required in ASCs for robust beige regulator expression and downstream nutrient oxidation in adipocytes. Transiently re-activating NR2F2 with ligand prior to differentiation in ASCs from n6-FA exposed pups, restored their FAO capacity as adipocytes by increasing the PPARγ-PGC1α axis, mitochondrial FA transporter CPT1A, ATP5 family synthases, and NDUF family Complex I proteins. Our findings suggest that excessive n6-FA exposure early in life dampens an NR2F2-mediated induction of beige adipocyte regulators, resulting in metabolic programming that is shifted towards nutrient storage.

Compression of an Autograft Biceps into an Augmentation Patch does not Cause Mechanical Damage to the Tenocyte.

PURPOSE: A compression plate has recently been reported as a point of care processor for adapting the long head of the biceps into an autograft patch for rotator cuff augmentation. The purpose of this study was to evaluate the effects of this graft preparation technique on histological evidence of tenocyte mechanical damage. METHODS: A consecutive series of patients undergoing biceps tenodesis for shoulder pathology were evaluated. After supra-pectoral tenodesis, 27 mm of the long head of the biceps was secured for compression into the patch. The remaining length of residual tendon was longitudinally split, resulting in two equal lengths of remnant tendon from the same zone. One sample was sent to pathology with no preparation, and the other was prepared as a compressed biceps autograft patch according to the manufacturer's recommendations. Both grafts were sent to pathology for evaluation of tenocyte morphology. Records were reviewed to determine if compression resulted in mechanical damage to the tenocytes at the time of biceps augmentation. RESULTS: 55 shoulder procedures and 110 samples were sent for pathology analysis. 42 of the 55 (76%) specimens demonstrated morphologically normal tenocytes in both the compressed and non-compressed groups, and 7 (13%) cases showed evidence of tenocyte necrosis or mechanical damage in both groups. The difference abnormal tenocyte morphology between the compressed group and the native group was not statistically significant (p=0.625). CONCLUSION: Autograft biceps compression into a point of care patch did not result in mechanical damage to tenocyte morphology at the time of insertion for augmentation of rotator cuff pathology. CLINICAL RELEVANCE: Free proximal biceps tendon compression can result in a patch that does not mechanically damage the tenocyte. The patch can be used as a biologic autograft to enhance shoulder rotator cuff repair, as well as subscapularis repair in the setting of shoulder arthroplasty.