Novel Loci ( EIF4A2, ADIPOQ, TPRG1 ) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).

Aims/hypothesis: Triglyceride (TG)/High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark. Methods: Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing. Results: Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL ( p =1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on 3q28 (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under 3q28 and identified two novel variants ( EIF4A2/ADIPOQ -rs114108468, p =5e-6, MAF=1.8%; TPRG1 -rs16864075, p =3e-6, MAF=8%; accounted for ∼28% and ∼29% of the linkage, respectively, and 57% jointly). While the former variant was associated with EIF4A2 ( p =7e-5) / ADIPOQ ( p =3.49e-2) RNA transcriptional levels, the latter variant was not associated with TPRG1 ( p =0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants ( p <3e-4). Conclusions: Our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants EIF4A2/ADIPOQ -rs114108468 and TPRG1 -rs16864075 on 3q28 for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.

Altered extracellular matrix correlates with an immunosuppressive tumor microenvironment and disease progression in younger adults with oral cavity squamous cell carcinoma.

Introduction: Oral cavity squamous cell carcinoma (OSCC) occurs most frequently in patients >60 years old with a history of tobacco and alcohol use. Epidemiological studies describe increased incidence of OSCC in younger adults (<45 years). Despite its poor prognosis, knowledge of OSCC tumor microenvironment (TME) characteristics in younger adults is scarce and could help inform possible resistance to emerging treatment options. Methods: Patients with OSCC were evaluated using TCGA-HNSC (n=121) and a stage and subsite-matched institutional cohort (n=8) to identify differential gene expression focusing on the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) processes in younger (≤45 years) vs. older adults (≥60 years). NanoString nCounter analysis was performed using isolated total RNA from formalin-fixed paraffin-embedded (FFPE) tumor samples. Stained tumor slides from young and old OSCC patients were evaluated for CD8+ T-cell counts using immunohistochemistry. Results: Younger OSCC patients demonstrated significantly increased expression of ECM remodeling and EMT process genes, as well as TME immunosuppression. Gene set enrichment analyses demonstrated increased ECM pathways and concurrent decreased immune pathways in young relative to old patients. Transcripts per million of genetic markers involved in ECM remodeling including LAMB3, VCAN, S100A9, COL5A1, and ITGB2 were significantly increased in tumors of younger vs. older patients (adjusted p-value < 0.10). Young patient TMEs demonstrated a 2.5-fold reduction in CD8+ T-cells as compared to older patients (p < 0.05). Conclusion: Differential gene expression impacting ECM remodeling and TME immunosuppression may contribute to disease progression in younger adult OSCC and has implications on response to evolving treatment modalities, such as immune checkpoint inhibitor therapy.

Obesity and Survival After Immune Checkpoint Inhibition for Head and Neck Squamous Cell Carcinoma.

Importance: For patients treated with immune checkpoint inhibitors (ICIs), recent data suggest that obesity has a beneficial effect on survival outcomes in various cancer types. Reports on this association in head and neck cancer are limited. Objectives: To compare overall survival (OS) to 5 years and functional outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with ICIs based on pretreatment body mass index (BMI). Design, Setting, and Participants: This retrospective population-based cohort study used data obtained from the TriNetX Global Collaborative Network database to identify patients with HNSCC who received ICI treatment between January 1, 2012, and December 31, 2023, resulting in a total of 166 patients (83 with BMI of 20.0-24.9 [normal BMI] and 83 with BMI of ≥30.0 [obesity BMI]) after propensity score matching (PSM) for pretreatment medical comorbidities and oncologic staging. Exposure: Normal BMI vs obesity BMI. Main Outcomes and Measures: Overall survival and functional outcomes (dysphagia, tracheostomy dependence, and gastrostomy tube dependence) were measured to 5 years after ICI treatment and compared between patients with obesity BMI and normal BMI. Additional analyses compared OS and functional outcomes in the cohort with normal BMI and cohorts with overweight BMI (25.0-29.9) and underweight BMI (<20.0). Results: Among the 166 patients included in the PSM analysis (112 men [67.1%]; mean [SD] age, 62.9 [15.4] years), obesity BMI was associated with significantly improved OS at 6 months (hazard ratio [HR], 0.54 [95% CI, 0.31-0.96]), 3 years (HR, 0.56 [95% CI, 0.38-0.83]), and 5 years (HR, 0.62 [95% CI, 0.44-0.86]) after ICI treatment, compared with patients with normal BMI. Obesity BMI was also associated with decreased risk of gastrostomy tube dependence at 6 months (odds ratio [OR], 0.41 [95% CI, 0.21-0.80]), 1 year (OR, 0.41 [95% CI, 0.21-0.78]), 3 years (OR, 0.35 [95% CI, 0.18-0.65]), and 5 years (OR, 0.34 [95% CI, 0.18-0.65]). Obesity was also associated with decreased risk for tracheostomy dependence at 1 year (OR, 0.52 [95% CI, 0.28-0.90]), 3 years (OR, 0.45 [95% CI, 0.45-0.90]), and 5 years (OR, 0.45 [95% CI, 0.45-0.90]). There were no differences in rates of dysphagia or immune-related adverse events between cohorts at any points. Conclusions and Relevance: Using population-level data for patients with HNSCC treated with ICIs, these results suggest that having obesity was associated with improved 6-month, 3-year, and 5-year OS compared with having normal BMI. Additionally, obesity was associated with decreased gastrostomy and tracheostomy tube dependence compared with normal BMI. Further investigation is required to understand the mechanism of these findings.

Impact of a family support intervention on hospitalization costs and hospital readmissions among ICU patients at high risk of death or severe functional impairment.

BACKGROUND: Patients with advanced critical illness often receive more intensive treatment than they would choose for themselves, which contributes to high health care costs near the end of life. The purpose of this study was to determine whether a family support intervention delivered by the interprofessional ICU team decreases hospitalization costs and hospital readmissions among critically ill patients at high risk of death or severe functional impairment. RESULTS: We examined index hospitalization costs as well as post-discharge utilization of acute care hospitals, rehabilitation and skilled nursing facilities, and hospice services for the PARTNER trial, a multicenter, stepped-wedge, cluster randomized trial of an interprofessional ICU family support intervention. We determined patients' total controllable and direct variable costs using a computerized accounting system. We determined post-discharge resource utilization (as defined above) by structured telephone interview at 6-month follow-up. We used multiple variable regression modelling to compare outcomes between groups. Compared to usual care, the PARTNER intervention resulted in significantly lower total controllable costs (geometric mean: $26,529 vs $32,105; log-linear coefficient: - 0.30; 95% CI - 0.49, - 0.11) and direct variable costs ($3912 vs $6034; - 0.33; 95% CI - 0.56, - 0.10). A larger cost reduction occurred for decedents ($20,304 vs. $26,610; - 0.66; 95% CI - 1.01, - 0.31) compared to survivors ($31,353 vs. $35,015; - 0.15; 95% CI - 0.35,0.05). A lower proportion in the intervention arm were re-admitted to an acute care hospital (34.9% vs 45.1%; 0.66; 95% CI 0.56, 0.77) or skilled nursing facility (25.3% vs 31.6%; 0.63; 95% CI 0.47, 0.84). CONCLUSIONS: A family support intervention delivered by the interprofessional ICU team significantly decreased index hospitalization costs and readmission rates over 6-month follow-up. Trial registration Trial registration number: NCT01844492.

Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships.

BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Impact of pre-operative abdominal MRI on survival for patients with resected pancreatic carcinoma: a population-based study.

Background: This study determined the impact of pre-operative abdominal MRI on all-cause mortality for patients with resected PDAC. Methods: All adult (≥18 years) PDAC patients who underwent pancreatectomy between January 2011 and December 2022 in Ontario, Canada, were identified for this population-based cohort study (ICD-O-3 codes: C250, C251, C252, C253, C257, C258). Patient demographics, comorbidities, PDAC stage, medical and surgical management, and survival data were sourced from multiple linked provincial administrative databases at ICES. All-cause mortality was compared between patients with and without a pre-operative abdominal MRI after controlling for multiple covariates. Findings: A cohort of 4579 patients consisted of 2432 men (53.1%) and 2147 women (46.9%) with a mean age of 65.2 years (standard deviation: 11.2 years); 2998 (65.5%) died while 1581 (34.5%) survived. Median follow-up duration post-resection was 22.4 months (interquartile range: 10.8-48.8 months), and median survival post-pancreatectomy was 25.9 months (95% confidence interval [95% CI]: 24.8, 27.5). Patients who underwent a pre-operative abdominal MRI had a median survival of 33.1 months (95% CI: 30.7, 37.2) compared to 21.1 months (95% CI: 19.8, 22.6) for all others. A total of 2354/4579 (51.4%) patients underwent a pre-operative abdominal MRI, which was associated with a 17.2% (95% CI: 11.0, 23.1) decrease in the rate of all-cause mortality, with an adjusted hazard ratio (aHR) of 0.828 (95% CI: 0.769, 0.890). Interpretation: Pre-operative abdominal MRI was associated with improved overall survival for PDAC patients who underwent pancreatectomy, possibly due to better detection of liver metastases than CT. Funding: Northern Ontario Academic Medicine Association (NOAMA) Clinical Innovation Fund.

Management of male obesity-related secondary hypogonadism: A clinical update.

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism (MOSH) with emerging evidence on the role of testosterone therapy. We aim to provide an updated and practical approach towards its management. We did a comprehensive literature search across MEDLINE (via PubMed), Scopus, and Google Scholar databases using the keywords "MOSH" OR "Obesity-related hypogonadism" OR "Testosterone replacement therapy" OR "Selective estrogen receptor modulator" OR "SERM" OR "Guidelines on male hypogonadism" as well as a manual search of references within the articles. A narrative review based on available evidence, recommendations and their practical implications was done. Although weight loss is the ideal therapeutic strategy for patients with MOSH, achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice. Therefore, androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity. However, there is conflicting evidence for the appropriate use of testosterone replacement therapy (TRT), and it can also be associated with complications. This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH. Before starting testosterone replacement in functional hypogonadism of obesity, it would be desirable to initiate lifestyle modification to ensure weight reduction. TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients. Balancing the risks and benefits of TRT should be considered in every patient before and during long-term management.

Growing three-dimensional objects with light.

Vat photopolymerization (VP) additive manufacturing enables fabrication of complex 3D objects by using light to selectively cure a liquid resin. Developed in the 1980s, this technique initially had few practical applications due to limitations in print speed and final part material properties. In the four decades since the inception of VP, the field has matured substantially due to simultaneous advances in light delivery, interface design, and materials chemistry. Today, VP materials are used in a variety of practical applications and are produced at industrial scale. In this perspective, we trace the developments that enabled this printing revolution by focusing on the enabling themes of light, interfaces, and materials. We focus on these fundamentals as they relate to continuous liquid interface production (CLIP), but provide context for the broader VP field. We identify the fundamental physics of the printing process and the key breakthroughs that have enabled faster and higher-resolution printing, as well as production of better materials. We show examples of how in situ print process monitoring methods such as optical coherence tomography can drastically improve our understanding of the print process. Finally, we highlight areas of recent development such as multimaterial printing and inorganic material printing that represent the next frontiers in VP methods.

Validation of Two Scoring Tools to Predict Risk of Augmented Renal Clearance in Trauma Patients.

INTRODUCTION: Augmented renal clearance (ARC) is prevalent in trauma populations. Identification is underrecognized by calculated creatinine clearance or estimated glomerular filtration rate equations. Predictive scores may assist with ARC identification. The goal of this study was to evaluate validity of the ARCTIC score and ARC Predictor to predict ARC in critically ill trauma patients. METHODS: This single center, retrospective study was performed at an academic level 1 trauma center. Critically ill adult trauma patients undergoing 24-h urine-collection were included. Patients with serum creatinine >1.5 mg/dL, kidney replacement therapy, suspected rhabdomyolysis, chronic kidney disease, or inaccurate urine collection were excluded. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for ARCTIC Score and ARC Predictor were calculated. Receiver operating characteristic curves were created for ARCTIC score and ARC Predictor models. RESULTS: One-hundred and twenty-two patients with ARC and 78 patients without ARC were included. The ARCTIC score sensitivity, specificity, PPV, and NPV were 89%, 54%, 75%, and 75%, respectively. The ARC Predictor demonstrated sensitivity, specificity, PPV, and NPV of 77%, 88%, 91%, and 71%, respectively. Regression analyses revealed both ARCTIC score ≥6 and ARC Predictor threshold >0.5 as significant risk factors for ARC in presence of traumatic brain injury, obesity, injury severity score, and negative nitrogen balance (ARCTIC ≥6: odds ratio 8.59 [95% confidence interval 3.90-18.92], P < 0.001; ARC Predictor >0.5: odds ratio 20.07 [95% confidence interval 8.53-47.19], P < 0.001). CONCLUSIONS: These findings corroborate validity of two pragmatic prediction tools to identify patients at high risk of ARC. Future studies evaluating correlations between ARCTIC score, ARC Predictor, and clinical outcomes are warranted.

Size matters: Total testicular volume predicts sperm count in Tanner V varicocele patients.

INTRODUCTION: It is known the prevalence of varicoceles in adolescent men is 14-29% but there is debate surrounding implications on fertility. As obtaining a semen analysis (SA) may be challenging, there is need for objective tests as measures of fecundity. Our aim was to investigate the relationship between testicular volume differential (TVD), varicocele grade, and total testicular volume (TTV) on seminal parameters including total motile sperm count (TMSC). MATERIALS AND METHODS: We conducted a retrospective single-center chart review over 14 years of 486 Tanner V adolescent males. Three hundred and four met inclusion of palpable, non-operated left-sided varicocele who underwent at least one SA and ultrasound. Abnormal TMSC was defined by World Health Organization 2010 criteria for minimal reference ranges. Multivariate logistic regression, receiver operating characteristic analysis with Youden J-statistic and descriptive statistics were performed. RESULTS: Three hundred and four Tanner V adolescents with median age of 18.0 years (18.0-19.0), median TTV of 34.5 cc (28.9, 40.2) and median TMSC of 62.5 million/ejaculate (25.4, 123.4) were evaluated. TTV cutoff of 29.5 cc was found to predict TMSC of <9 million/ejaculate with negative predictive value of 96.2% and odds ratio of 6.08 ([2.13-17.42], p < 0.001). TVD greater than 20% did not reach statistical significance with an odds ratio of 1.66 ([0.41-6.62], p = 0.50). DISCUSSION: In clinical practice, each patient will need to have an individualized plan. Based on our data, for older adolescents (17 or 18 years) with varicocele and an abnormal TTV, clinicians may have a lower threshold for advising SA, and if unable to obtain, surgical intervention and/or closer surveillance should be stressed. Patients should be informed of their six-fold increase in abnormal SA. Patients with normal TTV should be advised they are at lower risk of having abnormal SA. Younger patients with varicocele and an initial TVD>20%, should be followed closely but intervention delayed until 17 or 18 to better assess TTV. The importance of trending patient data should be emphasized as a single measurement has low predictive value for developing adolescents. Limitations of our study include a retrospective design and the lack of uniform correlation between adolescent SA and paternity. CONCLUSIONS: Total testicular volume less than 29.5 cc increased odds of abnormal semen analysis by over six times and had a negative predictive value of 96.2%. Ultrasound results may be useful for risk stratification and counselling on appropriateness of surgical intervention.

Shoulder Taps: Relationships Between a New Movement Screening Assessment with Body Composition and Physical Fitness in Law Enforcement Recruits.

The overhead squat, as part of the Functional Movement Screen (FMS), can analyze total- and lower-body mechanics. Shoulder taps, which incorporates a push-up position and challenges shoulder, trunk, and hip stability, may identify movement deficiencies indicated by multiple FMS actions which could be useful for law enforcement recruits. This study determined overhead squat and shoulder taps relationships, associations between these screens with body composition and fitness, and differences in body composition and fitness according to overhead squat/shoulder taps scores in recruits by sex. Retrospective analysis was conducted on 202 recruit datasets (158 males, 44 females), which included: overhead squat and shoulder taps scores; age, height, and body mass; skeletal muscle (SMM%) and body fat mass (BFM%) percentage; waist-to-hip ratio; grip strength; 60-s push-ups and sit-ups; 75-yard pursuit run; vertical jump; medicine ball throw; and multistage fitness test (MSFT). Spearman's correlations (p<0.05) determined relationships between the overhead squat and shoulder taps, and between the screens and other variables. Kruskall-Wallis H tests compared the variables when recruits were split into groups based on overhead squat/shoulder taps scores. A significant correlation was found between the screens for male (ρ=0.231) but not female (ρ=0.258) recruits. Overhead squat score had a moderate relationship with BFM% in females (ρ=-0.312). Shoulder taps had a small relationship with SMM% in males (ρ=0.163). There were no differences in body composition and fitness when recruits were split based on screen scores (p=0.086-0.994). While morphology may influence movement screen performance, the screens had minimal capacity for associating movement deficiencies to fitness.

Increased Patient Age as a Risk Factor Following Free Flap Reconstruction after Breast Cancer: A Single Institutional Review of 2,598 Cases.

BACKGROUND: Autologous breast reconstruction (ABR) after mastectomy is increasing due to benefits over implant-based reconstruction. However, free flap reconstruction is not universally offered to patients of advanced age due to perceived increased perioperative risk. METHODS: Patients undergoing free flap breast reconstruction at our institution from 2005 to 2018 were included. Risk-adjusted logistic regression models were fit while controlling for demographic and comorbid characteristics to determine the association of age with the probability of venous thromboembolism (VTE), delayed healing, skin necrosis, surgical site infection (SSI), seroma, hematoma, hernia, and flap loss. Linear predictions from risk-adjusted logistic regression models were used to create spline curves and determine the risk of outcomes associated with age. RESULTS: A cohort of 2,598 patients underwent free flap breast reconstruction in the period examined. The median age was 51 with approximately 9% of patients being 65 or older. Increased age was associated with a greater risk of delayed healing, skin necrosis, and hematoma after surgery. There was no increased risk of medical complications such as VTE or complications such as flap loss, seroma, or SSI. CONCLUSION: A set age cutoff for patients undergoing free flap breast reconstruction does not appear warranted. There is no difference in major surgical complications such as flap loss with increasing age. However, older age does predispose patients to specific wound complications such as hematoma, skin necrosis, and delayed wound healing, which should guide preoperative counseling. Further, medical complications do not increase with advanced age. Overall, however, the safety of ABR in older patients appears uncompromised.

Sequenced treatment effectiveness for posttraumatic stress (STEPS) trial: A protocol for a pragmatic comparative effectiveness trial with baseline results.

BACKGROUND: There have only been two efficacy trials reporting a head-to-head comparison of medications and psychotherapy for posttraumatic stress disorder (PTSD), and neither was conducted in primary care. Therefore, in this pragmatic trial we compare outcomes of primary care patients randomized to initially receive a brief trauma-focused psychotherapy or a choice of three antidepressants. In addition, because there are few trials examining the effectiveness of subsequent treatments for patients not responding to the initial treatment, we also compare the outcomes of those switching or augmenting treatments. METHOD: Patients screening positive for PTSD (n = 700) were recruited from the primary care clinics of 7 Federally Qualified Health Centers (FQHC) and 8 Department of Veterans Affairs (VA) Medical Centers and randomized in the ratio 1:1:2 to one of three treatment sequences: 1) selective serotonin reuptake inhibitor (SSRI) followed by augmentation with Written Exposure Therapy (WET), 2) SSRI followed by a switch to serotonin-norepinephrine reuptake inhibitor (SNRI), or 3) WET followed by a switch to SSRI. Participants complete surveys at baseline, 6 months, and 12 months. The primary outcome is PTSD symptom severity as measured by the PTSD Checklist (PCL-5). RESULTS: The average PCL-5 score was 52.8 (SD = 11.1), indicating considerable severity. The most common bothersome traumatic event for VA enrollees was combat (47.8%), and for FQHC enrollees was other (28.2%), followed by sexual assault (23.4%), and child abuse (19.8%). Only 22.4% were taking an antidepressant at baseline. CONCLUSION: Results will help healthcare systems and clinicians make decisions about which treatments to offer to patients. CLINICALTRIALS: govID - NCT04597190.

Predictive capacity of immune-related adverse events and cytokine profiling in neoadjuvant immune checkpoint inhibitor trials for head and neck squamous cell carcinoma.

OBJECTIVES: Certain low-level immune-related adverse events (irAEs) have been associated with survival benefits in patients with various solid tumors on immune checkpoint inhibitors (ICIs). We aimed to investigate the association between irAEs and response to neoadjuvant ICIs in patients with head and neck squamous cell carcinoma (HNSCC) and to identify differences in circulating cytokine levels based on irAE status. METHODS: This was a retrospective cohort study including three neoadjuvant clinical trials from July 2017 to January 2022: NCT03238365 (nivolumab ± tadalafil), NCT03854032 (nivolumab ± BMS986205), NCT03618654 (durvalumab ± metformin). The presence and type of irAEs, pathologic treatment response, and survival were compared. Canonical linear discriminant analysis (LDA) was performed to identify combinations of circulating cytokines predictive of irAEs using plasma sample multiplex assay. RESULTS: Of 113 participants meeting inclusion criteria, 32 (28.3%) developed irAEs during treatment or follow-up. Positive p16 status was associated with irAEs (odds ratio [OR] 2.489; 95% CI 1.069-6.119; p = 0.043). irAEs were associated with pathologic treatment response (OR 3.73; 95% CI 1.34-10.35; p = 0.011) and with higher OS in the combined cohort (HR 0.319; 95% CI 0.113-0.906; p = 0.032). Patients with irAEs within the nivolumab cohort had significant elevations of select cytokines pre-treatment. Canonical LDA identified key drivers of irAEs among all trials, which were highly predictive of future irAE status. CONCLUSIONS: irAEs are associated with response to neoadjuvant ICI therapy in HNSCC and can serve as clinical indicators for improved clinical outcomes. irAEs can be predicted by concentrations of several circulating cytokines prior to treatment.

A Neuropathology Case Report of a Woman with Down Syndrome who Remained Cognitively Stable.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

Three Levels of Neural Control Contributing to Performance-stabilizing Synergies in Multi-finger Tasks.

We tested a hypothesis on force-stabilizing synergies during four-finger accurate force production at three levels: (1) The level of the reciprocal and coactivation commands, estimated as the referent coordinate and apparent stiffness of all four fingers combined; (2) The level of individual finger forces; and (3) The level of firing of individual motor units (MU). Young, healthy participants performed accurate four-finger force production at a comfortable, non-fatiguing level under visual feedback on the total force magnitude. Mechanical reflections of the reciprocal and coactivation commands were estimated using small, smooth finger perturbations applied by the "inverse piano" device. Firing frequencies of motor units in the flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) were estimated using surface recording. Principal component analysis was used to identify robust MU groups (MU-modes) with parallel changes in the firing frequency. The framework of the uncontrolled manifold hypothesis was used to compute synergy indices in the spaces of referent coordinate and apparent stiffness, finger forces, and MU-mode magnitudes. Force-stabilizing synergies were seen at all three levels. They were present in the MU-mode spaces defined for MUs in FDS, in EDC, and pooled over both muscles. No effects of hand dominance were seen. The synergy indices defined at different levels of analysis showed no correlations across the participants. The findings are interpreted within the theory of control with spatial referent coordinates for the effectors. We conclude that force stabilization gets contributions from three levels of neural control, likely associated with cortical, subcortical, and spinal circuitry.

Elsberg Syndrome With Albuminocytologic Dissociation - A Guillain-Barré Syndrome Mimic or Guillain-Barré Syndrome Variant?

Introduction: Elsberg Syndrome is a presumed infectious lumbosacral radiculitis, with or without accompanying lumbar myelitis, that is often attributed to herpes simplex virus type 2 (HSV-2). Case: A 58-year-old man presented with lower extremity anesthesia, ataxic gait, radiological evidence of radiculitis, and CSF albuminocytologic dissociation. Polymerase chain reaction testing of CSF confirmed HSV-2 infection. Conclusion: A variety of presentations are reported within the scope of Elsberg Syndrome, potentially with distinct disease mechanisms. Delayed onset of neurological symptoms after resolution of rash and absence of pleocytosis raises the possibility that some patients meeting criteria for Elsberg Syndrome have a post-infectious immune-mediated neuropathy. We advise a lower threshold for PCR testing of herpes viruses in patients with acute neuropathy and albuminocytologic dissociation, particularly in cases with early sacral involvement.

Balancing the Scales: Caution in Reduction Mammaplasty Recommendations for Obesity Class III Patients.

INTRODUCTION: The prevalence of obesity has risen worldwide, posing a problem to surgeons as obesity is a well-known risk factor for surgical outcomes. While prior studies have suggested performing reduction mammaplasty (RM) in patients with obesity, the variance in outcomes and quality of life (QoL) for obesity classes are ill-defined. We investigated whether obesity classes should be considered for RM by examining the surgical outcomes and QoL across different weight classes, aiming to pinpoint when outcomes become less favorable. METHODS: Patients undergoing RM by nine surgeons from 2016 to 2022 were included. Body mass index (BMI) cohorts were formed according to the Center for Disease Control and Prevention (CDC) guidelines: Healthy (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), obesity class I (30-34.9 kg/m2), II (35-39.9 kg/m2), and III (>40 kg/m2). QoL was assessed by comparing preoperative and postoperative BREAST-Q scores within cohorts. A comparison analysis was performed between weight classes. RESULTS: A total of 461 RM patients were identified (healthy: 83, overweight: 178, I: 142, II: 39, III: 19). Percentage of Black patients, procedure length, weight of tissue removed, and inferior pedicle technique all significantly increased as BMI increased (P < 0.001). Higher BMI cohorts, especially class III, had significantly higher rates of surgical site infections (healthy: 0%, overweight: 1.1%, I: 1.4%, II: 0%, III: 15.8%, P < 0.01), fat necrosis (healthy: 1.2%, overweight: 5.1%, I: 7%, II: 0%, III: 22.2%, P = 0.01), dehiscence (healthy: 3.6%, overweight: 2.8%, I: 2.1%, II: 5.1%, III: 31.6%, P < 0.01), delayed healing (health: 4.8%, overweight: 11.2%, I: 16.9%, II: 28.2%, III: 42.1%, P < 0.01), minor T-point breakdown (healthy: 10.8%, overweight: 15.7%, I: 23.9%, II: 23.1%, III: 52.6%, P = 0.01), and surgical site occurrence requiring procedural intervention (healthy: 6.0%, overweight: 5.6%, I: 6.3%, II: 15.4%, III: 21.1%, P < 0.05). When compared to the other weight classes independently, class III was associated with unfavorable outcomes (P < 0.05). Significant improvement in average postoperative QoL scores in satisfaction with breast, psychosocial well-being, sexual well-being, and physical well-being were seen in all cohorts except class III (P < 0.05). CONCLUSIONS: Severe obesity class III patients undergoing RM have a higher yet still acceptable risk profile and should be counseled on the risks despite its improved quality of life.