Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

Bayesian Estimation Improves Prediction of Outcomes after Epilepsy Surgery.

Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We quantified the statistical power and magnitude error of studies of epilepsy surgery outcomes. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4 (median odds ratio 9.3 vs. median true odds ratio 1.7), while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6 (2.7 vs. 1.7). We conclude that Bayesian estimation of odds ratio attenuates the exaggeration of significant effect sizes in underpowered studies. This approach could help improve patient counseling about the chance of seizure freedom after epilepsy surgery.

Proactive Therapeutic Drug Monitoring Is Associated With Increased Drug Persistence in Patients With Inflammatory Bowel Disease Treated With Intravenous Vedolizumab.

BACKGROUND: There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). This study aimed to evaluate the efficacy of proactive TDM in IBD patients treated with intravenous (iv) vedolizumab (VDZ). METHODS: This single-center retrospective cohort study included consecutive IBD patients treated with maintenance iv VDZ therapy undergoing TDM from November 2016 to March 2023. Patients were followed through June 2023 and were divided in to 2 groups: those who had at least 1 proactive TDM vs those who underwent only reactive TDM. A survival analysis was performed to evaluate drug persistence, defined as no need for drug discontinuation due to loss of response, serious adverse event, or an IBD-related surgery. RESULTS: The study population consisted of 94 patients (proactive TDM, n = 72) with IBD (ulcerative colitis, n = 53). Patients undergoing at least 1 proactive TDM compared with patients having only reactive TDM demonstrated a higher cumulative probability of drug persistence (Log-rank P < .001). In multivariable Cox proportional hazard regression analysis, at least 1 proactive TDM was the only factor associated with drug persistence (hazard ratio, 14.3; 95% confidence interval [CI], 3.8-50; P < .001). A ROC analysis identified a VDZ concentration of 12.5 µg/mL as the optimal drug concentration threshold associated with drug persistence (area under the ROC curve: 0.691; 95% CI, 0.517-0.865; P = .049). CONCLUSION: In this single-center retrospective study reflecting real-life clinical practice, proactive TDM was associated with increased drug persistence in patients with IBD treated with iv VDZ.

There are limited data regarding therapeutic drug monitoring (TDM) of non-anti-tumor necrosis factor therapy in inflammatory bowel disease (IBD). We found that proactive TDM was associated with drug persistence in patients with IBD treated with vedolizumab. Moreover, a vedolizumab concentration of 12.5 µg/mL was identified as the optimal drug concentration threshold associated with drug persistence.

Severe Hypertrophic Cardiomyopathy Associated With Hydroxychloroquine in a Young Woman With Systemic Lupus Erythematosus: A Case Report and Review of the Literature.

The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage, prevents disease flare, and improves overall survival. The mechanism of action of hydroxychloroquine includes interference with lysosomal degradation of cells leading to the accumulation of vacuoles. Retinopathy is a well-described adverse effect of hydroxychloroquine, thus requiring screening with an ophthalmologist after prolonged use. Although rarely reported, cardiac adverse effects of hydroxychloroquine can also occur. In this report, we present a case of a 23-year-old woman with systemic lupus erythematosus on hydroxychloroquine who presented with stroke possibly due to Libman-Sacks endocarditis and was found to have severe hypertrophic cardiomyopathy on transthoracic echocardiogram.

Rare Variant in MRC2 Associated With Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome.

BACKGROUND: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model. METHODS: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice. RESULTS: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration. CONCLUSIONS: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.

The Impact of Perilesional Heatsink Structures on Ablation Volumes in Laser Interstitial Thermal Therapy for Brain Metastases.

BACKGROUND AND OBJECTIVES: Laser interstitial thermal therapy (LITT) has demonstrated promise in surgical neuro-oncology because of its effectiveness in delivering precise thermal energy to lesions. The extent of ablation (EOA) is a prognostic factor in improving patient outcomes but is often affected by perilesional heatsink structures, which can lead to asymmetric ablations. The purpose of this study was to quantitatively evaluate the impact of various perilesional heatsink structures on the EOA in LITT for brain metastases. METHODS: Twenty-seven procedures for 22 unique patients with brain metastases fit the inclusion criteria. Intracranial heatsink structures were identified: sulci, meninges, cerebrospinal fluid (CSF) spaces, and vasculature. Asymmetric ablation was determined by measuring 3 pairs of orthogonal distances from the proximal, midpoint, and distal locations along the laser catheter to the farthest edge of the ablation zone bilaterally. Distances from the same points on the laser catheter to the nearest heatsink were also recorded. The Heatsink Effect Index was created to serve as a proxy for asymmetric ablation. Pearson correlations, t-tests, and analysis of variance were the statistical analyses performed. RESULTS: From the midpoint of the catheter, the 27 heatsinks were meninges (40.7%), sulci (22.2%), vasculature (22.2%), and CSF spaces (14.8%). Across all points along the catheter track, there was a significant generalized heatsink effect on asymmetric ablations (P < .0001). There was a negative correlation observed between asymmetric ablations and EOA from the midpoint of the laser catheter (r = -0.445, P = .020). Compared with sulci, CSF spaces trended toward a greater effect on asymmetric ablation volumes (P = .069). CONCLUSION: This novel quantitative analysis shows that perilesional heatsinks contribute to asymmetric ablations. CSF spaces trended toward higher degrees of asymmetric ablations. Importantly, neurosurgeons may anticipate asymmetric ablations preoperatively if heatsinks are located within 13.3 mm of the laser probe midpoint. These preliminary results may guide surgical decision-making in LITT for metastatic brain lesions.

Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk.

Importance: Prostate cancer, a leading cause of cancer death among men, urgently requires new prevention strategies, which may involve targeting men with an underlying genetic susceptibility. Objective: To explore differences in risk of early prostate cancer death among men with higher vs lower genetic risk to inform prevention efforts. Design, Setting, and Participants: This cohort study used a combined analysis of genotyped men without prostate cancer at inclusion and with lifestyle data in 2 prospective cohort studies in Sweden and the US, the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS), followed up from 1991 to 2019. Data were analyzed between April 2023 and April 2024. Exposures: Men were categorized according to modifiable lifestyle behaviors and genetic risk. A polygenic risk score above the median or a family history of cancer defined men at higher genetic risk (67% of the study population); the remaining men were categorized as being at lower genetic risk. Main Outcomes and Measures: Prostate cancer death analyzed using time-to-event analysis estimating hazard ratios (HR), absolute risks, and preventable deaths by age. Results: Among the 19 607 men included for analysis, the median (IQR) age at inclusion was 59.0 (53.0-64.7) years (MDCS) and 65.1 (58.0-71.8) years (HPFS). During follow-up, 107 early (by age 75 years) and 337 late (after age 75 years) prostate cancer deaths were observed. Compared with men at lower genetic risk, men at higher genetic risk had increased rates of both early (HR, 3.26; 95% CI, 1.82-5.84) and late (HR, 2.26; 95% CI, 1.70-3.01) prostate cancer death, and higher lifetime risks of prostate cancer death (3.1% vs 1.3% [MDCS] and 2.3% vs 0.6% [HPFS]). Men at higher genetic risk accounted for 94 of 107 early prostate cancer deaths (88%), of which 36% (95% CI, 12%-60%) were estimated to be preventable through adherence to behaviors associated with a healthy lifestyle (not smoking, healthy weight, high physical activity, and a healthy diet). Conclusions and Relevance: In this 20-year follow-up study, men with a genetic predisposition accounted for the vast majority of early prostate cancer deaths, of which one-third were estimated to be preventable. This suggests that men at increased genetic risk should be targeted in prostate cancer prevention strategies.

The Influence of the Extracorporeal Membrane Oxygenation Circuit and Components on Anticoagulation Management: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the influence of extracorporeal membrane oxygenation (ECMO) circuit components on anticoagulation practices for pediatric ECMO for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Management of ECMO anticoagulation in the setting of different ECMO circuit components. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twenty-nine references were used for data extraction and informed recommendations, evidence-based consensus statements, and good practice statements. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for the influence of ECMO circuit and components on anticoagulation management. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One good practice statement, 2 weak recommendations, and 2 consensus statements are presented. CONCLUSIONS: The incorporation of new component technologies into clinical practice has outpaced clinical investigations of anticoagulation strategies for pediatric ECMO. Future investigations should leverage academic and industrial collaborations, translational platforms, and modern biostatistical methods to improve patient outcomes.

Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus. DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children. DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis). CONCLUSIONS: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population.

The Impact of a Pediatric Continuity Care Intensivist Program on Patient and Parent Outcomes: An Unblinded Randomized Controlled Trial.

Objectives We studied the impact of a standardized continuity care intensivists (CCIs) program on patient and family outcomes for long-stay patients in the pediatric intensive care unit (PICU), also assessing the intervention's acceptability and feasibility. Methods A patient-level, unblinded randomized-controlled trial in a PICU at a large children's hospital. Participants included: (1) patients with ≥ 7 days PICU admission and likely to stay another 7 days; (2) their parents; (3) PICU attendings participating as continuity attendings; and (4) PICU attendings providing usual care (UC). We examined a bundled intervention: (1) standardized continuity attending role, (2) communication training course for CCI, and (3) standardized timing of contact between CCI and patient/family. Results Primary outcome was patient PICU length of stay. Secondary outcomes included patient, parental, and clinician outcomes. We enrolled 115 parent-patient dyads (231 subjects), 58 patients were randomized into treatment arm and 56 into the UC arm. Thirteen attendings volunteered to serve as CCI, 10 as UC. No association was found between the intervention and patient PICU length of stay ( p = 0.5), other clinical factors, or parental outcomes. The intervention met a threshold for feasibility of enrollment, retention, and implementation while the majority of providers agreed the intervention was acceptable with more efficient decision making. Thirty percent CCIs felt the role took too much time, and 20% felt time was not worth the benefits. Conclusion CCI intervention did not impact patient or family outcomes. PICU attendings believed that the implementation of the CCI program was feasible and acceptable with potential benefits for efficiency of decision making.

Predictability of buprenorphine-naloxone treatment retention: A multi-site analysis combining electronic health records and machine learning.

BACKGROUND AND AIMS: Opioid use disorder (OUD) and opioid dependence lead to significant morbidity and mortality, yet treatment retention, crucial for the effectiveness of medications like buprenorphine-naloxone, remains unpredictable. Our objective was to determine the predictability of 6-month retention in buprenorphine-naloxone treatment using electronic health record (EHR) data from diverse clinical settings and to identify key predictors. DESIGN: This retrospective observational study developed and validated machine learning-based clinical risk prediction models using EHR data. SETTING AND CASES: Data were sourced from Stanford University's healthcare system and Holmusk's NeuroBlu database, reflecting a wide range of healthcare settings. The study analyzed 1800 Stanford and 7957 NeuroBlu treatment encounters from 2008 to 2023 and from 2003 to 2023, respectively. MEASUREMENTS: Predict continuous prescription of buprenorphine-naloxone for at least 6 months, without a gap of more than 30 days. The performance of machine learning prediction models was assessed by area under receiver operating characteristic (ROC-AUC) analysis as well as precision, recall and calibration. To further validate our approach's clinical applicability, we conducted two secondary analyses: a time-to-event analysis on a single site to estimate the duration of buprenorphine-naloxone treatment continuity evaluated by the C-index and a comparative evaluation against predictions made by three human clinical experts. FINDINGS: Attrition rates at 6 months were 58% (NeuroBlu) and 61% (Stanford). Prediction models trained and internally validated on NeuroBlu data achieved ROC-AUCs up to 75.8 (95% confidence interval [CI] = 73.6-78.0). Addiction medicine specialists' predictions show a ROC-AUC of 67.8 (95% CI = 50.4-85.2). Time-to-event analysis on Stanford data indicated a median treatment retention time of 65 days, with random survival forest model achieving an average C-index of 65.9. The top predictor of treatment retention identified included the diagnosis of opioid dependence. CONCLUSIONS: US patients with opioid use disorder or opioid dependence treated with buprenorphine-naloxone prescriptions appear to have a high (∼60%) treatment attrition by 6 months. Machine learning models trained on diverse electronic health record datasets appear to be able to predict treatment continuity with accuracy comparable to that of clinical experts.

Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis.

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient's circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity - IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

Background: Assessing COVID-19 vaccine effectiveness (VE) and severity of SARS-CoV-2 variants can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial genomic divergence from co-circulating XBB lineages. Methods: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated the effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. Results: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. Conclusions: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB lineage hospitalizations.

Healthy lifestyle and prostate cancer risk in the Million Veteran Program.

BACKGROUND: This study aims to assess the impact of healthy lifestyle on prostate cancer (PCa) risk in a diverse population. METHODS: Data for 281,923 men from the Million Veteran Program (MVP), a nationwide, health system-based cohort study, were analyzed. Self-reported information at enrollment included smoking status, exercise, diet, family history of PCa, and race/ethnicity. Body mass index (BMI) was obtained from clinical records. Genetic risk was assessed via a validated polygenic score. Cox proportional hazards models were used to assess associations with PCa outcomes. RESULTS: After accounting for ancestry, family history, and genetic risk, smoking was associated with an increased risk of metastatic PCa (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.64-2.02; p < 10-16) and fatal PCa (HR, 2.73; 95% CI, 2.36-3.25; p < 10-16). Exercise was associated with a reduced risk of fatal PCa (HR, 0.86; 95% CI, 0.76-0.98; p = .03). Higher BMI was associated with a slightly reduced risk of fatal PCa, and diet score was not independently associated with any end point. Association with exercise was strongest among those who had nonmetastatic PCa at MVP enrollment. Absolute reductions in the risk of fatal PCa via lifestyle factors were greatest among men of African ancestry (1.7% for nonsmokers vs. 6.1% for smokers) or high genetic risk (1.4% for nonsmokers vs. 4.3% for smokers). CONCLUSIONS: Healthy lifestyle is minimally related to the overall risk of developing PCa but is associated with a substantially reduced risk of dying from PCa. In multivariable analyses, both exercise and not smoking remain independently associated with reduced metastatic and fatal PCa.

Incidental Diagnosis of Four Lid Orbital Lymphoma during a Blepharoplasty.

Chronic lymphocytic leukemia is characterized by the accumulation of mature CD5-positive B-cells in the lymphoid organs.1 Extranodal involvement occurs in up to 10% of cases and can arise in various tissues, including the orbit. Less than 400 cases of orbital lymphoma are diagnosed per year in the United States, typically manifesting as a form of B-cell non-Hodgkin lymphoma, with extranodal marginal zone B-cell lymphoma being the most common subtype. Orbital lymphoma typically presents with proptosis and a palpable mass; however, patients may also have a relatively benign examination. Here, we present a 76-year-old man with symmetric dermatochalasis and marked fat prolapse of all four lids, who was incidentally diagnosed with secondary orbital lymphoma in all four eyelids during a cosmetic four lid blepharoplasty. His history was significant for RAI Stage 0 chronic lymphocytic leukemia diagnosed 15 years before consultation. Orbital lymphoma presenting as orbital fat prolapse has only been reported a few times in the literature. To our knowledge, this is the first case of secondary orbital lymphoma in all four eyelids found incidentally during an aesthetic four lid blepharoplasty.

Anti-idiotype isolation of a broad and potent influenza A virus-neutralizing human antibody.

The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate anti-idiotype antibodies against germline versions of VH6-1 antibodies, use these to sort human leukocytes, and isolate a new VH6-1-class member, antibody L5A7, which potently neutralized diverse group 1 and group 2 influenza A strains. While its heavy chain derived from the canonical IGHV6-1 heavy chain gene used by the class, L5A7 utilized a light chain gene, IGKV1-9, which had not been previously observed in other VH6-1-class antibodies. The cryo-EM structure of L5A7 in complex with Indonesia 2005 hemagglutinin revealed a nearly identical binding mode to other VH6-1-class members. The structure of L5A7 bound to the isolating anti-idiotype antibody, 28H6E11, revealed a shared surface for binding anti-idiotype and hemagglutinin that included two critical L5A7 regions: an FG motif in the third heavy chain-complementary determining region (CDR H3) and the CDR L1 loop. Surprisingly, the chemistries of L5A7 interactions with hemagglutinin and with anti-idiotype were substantially different. Overall, we demonstrate anti-idiotype-based isolation of a broad and potent influenza A virus-neutralizing antibody, revealing that anti-idiotypic selection of antibodies can involve features other than chemical mimicry of the target antigen.

Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Sinus Node Dysfunction Triggered by Tonsillar Abscess: Effects of Vagal Nerve Compression.

BACKGROUND Compression of the vagus nerve by a pharyngeal mass is a well-documented condition that can result in sinus node dysfunction (SND). However, there is scarce literature on extrinsic vagal nerve compression from a tonsillar abscess. CASE REPORT A 59-year-old woman with a history of asthma and chronic throat discomfort presented to the Emergency Department with bradycardia, palpitations, and voice changes. Following a shellfish allergy hospitalization, an otolaryngology evaluation revealed an enlarged right tonsil, recommending tonsillectomy, but scheduling challenges persisted. The patient reported mild throat pain, dysphagia, hoarseness, rhinorrhea, and exertional dyspnea and was admitted for the evaluation of peritonsillar mass. She was found to be bradycardic with a heart rate of 47, with an electrocardiogram revealing SND. Albuterol and ipratropium nebulizers, as well as dexamethasone and pantoprazole, were initiated. With this treatment, the patient symptomatically improved with a new heart rate of 68. She was discharged with outpatient appointments, but was unfortunately lost to follow-up. CONCLUSIONS This case reveals sinus node dysfunction resulting from extrinsic vagal nerve compression by a tonsillar abscess. Pressure on the vagus nerve can trigger bradycardia and low blood pressure, possibly due to compensatory overfiring of afferent vagal nerve signals from local mass effect. Early recognition and antibiotic treatment are essential to prevent cardiac complications. Clinicians must remain vigilant for such extrinsic causes, particularly in patients with chronic sore throat and cardiac symptoms. Further research and case reports are needed to deepen our understanding of this rare yet significant association.

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

Background: It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. Methods: This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. Results: On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Conclusion: Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.