Extratunical grafting for minimally invasive management of complex Peyronie's disease deformities.

BACKGROUND: Penile deformities due to Peyronie's Disease (PD) often significantly impair men's sexual health and quality of life. AIM: In this article we discuss the extratunical graft (ETG) procedure as a management strategy for PD patients with hourglass or indent penile deformities. METHODS: We compiled descriptions of surgical techniques and performed a review of the literature regarding ETG for PD. OUTCOMES: The ETG procedure appears to have promising results in the management of indent/hourglass deformity of PD. RESULTS: The findings of this review of the literature demonstrate that ETG is a safe and effective reconstructive technique for penile deformity with minimal side effects. CLINICAL IMPLICATIONS: We recommend utilizing ETG with or without plication for PD patients with indent or hourglass deformities. STRENGTHS AND LIMITATIONS: Strengths of ETG are the improvement in patients with tunical indents and hourglass deformities secondary to PD. Additionally, patients who underwent ETG maintained sexual function given no significant change in penile length and intact erectile function. Limitations, however, are that the procedure is relatively new, and data are limited to small cohorts. CONCLUSION: The ETG procedure is a safe and effective for management of complex PD in the short- and intermediate-term follow-up cohort.

Neuroprotective and Neurite Outgrowth Stimulating Effects of New Low-Basicity 5-HT7 Receptor Agonists: In Vitro Study in Human Neuroblastoma SH-SY5Y Cells.

There is some evidence that the serotonin receptor subtype 7 (5-HT7) could be new therapeutic target for neuroprotection. The aim of this study was to compare the neuroprotective and neurite outgrowth potential of new 5-HT7 receptor agonists (AH-494, AGH-238, AGH-194) with 5-CT (5-carboxyamidotryptamine) in human neuroblastoma SH-SY5Y cells. The results revealed that 5-HT7 mRNA expression was significantly higher in retinoic acid (RA)-differentiated cells when compared to undifferentiated ones and it was higher in cell cultured in neuroblastoma experimental medium (DMEM) compared to those placed in neuronal (NB) medium. Furthermore, the safety profile of compounds was favorable for all tested compounds at concentration used for neuroprotection evaluation (up to 1 µM), whereas at higher concentrations (above 10 µM) the one of the tested compounds, AGH-194 appeared to be cytotoxic. While we observed relatively modest protective effects of 5-CT and AH-494 in UN-SH-SY5Y cells cultured in DMEM, in UN-SH-SY5Y cells cultured in NB medium we found a significant reduction of H2O2-evoked cell damage by all tested 5-HT7 agonists. However, 5-HT7-mediated neuroprotection was not associated with inhibition of caspase-3 activity and was not observed in RA-SH-SY5Y cells exposed to H2O2. Furthermore, none of the tested 5-HT7 agonists altered the damage induced by 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenylpyridinium ion (MPP +) and doxorubicin (Dox) in UN- and RA-SH-SY5Y cells cultured in NB. Finally we showed a stimulating effect of AH-494 and AGH-194 on neurite outgrowth. The obtained results provide insight into neuroprotective and neurite outgrowth potential of new 5-HT7 agonists.

The association between overuse and musculoskeletal injuries and the female athlete triad in Division I collegiate athletes.

INTRODUCTION: Although the female athlete triad (Triad) has been associated with increased risk of bone-stress injuries (BSIs), limited research among collegiate athletes has addressed the associations between the Triad and non-BSI injuries. OBJECTIVE: To elucidate the relationship between Triad and both BSI and non-BSI in female athletes. DESIGN: Retrospective cohort study. SETTING: Primary and tertiary care student athlete clinic. PARTICIPANTS: National Collegiate Athletic Association Division I female athletes at a single institution. INTERVENTION: Participants completed a pre-participation questionnaire and dual-energy x-ray absorptiometry, which was used to generate a Triad cumulative risk assessment score (Triad score). The number of overuse musculoskeletal injuries that occurred while the athletes were still competing collegiately were identified through chart review. MAIN OUTCOME MEASURE: BSI and non-BSI were treated as count variables. The association between BSI, non-BSI, and Triad score was measured using Poisson regression to calculate rate ratios. RESULTS: Of 239 athletes, 43% of athletes (n = 103) sustained at least one injury. Of those, 40% (n = 95) sustained at least one non-BSI and 10% (n = 24) sustained at least one BSI over an average follow-up 2.5 years. After accounting for sport type (non-lean, runner, other endurance sport, or other lean advantage sport) and baseline age, we found that every additional Triad score risk point was associated with a significant 17% increase in the rate of BSI (rate ratio [RR] 1.17, 95% confidence interval [CI] 1.03-1.33; p = .016). However, Triad score was unrelated to non-BSI (1.00, 95% CI 0.91-1.11; p = .99). Compared with athletes in non-lean sports (n = 108), athletes in other lean advantage sports (n = 30) had an increased rate of non-BSI (RR: 2.09, p = .004) whereas distance runners (n = 46) had increased rates of BSI (RR: 7.65, p < .001) and non-BSI (RR: 2.25, p < .001). CONCLUSIONS: Higher Triad score is associated with an increased risk of BSI but not non-BSI in collegiate athletes.

Staying in the Game: Interventions for Managing Achilles Tendinopathy in the In-Season Athlete.

ABSTRACT: Achilles tendinopathy is a common overuse injury that is traditionally managed with activity modification and a progressive eccentric strengthening program. This narrative review describes the available evidence for adjunctive procedural interventions in the management of midportion and insertional AT, specifically in the athletic population. Safety and efficacy data from available literature on extracorporeal shockwave therapy, platelet-rich plasma, high-volume injectate with or without tendon scraping, and percutaneous needle tenotomy are used to propose an algorithm for treatment of Achilles tendinopathy for the in-season athlete.

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.

Methionine oxidation of clusterin in Alzheimer's disease and its effect on clusterin's binding to beta-amyloid.

Clusterin is a secreted glycoprotein that participates in multiple physiological processes through its chaperon function. In Alzheimer's disease, the brain functions under an increased oxidative stress condition that causes an elevation of protein oxidation, resulting in enhanced pathology. Accordingly, it is important to determine the type of human brain cells that are mostly prone to methionine oxidation in Alzheimer's disease and specifically monitoring the methionine-oxidation levels of clusterin in human and mice brains and its effect on clusterin's function. We analyzed the level of methionine sulfoxide (MetO)-clusterin in these brains, using a combination of immunoprecipitation and Western-blott analyses. Also, we determine the effect of methionine oxidation on clusterin ability to bind beta-amyloid, in vitro, using calorimetric assay. Our results show that human neurons and astrocytes of Alzheimer's disease brains are mostly affected by methionine oxidation. Moreover, MetO-clusterin levels are elevated in postmortem Alzheimer's disease human and mouse brains in comparison to controls. Finally, oxidation of methionine residues of purified clusterin reduced its binding efficiency to beta-amyloid. In conclusion, we suggest that methionine oxidation of brain-clusterin is enhanced in Alzheimer's disease and that this oxidation compromises its chaperon function, leading to exacerbation of beta-amyloid's toxicity in Alzheimer's disease.

FICD deficiency protects mice from hypertrophy-induced heart failure via BiP-mediated activation of the UPR ER and ER-phagy.

Cardiomyocytes require the HSP70 chaperone BiP to maintain proteostasis in the endoplasmic reticulum (ER) following cardiac stress. The adenylyl transferase (AMPylase) FICD is increasingly recognized to regulate BiP activity through the post-translational addition of an adenosine monophosphate moiety to BiP surface residues. However, the physiological impact of FICD-mediated BiP regulation in the context of cardiovascular health is unknown. Here, we find that FICD deficiency prevents pressure overload-associated heart failure, hypertrophy, and fibrosis, and that FICD knockout mice maintain normal cardiac function after cardiac pressure overload. At a cellular level, we observe that FICD-mediated BiP AMPylation blunts the induction of the unfolded protein response (UPR ER ) and impairs BiP interaction with FAM134B, an ER-phagy receptor, thus limiting ER-phagy induction under stress. In contrast, FICD loss significantly increases BiP-dependent UPR ER induction and ER-phagy in stressed cardiomyocytes. We also uncover cell type-specific consequences of FICD activity in response to ER stress, positioning FICD as a critical proteostasis regulator in cardiac tissue. Our results highlight a novel regulatory paradigm controlling stress resilience in cardiomyocytes and offer a rationale to consider FICD as a therapeutic target to treat cardiac hypertrophy.

A corpus of GA4GH Phenopackets: case-level phenotyping for genomic diagnostics and discovery.

The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present phenopacket-store. Version 0.1.12 of phenopacket-store includes 4916 phenopackets representing 277 Mendelian and chromosomal diseases associated with 236 genes, and 2872 unique pathogenic alleles curated from 605 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.

ROI for a Fall Prevention Intervention: Invest a Little, Save a Lot.

Patient falls within the hospital setting continue to be a significant challenge globally with almost one million hospital falls occurring in the U.S. annually. Recent calculations showed that the average total cost of a hospitalized patient fall was $62,521. One evidenced-based tool that has been shown to be effective is a colorful laminated poster, Fall TIPS poster, that was designed to engage and involve the patient in their fall prevention. One academic medical center utilized this implementation showing a successful return on investment (ROI). This project used a pre-post implementation design. After a successful pilot using the poster on one unit, the implementation was spread to all Adult Acute Care units (n = 10) within the institution. The outcome measures were fall and fall with injury counts and rates. The process measure was the completion of the fall prevention poster measured via audits. The calculation of ROI was completed using a four-step framework. The outcome data of fall and fall with injury showed a decrease from the pre-intervention months with both the fall count and rate decreasing by 23% and the fall with injury count and rate decreasing by 40%. The overall ROI calculation estimated an ROI of $982,700. The successful results from this project support the evidence that shows this program and the use of the Fall TIPS poster helps reduce patient falls within the hospital and yields a favorable ROI.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform.

Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.

Quantitative evaluation of the effects of flow diverter treatment on aneurysm hemodynamics using time-resolved rotational angiography.

BACKGROUND: There have been immense advancements in the hardware and software of digital subtraction angiography systems over the last several years. These advancements continue to make progress toward the goals of offering better visualization and reducing radiation exposure. A newer advancement in this arena is presenting three-dimension data over time resulting in four-dimensional-digital subtracted angiography visualization. We have evaluated these protocols related to the evaluation of the treatment of intracranial aneurysms with pipeline flow diversion. METHODS: Four-dimensional-digital subtracted angiography imaging was acquired on an Artis Q Biplane angiographic system (Siemens Healthcare AG, Forchheim, Germany). A six second four-dimensional-digital subtracted angiography protocol was performed pre and post flow diverter placement. Pre and post reconstructed images were sent through a dedicated prototype research workstation (Syngo X-Workplace; Siemens Healthineers AG) for further flow evaluation. RESULTS: The treatment of an aneurysm with flow diversion led to a filling delay of 0.278 ± 0.422 s inside the aneurysms, whereas distal to the aneurysms the filling of the vessel segment occurred earlier post procedural (negative filling delay of -0.15 ± 0.31 s. The flow ratio inside the aneurysm decreased to 63.6 ± 23% of its pre-treatment value and distal to the aneurysm the flow remained substantially the same (flow ratio: 95.6 ± 0.29%). Data showed a relative filling delay of the aneurysm normalized to the distal vessel of 0.43 ± 0.36 s. The relative flow ratio of the aneurysm in comparison to the distal parent vessel was 72.2 ± 31%. CONCLUSIONS: Analysis of a four-dimensional-digital subtracted angiography acquisition allows assessment of the effects of flow diversion treatment on aneurysm hemodynamic parameters and shows a significant decrease in flow inside the aneurysm compared to the parent vessel distal to the aneurysm.

Dynamic structural evolution of MgO-supported palladium catalysts: from metal to metal oxide nanoparticles to surface then subsurface atomically dispersed cations.

Supported noble metal catalysts, ubiquitous in chemical technology, often undergo dynamic transformations between reduced and oxidized states-which influence the metal nuclearities, oxidation states, and catalytic properties. In this investigation, we report the results of in situ X-ray absorption spectroscopy, scanning transmission electron microscopy, and other physical characterization techniques, bolstered by density functional theory, to elucidate the structural transformations of a set of MgO-supported palladium catalysts under oxidative treatment conditions. As the calcination temperature increased, the as-synthesized supported metallic palladium nanoparticles underwent oxidation to form palladium oxides (at approximately 400 °C), which, at approximately 500 °C, were oxidatively fragmented to form mixtures of atomically dispersed palladium cations. The data indicate two distinct types of atomically dispersed species: palladium cations located at MgO steps and those embedded in the first subsurface layer of MgO. The former exhibit significantly higher (>500 times) catalytic activity for ethylene hydrogenation than the latter. The results pave the way for designing highly active and stable supported palladium hydrogenation catalysts with optimized metal utilization.

Diet modulates the gut microbiome, metabolism, and mammary gland inflammation to influence breast cancer risk.

Several studies have indicated a strong link between obesity and the risk of breast cancer. Obesity decreases gut microbial biodiversity and modulates Bacteroidetes-to-Firmicutes proportional abundance, suggesting that increased energy-harvesting capacity from indigestible dietary fibers and elevated lipopolysaccharide bioavailability may promote inflammation. To address the limited evidence linking diet-mediated changes in the gut microbiota to breast cancer risk, we aimed to determine how diet affects the microbiome and breast cancer risk. Female 3-week-old BALB/c mice were fed six different diets (control, high-sugar, lard, coconut oil, lard+flaxseed oil, and lard+safflower oil) for 10 weeks. Fecal 16s sequencing was performed for each group. Diet shifted fecal microbiome populations and modulated mammary gland macrophage infiltration. Fecal conditioned media shifted macrophage polarity and inflammation. In our DMBA-induced breast cancer model, diet differentially modulated tumor and mammary gland metabolism. We demonstrated how dietary patterns change metabolic outcomes, and gut microbiota, which may contribute to breast tumor risk. Furthermore, we showed the influence of diet on metabolism, inflammation, and macrophage polarity. This study suggests that dietary-microbiome interactions are key mediators of breast cancer risk.

Broadening Eligibility Criteria and Diversity among Patients for Cancer Clinical Trials.

BACKGROUND: Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown. METHODS: Using a nationwide electronic health record-derived deidentified database, we identified a retrospective cohort of patients diagnosed with 22 cancer types between April 1, 2013 and December 31, 2022 who received systemic therapy (N=235,234) for cancer. We evaluated strict versus broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy. We performed logistic regression to estimate odds ratios for exclusion by strict criteria and their association with measures of patient diversity, including sex, age, race or ethnicity, and area-level socioeconomic status (SES); estimated the impact of broadening criteria on the number and distribution of eligible patients; and performed Cox regression to estimate hazard ratios for real-world overall survival (rwOS) comparing patients meeting strict versus broadened criteria. RESULTS: When applying common strict cutoffs for eligibility criteria to patients with complete data and weighting each cancer type equally, 48% of patients were eligible for clinical trials. Female (odds ratio, 1.30; 95% confidence interval [CI], 1.25 to 1.35), older (age 75+ vs. 18 to 49 years old: odds ratio, 3.04; 95% CI, 2.85 to 3.24), Latinx (odds ratio, 1.46; 95% CI, 1.39 to 1.54), non-Latinx Black (odds ratio, 1.11; 95% CI, 1.06 to 1.16), and lower-SES patients were more likely to be excluded using strict eligibility criteria. Broadening criteria increased the number of eligible patients by 78%, with the strongest impact for older, female, non-Latinx Black, and lower-SES patients. Patients who met only broadened criteria had worse rwOS versus those with strict criteria (hazard ratio, 1.31; 95% CI, 1.27 to 1.34). CONCLUSIONS: Data-driven evaluation of clinical trial eligibility criteria may optimize the eligibility of certain historically underrepresented groups and promote access to more inclusive trials. (Sponsored by Flatiron Health.).

Machine learning for clinical outcome prediction in cerebrovascular and endovascular neurosurgery: systematic review and meta-analysis.

BACKGROUND: Machine learning (ML) may be superior to traditional methods for clinical outcome prediction. We sought to systematically review the literature on ML for clinical outcome prediction in cerebrovascular and endovascular neurosurgery. METHODS: A comprehensive literature search was performed, and original studies of patients undergoing cerebrovascular surgeries or endovascular procedures that developed a supervised ML model to predict a postoperative outcome or complication were included. RESULTS: A total of 60 studies predicting 71 outcomes were included. Most cohorts were derived from single institutions (66.7%). The studies included stroke (32), subarachnoid hemorrhage ((SAH) 16), unruptured aneurysm (7), arteriovenous malformation (4), and cavernous malformation (1). Random forest was the best performing model in 12 studies (20%) followed by XGBoost (13.3%). Among 42 studies in which the ML model was compared with a standard statistical model, ML was superior in 33 (78.6%). Of 10 studies in which the ML model was compared with a non-ML clinical prediction model, ML was superior in nine (90%). External validation was performed in 10 studies (16.7%). In studies predicting functional outcome after mechanical thrombectomy the pooled area under the receiver operator characteristics curve (AUROC) of the test set performances was 0.84 (95% CI 0.79 to 0.88). For studies predicting outcomes after SAH, the pooled AUROCs for functional outcomes and delayed cerebral ischemia were 0.89 (95% CI 0.76 to 0.95) and 0.90 (95% CI 0.66 to 0.98), respectively. CONCLUSION: ML performs favorably for clinical outcome prediction in cerebrovascular and endovascular neurosurgery. However, multicenter studies with external validation are needed to ensure the generalizability of these findings.

Analysis of Costs Associated With Increased Length of Stay After Total Joint Arthroplasty at a Single Private Practice.

INTRODUCTION: As the demand for total hip arthroplasty (THA) and total knee arthroplasty (TKA) increases, so does the financial burden of these services. Despite efforts to optimize spending and bundled care payments, THA and TKA costs still need to be assessed. Our study explores the relationship between perioperative costs and length of stay (LOS) for THA and TKA. METHODS: A total of 614 patients undergoing THA or TKA at a single private practice with LOS from zero to 3 days were identified. All patients were insured by private or Medicare Advantage insurance from a single provider. Primary outcomes included total costs and their relationship with LOS, classified into surgeon reimbursement, facility costs, and anesthesia costs. Secondary outcomes included readmission rates and discharge disposition. Analyses involved Student t-test, analysis of variance, and chi-square tests. RESULTS: Longer LOS was associated with increased total, facility, and anesthesia costs. Costs for THA patients were stable except for reduced surgeon reimbursement with longer LOS. Patients undergoing TKA experienced an increase in facility costs with longer LOS. Total facility and anesthesia costs increased with LOS for Medicare Advantage patients, but surgeon reimbursement remained stable. Privately insured patients experienced higher total and facility costs but stable surgeon reimbursement and anesthesia costs regardless of LOS. CONCLUSION: Our study shows an increase in total cost with longer LOS, especially pronounced in privately insured patients. A notable reduction was observed in the surgeon reimbursement for Medicare Advantage patients with extended LOS. These findings underscore the need for efficient surgical practices and postoperative care strategies to optimize hospital stays and control costs.

Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

Kidney Transplantation Contraindications: Variation in Nephrologist Practice and Training Vintage.

Introduction: Health system leaders aim to increase access to kidney transplantation in part by encouraging nephrologists to refer more patients for transplant evaluation. Little is known about nephrologists' referral decisions and whether nephrologists with older training vintage weigh patient criteria differently (e.g., more restrictively). Methods: Using a novel, iteratively validated survey of US-based nephrologists, we examined how nephrologists assess adult patients' suitability for transplant, focusing on established, important criteria: 7 clinical (e.g., overweight) and 7 psychosocial (e.g., insurance). We quantified variation in nephrologist restrictiveness-proportion of criteria interpreted as absolute or partial contraindications versus minor or negligible concerns-and tested associations between restrictiveness and nephrologist age (proxy for training vintage) in logistic regression models, controlling for nephrologist-level and practice-level factors. Results: Of 144 nephrologists invited, 42 survey respondents (29% response rate) were 85% male and 54% non-Hispanic White, with mean age 52 years, and 67% spent ≥1 day/wk in outpatient dialysis facilities. Nephrologists interpreted patient criteria inconsistently; consistency was lower for psychosocial criteria (intraclass correlation coefficient: 0.28) than for clinical criteria (intraclass correlation coefficient: 0.43; P < 0.01). With each additional 10 years of age, nephrologists' odds of interpreting criteria restrictively (top tertile) doubled (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI]: 0.95-4.07), with marginal statistical significance. This relationship was significant when interpreting psychosocial criteria (aOR: 3.18; 95% CI: 1.16-8.71) but not when interpreting clinical criteria (aOR: 1.12; 95% CI: 0.52-2.38). Conclusion: Nephrologists interpret evaluation criteria variably when assessing patient suitability for transplant. Guideline-based educational interventions could influence nephrologists' referral decision-making differentially by age.

Ultrapotent Broadly Neutralizing Human-llama Bispecific Antibodies against HIV-1.

Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL-1, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.