Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa.

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3,963 cases and 3,509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. OBJECTIVES: The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. METHODS: Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. RESULTS: Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). CONCLUSIONS: In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

High prevalence of dysfunctional uterine bleeding in candidates for metabolic/bariatric surgery: increased endometrial cancer risk?

BACKGROUND: Endometrial cancer (EC) is the strongest obesity-associated malignancy and the fastest-growing cancer in young women. Early identification of EC and other endometrial pathology (malignant and nonmalignant) in women with severe obesity may improve treatment options and uterine preservation. Screening for endometrial pathology using abnormal or postmenopausal uterine bleeding (APUB) as a surrogate in women pursuing metabolic/bariatric surgery may be clinically beneficial, but data supporting this effort are limited. OBJECTIVE: To develop and institute a screening program for APUB as a surrogate for endometrial pathology in bariatric surgery candidates. SETTING: Two, academic metabolic/bariatric surgery programs in Louisiana, United States. METHODS: The Modified SAMANTA is a 10-item questionnaire that was implemented to identify patients with APUB, specifically combining tools designed to identify anovulatory/postmenopausal and heavy menstrual bleeding. Demographic (age, race), body mass index, and questionnaire data were analyzed with respect to positive screening using data from March 2021 through May 2023. RESULTS: Of 1371 eligible women presenting for surgical evaluation, 664 (48.4%) positive screens were identified and referred for gynecologic evaluation to rule out endometrial hyperplasia/cancer or other endometrial pathology. The likelihood of positive screening for APUB was associated with increasing BMI (P = .001) and Black/African American race (P = .003), as well as increasing SAMANTA score (P < .001). In contrast, risk of positive screening was negatively associated with increasing age (P < .001). CONCLUSIONS: Women presenting for metabolic/bariatric surgery have a high prevalence of APUB and, given this dysfunctional bleeding and concurrent obesity, are at greater risk for underlying EC. Potential risk factors for APUB, given their associations with screening positive, include increased body mass index, younger age, and Black/African American race. Standardized screening with appropriate gynecologic referral should be a routine part of the overall evaluation for women with severe obesity.

Increased Risk of New-Onset Hypertension in Patients With Narcolepsy Initiating Sodium Oxybate: A Real-World Study.

OBJECTIVE: To compare intermediate-term risk of new-onset hypertension between normotensive patients with narcolepsy initiating sodium oxybate (SXB cohort) and those not initiating sodium oxybate (control cohort). PATIENTS AND METHODS: This retrospective cohort study used MarketScan administrative claims data from January 1, 2014, to February 29, 2020. Eligible patients were 18 years of age or older with continuous enrollment (≥180 days before and after cohort entry), had one or more narcolepsy claims or a prescription fill for sodium oxybate, had no history of hypertension or antihypertensive medication use, and had no use of sodium oxybate within 13 months before cohort entry. Patients in the SXB and control cohorts were matched 1:2 for the propensity score to balance baseline characteristics. End points were (1) a composite of new-onset hypertension diagnosis or antihypertensive medication initiation and (2) new-onset hypertension diagnosis. Patients were monitored for 180 days, until outcome occurrence, sodium oxybate discontinuation (SXB cohort), or sodium oxybate initiation (control cohort). Risk per 100 patients was reported; differences were evaluated using logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The SXB and control cohorts included 954 and 1908 patients, respectively. Risk of new-onset hypertension diagnosis or antihypertensive medication initiation was higher in the SXB cohort than in the control cohort (6.60 vs 4.20 per 100 patients; OR, 1.61; 95% CI, 1.15 to 2.27). Risk of a new-onset hypertension diagnosis only in the SXB cohort was 0.94 per 100 patients and 0.52 per 100 patients in the control cohort (OR, 1.81; 95% CI, 0.73 to 4.46). CONCLUSION: In this study, sodium oxybate use was associated with a new-onset hypertension diagnosis or antihypertensive medication initiation in normotensive patients with narcolepsy.

Rare events model of the MBSAQIP database: risk of early bowel obstruction following metabolic surgery.

BACKGROUND: Early small bowel obstruction (eSBO) (within 30-days) is a rare but important complication that is associated with high rates of morbidity, including readmission, reintervention, and reoperation. OBJECTIVES: To identify patient-specific and operation-specific characteristics that predispose patients to eSBO and to identify at-risk individuals preoperatively. SETTING: 2015-2021 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). METHODS: Utilizing the 2015-2021 MBSAQIP PUF, 1,016,484 records were analyzed. Pediatric, revisional, open-conversion, and cases with incomplete data in sex, body mass index, operative-time, 30-day-follow-up variables were excluded. Case details were compared using Fisher's exact & Wilcoxon -Mann -Whitney tests to identify at-risk patients. The likelihood of eSBO was modeled with rare event logistic regression. RESULTS: Incidence of eSBO was .40%. Of the 4103 occurrences of eSBO, RYGB (Roux-en-Y gastric bypass), SG (sleeve gastrectomy), and DS (duodenal switch) accounted for 79.4%, 19.3%, and 1.3%, respectively. Many patient-specific characteristics were significantly associated with eSBO. History of prior foregut surgery, a non-metabolic surgery trained operator, and longer operative times were all associated with increased eSBO (P < .0001). While simultaneously controlling for these factors, eSBO remained higher in DS (OR 9.55, P < .0001) and RYGB (OR 5.18, P < .0001) compared to SG. Increased length of operation (OR 1.03, P < .0001) and non -MS-trained operators (OR 1.33, P < .0001) remained highly significant. Male-sex (OR .70, P < .0001) and diabetes (OR .78, P < .0001) were both protective. CONCLUSIONS: In the largest analysis to date, eSBO remains a rare event. RYGB accounts for the largest proportion of eSBO, however, DS has a higher risk adjusted rate of eSBO.

Impact of progressive chronic kidney disease stage on postoperative outcomes in metabolic surgery-a propensity-matched analysis using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement database.

BACKGROUND: Metabolic surgery (MS) is effective in improving renal parameters for individuals with obesity and chronic kidney disease (CKD). Despite recognized benefits, concerns linger about the perioperative safety of patients with CKD undergoing MS. This study aimed to identify the CKD stage associated with the most significant increase in postoperative complications. METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database (2017-2021) was used to identify patients undergoing laparoscopic gastric sleeve (SG) or Roux-en-Y gastric bypass (RYGB). Propensity matching was used to quantify the risk for adverse outcomes associated with progressive CKD stage. RESULTS: In total, 688,583 patients (483,898 without CKD and 204,685 with CKD stages I-V) were examined. Endpoints included length of stay (LOS) >5 days, infection, serious complications, major adverse cardiovascular events (MACE), and death. Both SG and RYGB exhibited a linear increase in risk of infection and death. For SG, patients who were stage IIIa/IIIb demonstrated the greatest risk for LOS >5 days (odds ratio [OR] 1.23; 95% confidence interval [CI] (1.05-1.45); P = .011), serious complications (OR 2.83; 95% CI 1.87-4.30; P < .001), and MACE (OR 2.82; 95% CI 1.81-4.37; P < .001). For RYGB, patients who were stage IIIa/IIIb the exhibited greatest risk of MACE (OR 1.67; 95% CI 1.06-2.62; P = .027). CONCLUSIONS: Although it is generally accepted that worsening CKD correlates with greater surgical risk, this analysis identified CKD stage III as a major inflection point for risk of LOS >5 days, serious complications, and MACE. These findings are useful for counseling and procedure selection and suggest a need for heightened attention to CKD stage III patients undergoing MS.

Early marginal ulceration prevalence following primary RYGB: a rare events model of the MBSAQIP 2015-2021.

PURPOSE: Marginal ulceration (MU) following Roux-en-Y gastric bypass (RYGB) is an established complication, with early MU (within 30-days of operation) being less understood compared to its late counterpart. This study aims to identify risk factors for early MU in patients undergoing primary RYGB. METHODS: Utilizing data from the Metabolic and Bariatric Surgery Accreditation Quality Improvement Project (MBSAQIP 2015-2021), 1,346,468 records were evaluated. After exclusions for revisions, conversions, pediatric cases, nonbinary gender, missing body mass index (BMI) data, and missing operative time; 291,625 cases of primary RYGB were included for full analysis and rare events modeling of early MU. RESULTS: The prevalence of early MU was .29% (n = 850). Higher rates of early MU were associated with BMI, race, history of diabetes mellitus (DM), prior thrombotic complications (deep vein thrombosis (DVT) and pulmonary embolism (PE)), prior percutaneous cardiac intervention (PTC), immunosuppressive therapy, and anticoagulation status. Additionally, procedural aspects like the nonspecialization of the surgeon and longer operative times also correlated with higher early MU rates. Rare-events regression modeling noted significant associations of early MU with younger age, diabetes requiring insulin, history of PTC, DVT, immunosuppressive therapy, and anticoagulation status. CONCLUSION: Early MU remains a relatively rare complication. The lower than previously reported occurrence suggests possible improvements in both patient preparation and surgical technique. The identification of relevant risk factors enables better perioperative and intraoperative management of patients at risk of developing early MU.

BMI ≥ 70: A Multi-Center Institutional Experience of the Safety and Efficacy of Metabolic and Bariatric Surgery Intervention.

PURPOSE: With the escalating prevalence of obesity, healthcare providers are increasingly managing patients with a body mass index (BMI) exceeding 70. The aim of this study was to describe the perioperative experiences of this demographic group at two institutions. METHODS: An analysis encompassing 84 patients presenting with BMI ≥ 70 kg/m2 from two institutions was conducted. Data included patient demographics, 30-day postoperative outcomes, and weight-loss at different intervals (30 days, 6 months, 1 year). Additionally, rates of emergency department (ED) utilization, readmission, and reoperation in the first postoperative year were examined. RESULTS: Most patients were black (66.7%) and female (86.9%) with a mean age of 41.7 years. The majority underwent laparoscopic sleeve gastrectomy (SG, 88.1%). Patients exhibited a marked decrease in BMI (7.84% at 30 days, 20.13% at 6 months, and 26.83% at 1 year). Average length of stay was comparable across procedure (F(3,80) = 0.016, p = .997). While 30-day complications were minimal (0.7%), 14.4% of patients experienced ED visits within 30 days, escalating to 19.6% by six months and 25% at 1 year. Readmission and reoperation rates at 1 year were 6.45% and 4.83%, respectively. CONCLUSION: With global obesity rates rising, clinicians are being challenged to care for patients with BMI ≥ 70 kg/m2. Analysis of two institutions demonstrated low rates of 30-days complications but increased readmission rates and ED utilization in this patient population. Despite increased resource utilization, the study suggests that BMI ≥ 70 kg/m2 alone should not be a deterrent for surgery, emphasizing the need for nuanced care in this expanding demographic.

Clinical Outcomes of Metabolic Surgery on Diuretic Use in Patients With Heart Failure.

The beneficial impacts of metabolic surgery (MS) on patients with heart failure (HF) are incompletely characterized. We aimed to describe the cardiac and metabolic effects of MS in patients with HF and hypothesized that patients with HF would experience both improved metabolic and HF profiles using glycemic control and diuretic dependency as surrogate markers. In this single-center, university-affiliated academic study in the United States, a review of 2,342 hospital records of patients who underwent MS (2017 to 2023) identified 63 patients with a medical history of HF. Preoperative characteristics, 30-day outcomes, and up to 2-year biometric and metabolic outcomes, medication usage, and emergency department utilization were collected. At 24 months, mean body mass index change was -16 kg/m2 (p <0.001) that corresponded to a mean percentage total body weight loss of 29% (p <0.001). Weight loss was accompanied by significant reductions in hemoglobin A1c (p <0.001) and a 65% decrease in diuretic use at 24 months after surgery (p <0.001). Similarly, emergency visits for cardiac conditions (p = 0.06) and intravenous diuresis (p = 0.07) trended favorably at 1 year after surgery compared with 1 year before surgery but were not statistically significant. In conclusion, in patients with HF who were carefully selected, MS appears to provide significant reduction in oral diuretic dependency, and metabolic improvements with trends toward lower rates of emergency department utilization.

Insurance payor status and risk of major adverse cardiovascular and cerebrovascular events after metabolic and bariatric surgery.

BACKGROUND: Patients with Medicare/Medicaid insurance receive metabolic and bariatric surgery (MBS) at lower rates than privately insured (PI) patients. Although studies on some surgical procedures report that Medicare/Medicaid insurance confers increased postoperative complication rates and a longer length of stay, less is known about these outcomes after MBS. Among often-feared postoperative complications are major adverse cardiovascular and cerebrovascular events (MACEs). Although these events are rare after MBS, they have a significant impact on morbidity and mortality. OBJECTIVES: This study aimed to examine the effect of insurance payor status on MACEs after MBS. SETTING: The Healthcare Cost and Utilization Project National Inpatient Sample (HCUP-NIS). METHODS: HCUP-NIS was queried for cases including sleeve gastrectomy or Roux-en-Y gastric bypass between 2012 and 2019. Bivariate associations between patient-level factors and MACEs were assessed via Rao-Scott χ2 tests. Adjusted and unadjusted risks of insurance payor status for MACEs were evaluated using logistic regression. RESULTS: Incidence of MACEs was higher in both Medicare (.75% versus .11%; P < .001) and Medicaid (.15% versus .11%; P < .001) groups than in the PI group. After adjustment for high-risk demographics, high-risk co-morbidities, socioeconomic variables, and hospital factors, insurance status of Medicare (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.23, 2.07; P = .0026) or Medicaid (OR: 1.55, 95% CI: 1.12, 2.16; P = .0026) remained an independent risk factor for MACEs. CONCLUSIONS: Our findings underscore the significance of Medicaid/Medicare payor status as an independent predictor of postoperative MACEs in MBS. The results of this study can have a significant impact on deepening our understanding of socioeconomic and health system-related issues that can be targeted to improve outcomes in both MBS and other surgical specialties.

Limitations of the 2015-2021 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database for emergency bariatric operations.

BACKGROUND: The Metabolic and Bariatric Surgery Quality Improvement Project (MBSAQIP) is the largest bariatric surgery-specific clinical data set. OBJECTIVES: In 2020, the definition of emergency cases was altered to include only revisional or conversion cases and not primary cases. The aim of this study was to examine how this change affects the utility of the data set for emergency case tracking. SETTING: MBSAQIP database. METHODS: Emergency cases were extracted from available MBSAQIP data (2015-2021). A comparison of co-morbidity profiles was done, specifically before and after the recent change to how "emergency" is defined in the data set. RESULTS: Eleven thousand and twenty-nine of the 1,048,575 total cases were coded as "emergency cases." From 2015 to 2019, 10,574 emergency cases were performed (∼2115 cases/yr), markedly decreasing in 2020 and 2021 to 455 cases (∼228 cases/yr). Before 2020, the most common procedures were the unlisted procedure of the stomach (45.14%, n = 3101), gastric band removal (25.3%, n = 2676), and reduction of internal hernia (11.8%, n = 1244). Between 2020 and 2021, this distribution changed with Roux-en-Y gastric bypass (RYGB), the most common emergency procedure (29.23%, n = 133). As expected from the change that captured only revisional cases, the average operative length was greater between 2020 and 2021 (127.6 versus 86.5 min). CONCLUSIONS: Capturable emergency cases declined in 2020, a trend related to changing the definition of emergency as part of MBSAQIP standards. This change excludes data on internal hernia reduction and does not likely reflect a real change in the prevalence of emergency bariatric cases. Because capture for emergency cases has diminished, so has any prior utility of using MBSAQIP data for studying emergency cases.

Late-stage borreliosis and substance abuse.

Background: Infectious diseases can contribute to substance abuse. Here, a fatal case of borreliosis and substance abuse is reported. This patient had a history of multiple tick bites and increasing multisystem symptoms, yet diagnosis and treatment were delayed. He experimented with multiple substances including phencyclidine (PCP), an N-methyl-d-aspartate (NMDA) receptor antagonist that opposes NMDA agonism caused by Borrelia infection. During PCP withdrawal, he committed one homicide, two assaults, and suicide. Methods: Brain tissue was obtained from autopsy and stained for microglial activation and quinolinic acid (QA). Immunoflouresence (IFA) and fluorescence in situ hybridization (FISH) were used to identify the presence of pathogens in autopsy tissue. Results: Autopsy tissue evaluation demonstrated Borrelia in the pancreas by IFA and heart by IFA and FISH. Activated microglia and QA were found in the brain, indicating neuroinflammation. It is postulated that PCP withdrawal may exacerbate symptoms produced by Borrelia-induced biochemical imbalances in the brain. This combination may have greatly increased his acute homicidal and suicidal risk. Patient databases also demonstrated the risk of homicide or suicide in patients diagnosed with borreliosis and confirmed multiple symptoms in these patients, including chronic pain, anxiety, and anhedonia. Conclusions: Late-stage borreliosis is associated with multiple symptoms that may contribute to an increased risk of substance abuse and addictive disorders. More effective diagnosis and treatment of borreliosis, and attention to substance abuse potential may help reduce associated morbidity and mortality in patients with borreliosis, particularly in endemic areas.

Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Similar Risk of Kidney Failure among Patients with Blinding Diseases Who Receive Ranibizumab, Aflibercept, and Bevacizumab: An Observational Health Data Sciences and Informatics Network Study.

PURPOSE: To characterize the incidence of kidney failure associated with intravitreal anti-VEGF exposure; and compare the risk of kidney failure in patients treated with ranibizumab, aflibercept, or bevacizumab. DESIGN: Retrospective cohort study across 12 databases in the Observational Health Data Sciences and Informatics (OHDSI) network. SUBJECTS: Subjects aged ≥ 18 years with ≥ 3 monthly intravitreal anti-VEGF medications for a blinding disease (diabetic retinopathy, diabetic macular edema, exudative age-related macular degeneration, or retinal vein occlusion). METHODS: The standardized incidence proportions and rates of kidney failure while on treatment with anti-VEGF were calculated. For each comparison (e.g., aflibercept versus ranibizumab), patients from each group were matched 1:1 using propensity scores. Cox proportional hazards models were used to estimate the risk of kidney failure while on treatment. A random effects meta-analysis was performed to combine each database's hazard ratio (HR) estimate into a single network-wide estimate. MAIN OUTCOME MEASURES: Incidence of kidney failure while on anti-VEGF treatment, and time from cohort entry to kidney failure. RESULTS: Of the 6.1 million patients with blinding diseases, 37 189 who received ranibizumab, 39 447 aflibercept, and 163 611 bevacizumab were included; the total treatment exposure time was 161 724 person-years. The average standardized incidence proportion of kidney failure was 678 per 100 000 persons (range, 0-2389), and incidence rate 742 per 100 000 person-years (range, 0-2661). The meta-analysis HR of kidney failure comparing aflibercept with ranibizumab was 1.01 (95% confidence interval [CI], 0.70-1.47; P = 0.45), ranibizumab with bevacizumab 0.95 (95% CI, 0.68-1.32; P = 0.62), and aflibercept with bevacizumab 0.95 (95% CI, 0.65-1.39; P = 0.60). CONCLUSIONS: There was no substantially different relative risk of kidney failure between those who received ranibizumab, bevacizumab, or aflibercept. Practicing ophthalmologists and nephrologists should be aware of the risk of kidney failure among patients receiving intravitreal anti-VEGF medications and that there is little empirical evidence to preferentially choose among the specific intravitreal anti-VEGF agents. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparative Effectiveness of Second-line Antihyperglycemic Agents for Cardiovascular Outcomes: A Large-scale, Multinational, Federated Analysis of the LEGEND-T2DM Study.

Background: SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1-RAs) reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head trials. Methods: Across the LEGEND-T2DM network, we included ten federated international data sources, spanning 1992-2021. We identified 1,492,855 patients with T2DM and established cardiovascular disease (CVD) on metformin monotherapy who initiated one of four second-line agents (SGLT2is, GLP1-RAs, dipeptidyl peptidase 4 inhibitor [DPP4is], sulfonylureas [SUs]). We used large-scale propensity score models to conduct an active comparator, target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, we fit on-treatment Cox proportional hazard models for 3-point MACE (myocardial infarction, stroke, death) and 4-point MACE (3-point MACE + heart failure hospitalization) risk, and combined hazard ratio (HR) estimates in a random-effects meta-analysis. Findings: Across cohorts, 16·4%, 8·3%, 27·7%, and 47·6% of individuals with T2DM initiated SGLT2is, GLP1-RAs, DPP4is, and SUs, respectively. Over 5·2 million patient-years of follow-up and 489 million patient-days of time at-risk, there were 25,982 3-point MACE and 41,447 4-point MACE events. SGLT2is and GLP1-RAs were associated with a lower risk for 3-point MACE compared with DPP4is (HR 0·89 [95% CI, 0·79-1·00] and 0·83 [0·70-0·98]), and SUs (HR 0·76 [0·65-0·89] and 0·71 [0·59-0·86]). DPP4is were associated with a lower 3-point MACE risk versus SUs (HR 0·87 [0·79-0·95]). The pattern was consistent for 4-point MACE for the comparisons above. There were no significant differences between SGLT2is and GLP1-RAs for 3-point or 4-point MACE (HR 1·06 [0·96-1·17] and 1·05 [0·97-1·13]). Interpretation: In patients with T2DM and established CVD, we found comparable cardiovascular risk reduction with SGLT2is and GLP1-RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of GLP1-RAs and SGLT2is should be prioritized as second-line agents in those with established CVD. Funding: National Institutes of Health, United States Department of Veterans Affairs.

Stimuli-Responsive Polymers for Engineered Emulsions.

Emulsions are complex. Dispersing two immiscible phases, thus expanding an interface, requires effort to achieve and the resultant dispersion is thermodynamically unstable, driving the system toward coalescence. Furthermore, physical instabilities, including creaming, arise due to presence of dispersed droplets of different densities to a continuous phase. Emulsions allow the formulation of oils, can act as vehicles to solubilize both hydrophilic and lipophilic molecules, and can be tailored to desirable rheological profiles, including "gel-like" behavior and shear thinning. The usefulness of emulsions can be further expanded by imparting stimuli-responsive or "smart" behaviors by inclusion of a stimuli-responsive emulsifier, polymer or surfactant. This enables manipulation like gelation, breaking, or aggregation, by external triggers such as pH, temperature, or salt concentration changes. This platform generates functional materials for pharmaceuticals, cosmetics, oil recovery, and colloid engineering, combining both smart behaviors and intrinsic benefit of emulsions. However, with increased functionality comes greater complexity. This review focuses on the use of stimuli-responsive polymers for the generation of smart emulsions, motivated by the great adaptability of polymers for this application and their efficacy as steric stabilizers. Stimuli-responsive emulsions are described according to the trigger used to provide the reader with an overview of progress in this field.

Early Experience with the Senhance Surgical System in Bariatric Surgery.

Background and Objectives: Robotic-assisted surgery advancements have paralleled growing bariatric surgery demands. The Senhance robotic platform offers an alternative to the da Vinci surgical system but there are limited studies evaluating the Senhance system in bariatric surgery. This study aims to review a single surgeon's experience comparing outcomes between traditional laparoscopic and Senhance-assisted sleeve gastrectomy. Materials and Methods: All sleeve gastrectomies performed laparoscopically, Senhance-assisted, or da Vinci-assisted by a single surgeon at an academic center from January 2019 to July 2021 were retrospectively reviewed. Primary outcomes and quality measures were 30-day complications, operative times and length of stay. Results: A total of 268 patients, including 162 laparoscopic, 92 Senhance, and 14 da Vinci cases, were included. Operative times were significantly longer with Senhance (115.7 min) and da Vinci (122.7 min), compared to laparoscopic (94.8 min, P < .0001). Length of stay (measured in days) was significantly longer in the Senhance (1.8) and da Vinci (2.2) groups compared to laparoscopic cases (1.5, P < .0001). These differences remained significant after controlling for age, sex and body mass index. 30-day complication rates were 8.7% (n = 8) in the Senhance group, 7.1% (n = 1) in the da Vinci group and 2.5% (n = 4) in the laparoscopic group (P = .0567). Conclusion: Senhance-assisted sleeve gastrectomy is safe in bariatric surgery and comparable to laparoscopic sleeve gastrectomy with respect to 30-day complications.

Improved survival for dose-intensive chemotherapy in primary mediastinal B-cell lymphoma: a systematic review and meta-analysis of 4,068 patients.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity. Currently, there is a paucity of randomized prospective data to inform on optimal front-line chemoimmunotherapy (CIT) and use of consolidative mediastinal radiation (RT). To assess if distinct CIT approaches are associated with disparate survival outcomes, we performed a systematic review and meta-analysis comparing dose-intensive (DI-CIT) versus standard CIT for the front-line treatment of PMBCL. Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT. DI-CIT were defined as regimens with increased frequency, dose, and/or number of systemic agents. We reviewed data on 4,068 patients (2,517 DI-CIT; 1,551 S-CIT) with a new diagnosis of PMBCL. Overall survival for DI-CIT patients was 88% (95% CI: 85-90) compared to 80% for the S-CIT cohort (95% CI: 74-85). Meta-regression revealed an 8% overall survival (OS) benefit for the DI-CIT group (P<0.01). Survival benefit was maintained when analyzing rituximab only regimens; OS was 91% (95% CI: 89-93) for the rituximab-DI-CIT arm compared to 86% (95% CI: 82-89) for the R-CHOP-21 arm (P=0.03). Importantly, 55% (95% CI: 43-65) of the S-CIT group received RT compared to 22% (95% CI: 15-31) of DI-CIT patients (meta-regression P<0.01). To our knowledge, this is the largest meta-analysis reporting efficacy outcomes for the front-line treatment of PMBCL. DI-CIT demonstrates a survival benefit, with significantly less radiation exposure, curtailing long-term toxicities associated with radiotherapy. As we await results of randomized prospective trials, our study supports the use of dose-intensive chemoimmunotherapy for the treatment of PMBCL.