Occupation, Retirement Age, and 20-Year Cognitive Decline: The Atherosclerosis Risk in Communities Neurocognitive Study.

INTRODUCTION: We examined the association of both midlife occupation and age at retirement with cognitive decline in the Atherosclerosis Risk in Communities (ARIC) biracial community-based cohort. METHODS: Current or most recent occupation at ARIC baseline (1987-89; ages 45-64y) was categorized based on 1980 US census major occupation groups and tertiles of the Nam-Powers-Boyd occupational status score (n=14,090). Retirement status via annual follow-up questionnaires administered ascertained in 1999-2007 was classified as occurring before or after age 70 (n=7,503). Generalized estimating equation models were used to examine associations of occupation and age at retirement with trajectories of global cognitive factor scores, assessed from visit 2 (1990-92) to visit 5 (2011-2013). Models were a priori stratified by race and sex and adjusted for demographics and comorbidities. RESULTS: Low occupational status and blue-collar occupations were associated with low baseline cognitive scores in all race-sex strata. Low occupational status and homemaker status were associated with faster decline in White women but slower decline in Black women compared to high occupational status. Retirement before age 70 was associated with slower cognitive decline in White men and women and in Black men. Results did not change substantially after accounting for attrition. CONCLUSION: Low occupational status was associated with cognitive decline in women but not in men. Earlier retirement was associated with a slower cognitive decline in White participants and in Black men. Further research should explore reasons for the observed associations and race-sex differences.

Associations between the EQ-5D-5L and exacerbations of chronic obstructive pulmonary disease in the ETHOS trial.

PURPOSE: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with deteriorating health and health-related quality of life (HRQoL) among people with COPD during and after events. HRQoL data are key to evaluating treatment cost-effectiveness and informing reimbursement decisions in COPD. EuroQoL 5-dimension 5-level (EQ-5D-5L) utility scores, based on various HRQoL measures, are used in economic evaluations of pharmacotherapy. These analyses estimated associations between EQ-5D-5L utility scores and exacerbations (new and previous) in patients with moderate-to-very severe COPD. METHODS: Longitudinal mixed models for repeated measures (MMRM), adjusted for time and treatment, were conducted using data from the ETHOS study (NCT02465567); models regressed EQ-5D-5L on current and past exacerbations that occurred during the study, adjusting for other patient reported outcomes and clinical factors. RESULTS: Based on the simplest covariate adjusted model (adjusted for current exacerbations and number of previous exacerbations during the study), a current moderate exacerbation was associated with an EQ-5D-5L disutility of 0.055 (95% confidence interval: 0.048, 0.062) with an additional disutility of 0.035 (0.014, 0.055) if the exacerbation was severe. After resolving, each prior exacerbation was associated with a disutility that persisted for the remainder of the study (moderate exacerbation, 0.014 [0.011, 0.016]; further disutility for severe exacerbation, 0.011 [0.003, 0.018]). CONCLUSION: An EQ-5D-5L disutility of 0.090 was associated with a current severe exacerbation in ETHOS. Our findings suggest incorporating the effects of current, recently resolved, and cumulative exacerbations into economic models when estimating benefits and costs of COPD pharmacotherapy, as exacerbations have both acute and persistent effects.

Patient sex, racial and ethnic disparities in emergency department triage: A multi-site retrospective study.

OBJECTIVES: There is limited evidence on sex, racial, and ethnic disparities in Emergency Department (ED) triage across diverse settings. We evaluated differences in the assignment of Emergency Severity Index (ESI) by patient sex and race/ethnicity, accounting for age, clinical factors, and ED operating conditions. METHODS: We conducted a multi-site retrospective study of adult patients presenting to high-volume EDs from January 2019-February 2020. Patient-level data were obtained and analyzed from three EDs (academic, metropolitan community, and rural community) affiliated with a large health system in the Southeastern United States. For the study outcome, ESI levels were grouped into three categories: 1-2 (highest acuity), 3, and 4-5 (lowest acuity). Multinomial logistic regression was used to compare ESI categories by patient race/ethnicity and sex jointly (referent = White males), adjusted for patient age, insurance status, ED arrival mode, chief complaint category, comorbidity score, time of day, day of week, and average ED wait time. RESULTS: We identified 186,840 eligible ED visits with 56,417 from the academic ED, 69,698 from the metropolitan community ED, and 60,725 from the rural community ED. Patient cohorts between EDs varied by patient age, race/ethnicity, and insurance status. The majority of patients were assigned ESI 3 in the academic and metropolitan community EDs (61% and 62%, respectively) whereas 47% were assigned ESI 3 in the rural community ED. In adjusted analyses, White females were less likely to be assigned ESI 1-2 compared to White males although both groups were roughly comparable in the assignment of ESI 4-5. Non-White and Hispanic females were generally least likely to be assigned ESI 1-2 in all EDs. Interactions between ED wait time and race/ethnicity-sex were not statistically significant. CONCLUSIONS: This retrospective study of adult ED patients revealed sex and race/ethnicity-based differences in ESI assignment, after accounting for age, clinical factors, and ED operating conditions. These disparities persisted across three different large EDs, highlighting the need for ongoing research to address inequities in ED triage decision-making and associated patient-centered outcomes.

Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

Emerging green synthetic routes for thiazole and its derivatives: Current perspectives.

This review article provides an overview of the green synthesis of thiazole derivatives, emphasizing sustainable and environmentally friendly methodologies. Thiazole derivatives possess significant value and find diverse applications across various fields. However, conventional synthesis methods often involve hazardous reagents and generate substantial waste, posing environmental concerns. The green synthesis of thiazole derivatives employs renewable starting materials, nontoxic catalysts, and mild reaction conditions to minimize environmental impact. Innovative techniques such as microwave irradiation, ultrasound synthesis, green solvents, a green catalyst-based approach, and mechanochemistry-mediated synthesis are employed, offering advantages in terms of scalability, cost-effectiveness, and purification simplicity. The resulting thiazole derivatives exhibit comparable or enhanced biological activities, showcasing the feasibility and practicality of green synthesis in drug discovery. This review paper underscores the importance of sustainable approaches in functional molecular synthesis and encourages further research in this domain.

The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia.

OBJECTIVE: To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia. METHODS: Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance. RESULTS: In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=-0.5 [P<.001]; 3 mg/d=-0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=-1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; -2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073). CONCLUSION: These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

EMS Involvement in COVID-19 Vaccination Efforts - Results of a North Carolina Statewide Survey.

Objective: The COVID-19 pandemic has necessitated the vaccination of large numbers of people across the United States, mobilizing public health resources on a massive scale. The purpose of this study is to determine how emergency medical services (EMS) clinicians and agencies in North Carolina have been utilized in these vaccination efforts.Methods: This retrospective survey was sent to EMS medical directors and EMS system administrators for all 100 county EMS systems in North Carolina. Participation was voluntary, and survey questions asked about the contribution of EMS systems to vaccination efforts, the levels of EMS clinicians being utilized, the activities carried out by those clinicians, and any identifiable barriers to EMS involvement in COVID-19 vaccination efforts.Results: Ninety-eight of the 100 counties in North Carolina responded to the survey, with 88 contributing to vaccination efforts in the communities. Reasons cited by the 10 counties for not being involved in vaccination efforts include: county health departments not needing assistance (two counties), vaccine hesitancy amongst clinicians and the politicization of COVID (three counties), inadequate staffing (one county), and the presence of "robust vaccination clinics" in the community (one county). An additional 12 counties listed staffing shortages as limiting their vaccination efforts. Among the counties supporting vaccine efforts, activities included planning and logistics (54 counties), non-medical roles (38 counties), vaccine preparation (35 counties), medical screening pre-vaccination (41 counties), vaccine administration (74 counties), medical observation post-vaccination (79 counties), and home vaccinations (53 counties). Of the 74 counties that used EMS personnel in vaccine administration, 27 used EMTs (37%), 36 used Advanced EMTs (49%), and 73 used Paramedics (99%).Conclusion: This study demonstrates the large role that EMS clinicians and systems have played and continue to play in COVID-19 vaccination efforts in the state of North Carolina, including planning and logistics, patient screening and observation, vaccine preparation and administration, and home vaccination. Furthermore, it supports the expanded use of EMTs as a potential vaccination workforce. As the public health response to this pandemic continues, EMS clinicians and systems are a valuable resource to their communities and states.

Prehospital Fluid Administration for Suspected Sepsis in a Large EMS System: Opportunities to Improve Goal Fluid Delivery.

OBJECTIVES: Despite EMS-implemented screening and treatment protocols for suspected sepsis patients, prehospital fluid therapy is variable. We sought to describe prehospital fluid administration in suspected sepsis patients, including demographic and clinical factors associated with fluid outcomes. METHODS: A retrospective cohort of adult patients from a large, county-wide EMS system from January 2018-February 2020 was identified. Patient care reports for suspected sepsis were included, as identified by EMS clinician impression of sepsis, or keywords "sepsis" or "septic" in the narrative. Outcomes were the proportions of suspected sepsis patients for whom intravenous (IV) therapy was attempted and those who received ≥500 mL IV fluid if IV access was successful. Associations between patient demographics and clinical factors with fluid outcomes were estimated with multivariable logistic regression adjusting for transport interval. RESULTS: Of 4,082 suspected sepsis patients identified, the mean patient age was 72.5 (SD 16.2) years, 50.6% were female, and 23.8% were Black. Median (interquartile range [IQR]) transport interval was 16.5 (10.9-23.2) minutes. Of identified patients, 1,920 (47.0%) had IV fluid therapy attempted, and IV access was successful in 1,872 (45.9%). Of those with IV access, 1,061 (56.7%) received ≥500mL of fluid from EMS. In adjusted analyses, female (versus male) sex (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.69-0.90), Black (versus White) race (OR 0.57, 95% CI 0.49-0.68), and end stage renal disease (OR 0.51, 95% CI 0.32-0.82) were negatively associated with attempted IV therapy. Systolic blood pressure (SBP) <90 mmHg (OR 3.89, 95% CI 3.25-4.65) and respiratory rate >20 (OR 1.90, 95% CI 1.61-2.23) were positively associated with attempted IV therapy. Female sex (OR 0.72, 95% CI 0.59-0.88) and congestive heart failure (CHF) (OR 0.55, 95% CI 0.40-0.75) were negatively associated with receiving goal fluid volume while SBP <90 mmHg (OR 2.30, 95% CI 1.83-2.88) and abnormal temperature (>100.4 F or <96 F) (OR 1.41, 95% CI 1.16-1.73) were positively associated. CONCLUSIONS: Fewer than half of EMS sepsis patients had IV therapy attempted, and of those, approximately half met fluid volume goal, especially when hypotensive and no CHF. Further studies are needed on improving EMS sepsis training and prehospital fluid delivery.

Effectiveness of a Novel Rapid Infusion Device and Clinician Education for Early Fluid Therapy by Emergency Medical Services in Sepsis Patients: A Pre-Post Observational Study.

OBJECTIVE: Emergency medical services (EMS) clinicians are tasked with early fluid resuscitation for patients with sepsis. Traditional methods for prehospital fluid delivery are limited in speed and ease-of-use. We conducted a comparative effectiveness study of a novel rapid infusion device for prehospital fluid delivery in suspected sepsis patients. METHODS: This pre-post observational study evaluated a hand-operated, rapid infusion device in a single large EMS system from July 2021-July 2022. Prior to device deployment, EMS clinicians completed didactic and simulation-based device training. Data were extracted from the EMS electronic health record. Eligible patients included adults with suspected sepsis treated by EMS with intravenous fluids. The primary outcome was the proportion of patients receiving goal fluid volume (at least 500 mL) prior to hospital arrival. Secondary outcomes included in-hospital mortality, disposition, and length of stay. Multivariable logistic regression was used to compare outcomes between 6-month pre- and post-implementation periods (July-December 2021 and February-July 2022, respectively), adjusting for patient demographics, abnormal prehospital vital signs, and EMS transport interval. RESULTS: Of 1,180 eligible patients (552 in the pre-implementation period; 628 in the post-implementation period), the mean age was 72 years old, 45% were female, and 25% were minority race-ethnicity. Median (interquartile range) fluid volume (in mL) increased between the pre- and post-implementation periods (600 [400,1,000] and 850 [500-1,000], respectively). Goal fluid volume was achieved in 70% of pre-implementation patients and 82% of post-implementation patients. In adjusted analysis, post-implementation patients were significantly more likely to receive goal fluid volume than pre-implementation patients (adjusted odds ratio (aOR) 2.00, 95% confidence interval (CI) 1.51-2.66). Pre-post in-hospital mortality was not significantly different (aOR 0.91, 95% CI 0.59-1.39). CONCLUSION: In a single EMS system, sepsis education and introduction of a rapid infusion device was associated with achieving goal fluid volume for suspected sepsis. Further research is needed to assess the clinical effectiveness of infusion device implementation to improve sepsis patient outcomes.

Community socioeconomic and urban-rural differences in emergency medical services times for suspected stroke in North Carolina.

OBJECTIVE: Our objectives were to describe time intervals of EMS encounters for suspected stroke patients in North Carolina (NC) and evaluate differences in EMS time intervals by community socioeconomic status (SES) and rurality. METHODS: This cross-sectional study used statewide data on EMS encounters of suspected stroke in NC in 2019. Eligible patients were adults requiring EMS transport to a hospital following a 9-1-1 call for stroke-like symptoms. Incident street addresses were geocoded to census tracts and linked to American Community Survey SES data and to rural-urban commuting area (RUCA) codes. Community SES was defined as high, medium, or low based on tertiles of an SES index. Urban, suburban, and rural tracts were defined by RUCA codes 1, 2-6, and 7-10, respectively. Multivariable quantile regression was used to estimate how the median and 90th percentile of EMS time intervals varied by community SES and rurality, adjusting for each other; patient age, gender, and race/ethnicity; and incident characteristics. RESULTS: We identified 17,117 eligible EMS encounters of suspected stroke from 2028 census tracts. The population was 65% 65+ years old; 55% female; and 69% Non-Hispanic White. Median response, scene, and transport times were 8 (interquartile range, IQR 6-11) min, 16 (IQR 12-20) min, and 14 (IQR 9-22) minutes, respectively. In quantile regression adjusted for patient demographics, minimal differences were observed for median response and scene times by community SES and rurality. The largest median differences were observed for transport times in rural (6.7 min, 95% CI 5.8, 7.6) and suburban (4.7 min, 95% CI 4.2, 5.1) tracts compared to urban tracts. Adjusted rural-urban differences in 90th percentile transport times were substantially greater (16.0 min, 95% CI 14.5, 17.5). Low SES was modesty associated with shorter median (-3.3 min, 95% CI -3.8, -2.9) and 90th percentile (-3.0 min, 95% CI -4.0, -2.0) transport times compared to high SES tracts. CONCLUSIONS: While community-level factors were not strongly associated with EMS response and scene times for stroke, transport times were significantly longer rural tracts and modestly shorter in low SES tracts, accounting for patient demographics. Further research is needed on the role of community socioeconomic deprivation and rurality in contributing to delays in prehospital stroke care.

Community Socioeconomic and Urban-Rural Disparities in Prehospital Notification of Stroke by Emergency Medical Services in North Carolina.

OBJECTIVES: Notification by emergency medical services (EMS) to the destination hospital of an incoming suspected stroke patient is associated with timelier in-hospital evaluation and treatment. Current data on adherence to this evidence-based best practice are limited, however. We examined the frequency of EMS stroke prenotification in North Carolina by community socioeconomic status (SES) and rurality. METHODS: Using a statewide database of EMS patient care reports, we selected 9-1-1 responses in 2019 with an EMS provider impression of stroke or documented stroke care protocol use. Eligible patients were 18 years old and older with a completed prehospital stroke screen. Incident street addresses were geocoded to North Carolina census tracts and linked to American Community Survey socioeconomic data and urban-rural commuting area codes. High, medium, and low SES tracts were defined by SES index tertiles. Tracts were classified as urban, suburban, and rural. We used multivariable logistic regression to estimate independent associations between tract-level SES and rurality with EMS prenotification, adjusting for patient age, sex, and race/ethnicity; duration of symptoms; incident day of week and time of day; 9-1-1 dispatch complaint; EMS provider primary impression; and prehospital stroke screen interpretation. RESULTS: The cohort of 9527 eligible incidents was mostly at least 65 years old (65%), female (55%), and non-Hispanic White (71%). EMS prenotification occurred in 2783 (29%) patients. Prenotification in low SES tracts (27%) occurred less often than in medium (30%) and high (32%) SES tracts. Rural tracts had the lowest frequency (21%) compared with suburban (28%) and urban (31%) tracts. In adjusted analyses, EMS prenotification was less likely in low SES (vs high SES; odds ratio 0.76, 95% confidence interval 0.67-0.88) and rural (vs urban; odds ratio 0.64, 95% confidence interval 0.52-0.77) tracts. CONCLUSIONS: Across a large, diverse population, EMS prenotification occurred in only one-third of suspected stroke patients. Furthermore, low SES and rural tracts were independently associated with a lower likelihood of prehospital notification. These findings suggest the need for education and quality improvement initiatives to increase EMS stroke prenotification, particularly in underserved communities.

Thoracic surgery in patients on veno-venous extracorporeal membrane oxygenation for COVID-19 associated acute respiratory distress syndrome.

OBJECTIVES: The COVID-19 pandemic has generated a new type of acute respiratory distress syndrome (ARDS) arising as a complication of COVID-19 pneumonia. Extreme cases require the support of extracorporeal membrane oxygenation (ECMO). Here we present the outcomes of patients that underwent surgical tracheostomy or thoracic surgery at a single tertiary centre whilst on ECMO support for COVID-19 related ARDS. METHODS: 18 patients requiring thoracic input whilst on ECMO support during the first wave of COVID-19 (March-June 2020) were included. Thoracic surgery was required both for performing surgical tracheostomies in the operating theatre and for treating emergencies arising under the ECMO treatment such as bleeding complications. RESULTS: Thirteen patients underwent a surgical tracheostomy, whilst five patients had an invasive thoracic procedure. Anticoagulation was withheld for at least 12 h in the perioperative setting regardless of the indication. One patient was re-operated for haemothorax immediately after the end of the primary operation. 94.5% of the patients were successfully decannulated from ECMO support. Overall 30-day mortality in the cohort was 5.5% (1/18). CONCLUSIONS: Thoracic surgeons can play a valuable role in supporting an ECMO unit during the COVID pandemic, by treating ECMO related complications and by safely performing surgical tracheostomies. Withholding anticoagulation in the perioperative window was not associated with increased thromboembolic events and is desirable when interventions or surgery is indicated in this patient cohort to avoid excessive bleeding.

Statewide availability of acute stroke treatment, services, and programs: A survey of North Carolina Hospitals.

INTRODUCTION: We conducted a statewide assessment of the availability of stroke treatment, services, and programs in North Carolina (NC) hospitals. We also examined differences in stroke care capabilities between urban, suburban, and rural hospitals and trends over the past 2 decades. METHODS: An electronic survey was distributed to all 111 licensed hospitals in NC. Survey questions asked about stroke center certification status (i.e., standardized levels of stroke care capabilities), diagnostic testing, acute treatments and protocols, and post-acute management. Responses were collected from October 2020-April 2021. Select characteristics were compared to those from prior NC surveys in 1998, 2003, and 2008. RESULTS: All 111 hospitals responded to the survey (100% response rate). Among 108 hospitals providing acute stroke care, 12 (11%) were Comprehensive Stroke Centers or Thrombectomy-Capable Stroke Centers, which were all located in urban or suburban areas. While 38% of urban/suburban hospitals were non-certified, 48% of rural hospitals were non-certified. Non-contrast computed tomography (CT), CT angiography, and alteplase treatment were widely available (100%, 95%, and 99%, respectively). Endovascular thrombectomy was solely available in urban/suburban hospitals (29%). Of non-tertiary hospitals, 81% were using telestroke for treatment and transfer decisions. Compared to prior survey results, the availability of CT angiography (76% in 2008 to 95% in 2020-2021), alteplase treatment (69% in 2008 to 99% in 2020-2021), and acute stroke clinical pathways (47% in 2008 to 90% in 2020-2021) increased. However, having an in-house neurologist on staff dropped from approximately 55% in prior surveys to 21% in the current survey. CONCLUSIONS: Rural NC hospitals were less likely to have advanced diagnostic imaging and treatment capabilities for acute stroke. Temporal trends in staffing with an in-house neurologist and use of telestroke services should be further examined.

Testosterone Therapy is Associated With Depression, Suicidality, and Intentional Self-Harm: Analysis of a National Federated Database.

BACKGROUND: Long-term use of testosterone can be associated with mood destabilizing effects. Most studies investigating psychiatric complications of anabolic steroids have used small samples, but a comprehensive assessment of the risk of developing mental health disorders after testosterone use has not been performed at the population level. AIM: To determine whether testosterone therapy is associated with major depressive disorder or suicide attempts in men. METHODS: We conducted a retrospective cohort study of 70.3 million electronic health records collected from 46 healthcare organizations encompassing flagship hospitals, satellite hospitals, and outpatient clinics since 2008 to determine whether testosterone use is associated with major depressive disorder and suicide attempts in a large population. We included men 18 or older who either used testosterone or did not, defined by reported use, insurance claim, or prescription use of testosterone documented in the electronic health record. We propensity-score matched by age, race, ethnicity, obesity, and alcohol-related disorder. Additionally, a sub-group analysis was performed in testosterone deficient (<300 ng/dL) men comparing those with TD on testosterone therapy to a control group of men with TD who are not using testosterone. OUTCOMES: We determined measures of association with a new diagnosis of major depressive disorder and suicide attempt or intentional self-harm following testosterone use within 5 years. RESULTS: A total of 263,579 men who used testosterone and 17,838,316 men who did not were included in the analysis. Testosterone use was independently associated with both Major Depressive Disorder (OR 1.99, 95% CI 1.94-2.04, P < .0001) and Suicide Attempt/Intentional Self-Harm (OR 1.52, 95% CI 1.40-1.65, P < .0001). Results remained significant in testosterone deficient sub-group analysis. CLINICAL IMPLICATIONS: Men who use testosterone should be screened for and counseled about risks of depression and suicidality. STRENGTHS AND LIMITATIONS: Strengths of this study include a large sample size, the ability to account for chronology of diagnoses, the use of propensity score matching to control for potentially confounding variables, and the consistency of results with sub-group analyses. Limitations include the potential for incorrect coding within the electronic health record, a lack of granular information regarding testosterone therapy adherence, the possibility that unrecorded testosterone or anabolic steroid use were prevalent but not captured within the control group, and a lack of data regarding testosterone withdrawal. CONCLUSION: Testosterone use is independently associated with new-onset mental health disorders. Future studies are necessary to elucidate the role that androgen withdrawal plays and whether a causal relationship exists. Nackeeran S, Patel MS, Nallakumar DT, et al. Testosterone Therapy is Associated With Depression, Suicidality, and Intentional Self-Harm: Analysis of a National Federated Database. J Sex Med 2022;19:933-939.

A randomized controlled trial of glycopyrrolate administered by metered dose inhaler in patients with uncontrolled asthma despite ICS/LABA treatment.

OBJECTIVE: To evaluate the efficacy and safety of three doses of glycopyrrolate metered dose inhaler (GP MDI) in patients with uncontrolled asthma despite treatment with inhaled corticosteroid/long-acting ß2-agonists (ICS/LABA) with or without tiotropium, to characterize the benefit of triple therapy. METHOD: This phase II/III, double-blind study randomized patients to 24 weeks' treatment with twice-daily GP MDI 36 µg, 18 µg, 9 µg, or placebo MDI (all delivered via Aerosphere inhalers), or once-daily open-label tiotropium 2.5 µg. Patients continued their own ICS/LABA regimen throughout the study. The primary endpoint was change from baseline in forced expiratory volume in 1 s (FEV1) area under the curve from 0 - 4 h (AUC0 - 4) at Week 24. Secondary endpoints included patient questionnaires to measure asthma control or symptoms. Safety was also assessed. RESULTS: The primary analysis (modified intent-to-treat) population included 1066 patients. The primary study endpoint was not met (changes from baseline in FEV1 AUC0 - 4 at Week 24 were 294 mL, 284 mL, 308 mL, 240 mL, and 347 mL for GP MDI 36 µg, GP MDI 18 µg, GP MDI 9 µg, placebo, and open-label tiotropium, respectively). There were no significant differences between treatment and placebo in secondary endpoints at Week 24. Post-hoc analyses using post-bronchodilator FEV1 as the baseline measurement, or averaging values across multiple baseline visits, showed a dose-related response to GP MDI. The incidence of adverse events was low and similar across treatments. CONCLUSION: Although this study did not meet its primary endpoint, post hoc analyses identified a dose-related response to GP MDI when alternative definitions of baseline FEV1 were used in the analyses.

Probiotic Formulations: A Patent Landscaping Using the Text Mining Approach.

The outstanding research outcomes and registrations of myriads of probiotic strains have flooded the health market with various innovative probiotic-based products and their patents. The study of patented formulations of probiotics can give an overall insight into its existing application. A landscaping review of patents for probiotic-based preparations is presented in the current work. The patent search was performed over commercially available patent databased and analysis tool-PatSeer Pro®. Search strings containing words "Formulation" and "Composition" resulted in more than 3700 patents. Landscaping review of 400 + patents from the last 20 years (2000-2020) was performed using the Text-Mining approach. Text-Mining helped to identify 19 technological clusters which represent these patents. These clusters include the patents of probiotic preparations on animal feed, human food, cosmetics, antimicrobial, antidiabetic, arthritis, etc. A review of this massive number of patents unveiled many exciting preparations. Probiotic-based innovative products for depression, diabetes, Parkinson's, tumor, acne, and animal husbandry are reviewed comprehensively. The present work also unravels a few new-flanged products like probiotic layered condoms, products for acute alcoholism, and traditional Chinese medicine with probiotics. The patent landscape of probiotic-based preparations has presented a whole scenario of probiotic-based preparations. It has also revealed many unexplored areas where innovation can be excelled.

Birth Location in Infants with Prenatally Diagnosed Hypoplastic Left Heart Syndrome.

There are conflicting data on how delivery location impacts outcomes in neonates with ductal-dependent heart disease. Our goal was to evaluate the impact of delivery location on hospital length of stay and survival in infants with prenatally diagnosed hypoplastic left heart syndrome (HLHS) after stage 1 palliation (S1P). A multicenter cohort study was performed utilizing the National Pediatric Cardiology Quality Improvement Collaborative dataset for infants with prenatally diagnosed HLHS who underwent S1P from August 2016 to December 2018. Univariate comparisons of demographics, clinical, and outcome data were made and multivariable logistic regression was performed between groups stratified by distance from surgical center. A total of 790 patients from 33 centers were analyzed: 85% were born < 5 miles from the surgical center with 72% of those (486/673) born at the surgical center. Infants born < 5 miles from the surgical center were significantly (p < 0.05) more likely to be male, white, full term, have no non-cardiac anomaly, and have commercial health insurance; they were significantly more likely to breastfeed pre-operatively, and less likely to have pre-operative cardiac catheterizations, pre-operative mechanical ventilation, or delayed surgery. There was no significant difference between groups in hospital length of stay, 30-day survival, or survival to hospital discharge. In this multicenter dataset, hospital length of stay and survival after S1P did not differ based on distance from birth location to surgical center. However, neonates born < 5 miles from the surgical center had lower rates of potentially modifiable pre-operative risk factors including mechanical ventilation and delays to surgery.

Near-focus narrow-band imaging classification of villous atrophy in suspected celiac disease: development and international validation.

BACKGROUND AND AIMS: There are no agreed-on endoscopic signs for the diagnosis of villous atrophy (VA) in celiac disease (CD), necessitating biopsy sampling for diagnosis. Here we evaluated the role of near-focus narrow-band imaging (NF-NBI) for the assessment of villous architecture in suspected CD with the development and further validation of a novel NF-NBI classification. METHODS: Patients with a clinical indication for duodenal biopsy sampling were prospectively recruited. Six paired NF white-light endoscopy (NF-WLE) and NF-NBI images with matched duodenal biopsy sampling including the bulb were obtained from each patient. Histopathology grading used the Marsh-Oberhuber classification. A modified Delphi process was performed on 498 images and video recordings by 3 endoscopists to define NF-NBI classifiers, resulting in a 3-descriptor classification: villous shape, vascularity, and crypt phenotype. Thirteen blinded endoscopists (5 expert, 8 nonexpert) then undertook a short training module on the proposed classification and evaluated paired NF-WLE-NF-NBI images. RESULTS: One hundred consecutive patients were enrolled (97 completed the study; 66 women; mean age, 51.2 ± 17.3 years). Thirteen endoscopists evaluated 50 paired NF-WLE and NF-NBI images each (24 biopsy-proven VAs). Interobserver agreement among all validators for the diagnosis of villous morphology using the NF-NBI classification was substantial (κ = .71) and moderate (κ = .46) with NF-WLE. Substantial agreement was observed between all 3 NF-NBI classification descriptors and histology (weighted κ = 0.72-.75) compared with NF-WLE to histology (κ = .34). A higher degree of confidence using NF-NBI was observed when assessing the duodenal bulb. CONCLUSIONS: We developed and validated a novel NF-NBI classification to reliably diagnose VA in suspected CD. There was utility for expert and nonexpert endoscopists alike, using readily available equipment and requiring minimal training. (Clinical trial registration number: NCT04349904.).

Management of patients after failed peroral endoscopic myotomy: a multicenter study.

BACKGROUND: Although peroral endoscopic myotomy (POEM) is highly effective for the management of achalasia, clinical failures may occur. The optimal management of patients who fail POEM is not well known. This study aimed to compare the outcomes of different management strategies in patients who had failed POEM. METHODS: This was an international multicenter retrospective study at 16 tertiary centers between January 2012 and November 2019. All patients who underwent POEM and experienced persistent or recurrent symptoms (Eckardt score > 3) were included. The primary outcome was to compare the rates of clinical success (Eckardt score ≤ 3) between different management strategies. RESULTS : 99 patients (50 men [50.5 %]; mean age 51.4 [standard deviation (SD) 16.2]) experienced clinical failure during the study period, with a mean (SD) Eckardt score of 5.4 (0.3). A total of 29 patients (32.2 %) were managed conservatively and 70 (71 %) underwent retreatment (repeat POEM 33 [33 %], pneumatic dilation 30 [30 %], and laparoscopic Heller myotomy (LHM) 7 [7.1 %]). During a median follow-up of 10 (interquartile range 3 - 20) months, clinical success was highest in patients who underwent repeat POEM (25 /33 [76 %]; mean [SD] Eckardt score 2.1 [2.1]), followed by pneumatic dilation (18/30 [60 %]; Eckardt score 2.8 [2.3]), and LHM (2/7 [29 %]; Eckardt score 4 [1.8]; P = 0.12). A total of 11 patients in the conservative group (37.9 %; mean Eckardt score 4 [1.8]) achieved clinical success. CONCLUSION : This study comprehensively assessed an international cohort of patients who underwent management of failed POEM. Repeat POEM and pneumatic dilation achieved acceptable clinical success, with excellent safety profiles.

Myocardial involvement in children with post-COVID multisystem inflammatory syndrome: a cardiovascular magnetic resonance based multicenter international study-the CARDOVID registry.

BACKGROUND: Recent evidence shows an association between coronavirus disease 2019 (COVID-19) infection and a severe inflammatory syndrome in children. Cardiovascular magnetic resonance (CMR) data about myocardial injury in children are limited to small cohorts. The aim of this multicenter, international registry is to describe clinical and cardiac characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 using CMR so as to better understand the real extent of myocardial damage in this vulnerable cohort. METHODS AND RESULTS: Hundred-eleven patients meeting the World Health Organization criteria for MIS-C associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), having clinical cardiac involvement and having received CMR imaging scan were included from 17 centers. Median age at disease onset was 10.0 years (IQR 7.0-13.8). The majority of children had COVID-19 serology positive (98%) with 27% of children still having both, positive serology and polymerase chain reaction (PCR). CMR was performed at a median of 28 days (19-47) after onset of symptoms. Twenty out of 111 (18%) patients had CMR criteria for acute myocarditis (as defined by the Lake Louise Criteria) with 18/20 showing subepicardial late gadolinium enhancement (LGE). CMR myocarditis was significantly associated with New York Heart Association class IV (p = 0.005, OR 6.56 (95%-CI 1.87-23.00)) and the need for mechanical support (p = 0.039, OR 4.98 (95%-CI 1.18-21.02)). At discharge, 11/111 (10%) patients still had left ventricular systolic dysfunction. CONCLUSION: No CMR evidence of myocardial damage was found in most of our MIS-C cohort. Nevertheless, acute myocarditis is a possible manifestation of MIS-C associated with SARS-CoV-2 with CMR evidence of myocardial necrosis in 18% of our cohort. CMR may be an important diagnostic tool to identify a subset of patients at risk for cardiac sequelae and more prone to myocardial damage. CLINICAL TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov, Identifier NCT04455347, registered on 01/07/2020, retrospectively registered.