Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2-9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3',4'-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Tenecteplase versus alteplase for acute ischaemic stroke in the elderly patients: a post hoc analysis of the TRACE-2 trial.

BACKGROUND: The benefit-risk profile of tenecteplase in the elderly patients with acute ischaemic stroke (AIS) is uncertain. We sought to investigate the efficacy and safety of 0.25 mg/kg tenecteplase compared with alteplase for AIS patients aged ≥80 years. METHODS: We performed a post hoc analysis of the Tenecteplase Reperfusion Therapy in Acute Ischaemic Cerebrovascular Events-2 Trial, a randomised, phase 3, non-inferiority clinical trial. Disabling AIS patients aged ≥80 years who initiated intravenous thrombolytics within 4.5 hours of symptom onset were enrolled from June 2021 to May 2022 across 53 centres in China and were randomly allocated to receive 0.25 mg/kg tenecteplase or 0.9 mg/kg alteplase. The primary efficacy outcome was the proportion of participants with a modified Rankin Scale (mRS) score of 0-1 at 90 days. Symptomatic intracranial haemorrhage (sICH) within 36 hours was the safety outcome. RESULTS: Of 137 participants, mRS 0-1 at 90 days occurred in 37 (49.3%) of 75 in the tenecteplase group vs 20 (33.9%) of 59 in the alteplase group (risk ratio (RR) 1.47, 95% CI 0.96 to 2.23). sICH within 36 hours was observed in 3 (4.0%) of 76 in the tenecteplase group and two (3.3%) of 61 in the alteplase group (RR 1.30, 95% CI 0.20 to 8.41). CONCLUSIONS: The risk-benefit profile of tenecteplase thrombolysis was preserved in the elderly patients, which lends further support to intravenous 0.25 mg/kg tenecteplase as an alternative to alteplase in these patients.

Sex differences in the global burden of multidrug- resistant tuberculosis without extensive drug resistance in the general population and people living with HIV/AIDS, 1990-2019.

OBJECTIVE: Currently, human immunodeficiency virus (HIV) and multi-drug resistant tuberculosis (MDR-TB) without extensive drug resistance (XDR) are significant challenges in terms of the global burden of disease. This study aimed to evaluate the trends of the global burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR, focusing on differences in socioeconomic status and sex for 204 countries and territories across periods from 1990 to 2019. MATERIALS AND METHODS: Data from the Global Burden of Disease (GBD) 2019 study were obtained to construct a separate index measuring the burden of MDR-TB without XDR and HIV/AIDS-MDR-TB without XDR. Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated for each case and group. A population-attributable fraction approach was used to assess mortality and incidence of HIV/AIDS and MDR-TB coinfection. 95% uncertainty intervals (UIs) were presented for all measures. RESULTS: Our global estimates suggest that there were approximately 450,000 (95% UI 247,000-785,000) incident cases of MDR-TB without XDR and 109,000 (43,000-210,000) deaths caused by MDR-TB without XDR among individuals who were HIV-negative in 2019. For HIV-positive individuals, the corresponding figures were approximately 47,000 (33,000-67,000) incident cases of MDR-TB and 19,000 (8,000-36,000) deaths due to MDR-TB in the same year. In 2019, higher numbers of incident cases and deaths were observed in males compared to females among individuals who were HIV-negative. Conversely, for HIV-positive individuals, females had higher numbers of incident cases and deaths compared to males. Specifically, the estimated numbers for incident cases were 23,000 (15,000-33,000) for females and 24,000 (17,000-35,000) for males, while the estimated numbers for deaths were 9,600 (4,000-17,900) for females and 9,800 (4,100-18,500) for males. Male-to-female ratios have remained above 1.0 from 1990 to 2019 in both incident cases and number of deaths for HIV-negative individuals. However, for HIV and MDR-TB coinfection, both ratios were below 1.0 in most of the time series. CONCLUSIONS: Males had more cases and deaths due to MDR-TB without XDR than females in HIV-negative patients, while females faced a higher incidence and mortality in HIV/AIDS-MDR-TB without XDR. Interventions are needed to deal with such factors, which increase the burden of coinfection among females across the world.

Impact of discontinuation of contact precautions on surveillance- and whole genome sequencing-defined methicillin-resistant Staphylococcus aureus healthcare-associated infections.

Objective: Prior studies evaluating the impact of discontinuation of contact precautions (DcCP) on methicillin-resistant Staphylococcus aureus (MRSA) outcomes have characterized all healthcare-associated infections (HAIs) rather than those likely preventable by contact precautions. We aimed to analyze the impact of DcCP on the rate of MRSA HAI including transmission events identified through whole genome sequencing (WGS) surveillance. Design: Quasi experimental interrupted time series. Setting: Acute care medical center. Participants: Inpatients. Methods: The effect of DcCP (use of gowns and gloves) for encounters among patients with MRSA carriage was evaluated using time series analysis of MRSA HAI rates from January 2019 through December 2022, compared to WGS-defined attributable transmission events before and after DcCP in December 2020. Results: The MRSA HAI rate was 4.22/10,000 patient days before and 2.98/10,000 patient days after DcCP (incidence rate ratio [IRR] 0.71 [95% confidence interval 0.56-0.89]) with a significant immediate decrease (P = .001). There were 7 WGS-defined attributable transmission events before and 11 events after DcCP (incident rate ratio 0.90 [95% confidence interval 0.30-2.55]). Conclusions: DcCP did not result in an increase in MRSA HAI or, in WGS-defined attributable transmission events. Comprehensive analyses of the effect of transmission prevention measures should include outcomes specifically measuring transmission-associated HAI.

Changes in the cost-effectiveness of pneumococcal vaccination and of programs to increase its uptake in U.S. older adults.

BACKGROUND: Multiple factors, such as less complex U.S. adult pneumococcal recommendations that could increase vaccination rates, childhood pneumococcal vaccination indirect effects that decrease adult vaccination impact, and increased vaccine hesitancy (particularly in underserved minorities), could diminish the cost-effectiveness of programs to increase pneumococcal vaccination in older adults. Prior analyses supported the economic favorability of these programs. METHODS: A Markov model compared no vaccination and current recommendations (either 20-valent pneumococcal conjugate vaccine [PCV20] alone or 15-valent pneumococcal conjugate vaccine plus the 23-valent pneumococcal polysaccharide vaccine [PCV15/PPSV23]) without or with programs to increase vaccine uptake in Black and non-Black 65-year-old cohorts. Pre-pandemic population- and serotype-specific pneumococcal disease risk and illness/vaccine costs came from U.S. DATABASES: Program costs were $2.19 per vaccine-eligible person and increased absolute vaccination likelihood by 7.5%. Delphi panel estimates and trial data informed vaccine effectiveness values. Analyses took a healthcare perspective, discounting at 3%/year over a lifetime time horizon. RESULTS: Uptake programs decreased pneumococcal disease overall. In Black cohorts, PCV20 without program cost $216,805 per quality-adjusted life year (QALY) gained compared with no vaccination; incremental cost-effectiveness was $245,546/QALY for PCV20 with program and $425,264/QALY for PCV15/PPSV23 with program. In non-Black cohorts, all strategies cost >$200,000/QALY gained. When considering the potential indirect effects from childhood vaccination, all strategies became less economically attractive. Increased vaccination with less complex strategies had negligible effects. In probabilistic sensitivity analyses, current recommendations with or without programs were unlikely to be favored at thresholds <$200,000/QALY gained. CONCLUSION: Current U.S. pneumococcal vaccination recommendations for older adults were unlikely to be economically reasonable with or without programs to increase vaccine uptake. Alternatives to current pneumococcal vaccines that include pneumococcal serotypes associated with adult disease should be considered.

Optimizing Identification of Allergic Sensitization to Seasonal Inhalant Allergens in the USA: Implications for Constructing Optimal Panels to Evaluate Patients with Allergy.

INTRODUCTION: While a specific number and type of antigens are recognized to detect perennial inhalant allergies, the optimal number and combination of allergens to reliably identify seasonal allergic sensitization is unclear due to limited national data. This study analyzed aeroallergen testing data from a large US clinical reference laboratory to provide guidance for optimizing seasonal allergen test selection. METHODS: The 2019 serum IgE tests for seasonal inhalant allergens were identified from the Quest Diagnostics database. Patients with results for at least 1 of 31 seasonal allergens across 4 allergen classes (11 trees, 7 weeds, 5 grasses, and 8 molds) were analyzed. A step-by-step conditional approach was employed to determine the minimum number and species of allergens needed to identify at least 98% of sensitized patients for each class. RESULTS: Of 88,042 patients tested for ≥1 seasonal allergen, 1.5%, 1.8%, 1.3%, and 1.6% were tested for all trees, weeds, grasses, and molds, respectively. Of those tested for all allergens within a class, 40.4%, 38.6%, 29.5%, and 21.2% were sensitized to at least one tree, weed, grass, or mold allergen, respectively. Identification of ≥98% of sensitized patients within a class required 8 allergens for trees (mountain cedar, maple box elder, walnut, white ash, elm, birch, cottonwood, and hickory/pecan), 5 for weeds (common ragweed short, rough pigweed, English plantain, lamb's quarters/goosefoot, and Russian thistle), 3 for grasses (June/Kentucky blue grass, Johnson grass, and Bermuda grass), and 7 for molds (Alternaria alternata, Aspergillus fumigatus, Mucor racemosus, Epicoccum purpurascens, Penicillium notatum, Helminthosporium halodes, and Fusarium moniliforme). CONCLUSION: A minimum of 23 antigens is required to optimally detect sensitization to four classes of seasonal allergens (i.e., ≥98% identification). The addition of these allergens to unique perennial allergens (cat, dog, mouse, cockroach, and 2 dust mite species) results in a comprehensive elucidation of inhalant allergen sensitization. This knowledge provides a pivotal guide for clinical laboratories as they construct allergen panels to optimize diagnostic yield.

Three-Dimensional Computed Tomography Image Reformation for Comparison of Foraminal Cross-Sectional Dimension in Patients Who Have Undergone Laminoplasty and Laminectomy with Fusion.

PURPOSE OF THE STUDY: Laminectomy with fusion (LF) is commonly performed with laminoplasty (LP) for cervical myelopathy. Foraminal stenosis is important in the surgical treatment of cervical myelopathy. LF and LP can affect foraminal size in different ways. This study aimed to compare foraminal dimensions after LF and LP using a medical computer-assisted design (CAD) program. MATERIAL AND METHODS: Computed tomography (CT) scans of the cervical vertebrae of 16 patients with cervical myelopathy were retrospectively viewed in the Digital Imaging and Communications in Medicine format on a CAD program. CT images were reformatted in an oblique plane perpendicular to the long axis of each foramen from C2-C3 to C6-C7. The narrowest foraminal crosssectional dimension (FCD) was measured and compared between the LF and LP groups at the operated, non-operated, and C4-C5 levels. The difference between the preoperative and postoperative FCDs was also calculated and compared between the operated and C4-C5 levels. Intra- and interobserver reliabilities for FCD measurements were evaluated using intraclass correlation coefficients. RESULTS AND DISCUSSION: At the operated spinal levels, the LF and LP groups showed decreased and increased mean FCDs, respectively. At the adjacent non-operated levels, the mean FCD slightly increased in both the groups. In the LF group, the difference between the preoperative and postoperative FCDs in the C4-C5 levels was larger than that in the other operated levels, but this difference was insignificant. CONCLUSIONS: LF and LP showed contrary results for FCD. Therefore, FCD and kyphosis should be considered for LF and LP. KEY WORDS: three-dimensional, foraminal cross-sectional dimension, laminoplasty, laminectomy fusion, computer-aided design, drafting system, preoperative-postoperative comparison.

Loss of spontaneous vasomotion precedes impaired cerebrovascular reactivity and microbleeds in a mouse model of cerebral amyloid angiopathy.

Background: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease in which amyloid-ß accumulates in vessel walls. CAA is a leading cause of symptomatic lobar intracerebral hemorrhage and an important contributor to age-related cognitive decline. Recent work has suggested that vascular dysfunction may precede symptomatic stages of CAA, and that spontaneous slow oscillations in arteriolar diameter (termed vasomotion), important for amyloid-ß clearance, may be impaired in CAA. Methods: To systematically study the progression of vascular dysfunction in CAA, we used the APP23 mouse model of amyloidosis, which is known to develop spontaneous cerebral microbleeds mimicking human CAA. Using in vivo 2-photon microscopy, we longitudinally imaged unanesthetized APP23 transgenic mice and wildtype littermates from 7 to 14 months of age, tracking amyloid-ß accumulation and vasomotion in individual pial arterioles over time. MRI was used in separate groups of 12-, 18-, and 24-month-old APP23 transgenic mice and wildtype littermates to detect microbleeds and to assess cerebral blood flow and cerebrovascular reactivity with pseudo-continuous arterial spin labeling. Results: We observed a significant decline in vasomotion with age in APP23 mice, while vasomotion remained unchanged in wildtype mice with age. This decline corresponded in timing to initial vascular amyloid-ß deposition (∼8-10 months of age), although was more strongly correlated with age than with vascular amyloid-ß burden in individual arterioles. Declines in vasomotion preceded the development of MRI-visible microbleeds and the loss of smooth muscle actin in arterioles, both of which were observed in APP23 mice by 18 months of age. Additionally, evoked cerebrovascular reactivity was intact in APP23 mice at 12 months of age, but significantly lower in APP23 mice by 24 months of age. Conclusions: Our findings suggest that a decline in spontaneous vasomotion is an early, potentially pre-symptomatic, manifestation of CAA and vascular dysfunction, and a possible future treatment target.

Mental health sequelae in survivors of cardiogenic shock complicating myocardial infarction. A population-based cohort study.

PURPOSE: Cardiogenic shock secondary to acute myocardial infarction (AMI-CS) is associated with substantial short- and long-term morbidity and mortality. However, there are limited data on mental health sequelae that survivors experience following discharge. METHODS: We conducted a retrospective, population-based cohort study in Ontario, Canada of critically ill adult (≥ 18 years) survivors of AMI-CS, admitted to hospital between April 1, 2009 and March 31, 2019. We compared these patients to AMI survivors without shock. We captured outcome data using linked health administrative databases. The primary outcome was a new mental health diagnosis (a composite of mood, anxiety, or related disorders; schizophrenia/psychotic disorders; and other mental health disorders) following hospital discharge. We secondarily evaluated incidence of deliberate self-harm and death by suicide. We compared patients using overlap propensity score-weighted, cause-specific proportional hazard models. RESULTS: We included 7812 consecutive survivors of AMI-CS, from 135 centers. Mean age was 68.4 (standard deviation (SD) 12.2) years, and 70.3% were male. Median follow-up time was 767 days (interquartile range (IQR) 225-1682). Incidence of new mental health diagnosis among AMI-CS survivors was 109.6 per 1,000 person-years (95% confidence interval (CI) 105.4-113.9), compared with 103.8 per 1000 person-years (95% CI 102.5-105.2) among AMI survivors without shock. After propensity score adjustment, there was no difference in the risk of new mental health diagnoses following discharge [hazard ratio (HR) 0.99 (95% CI 0.94-1.03)]. Factors associated with new mental health diagnoses following AMI-CS included female sex, pre-existing mental health diagnoses, and discharge to a long-term hospital or rehabilitation institute. CONCLUSION: Survivors of AMI-CS experience substantial mental health morbidity following discharge. Risk of new mental health diagnoses was comparable between survivors of AMI with and without shock. Future research on interventions to mitigate psychiatric sequelae after AMI-CS is warranted.

StrokeClassifier: ischemic stroke etiology classification by ensemble consensus modeling using electronic health records.

Determining acute ischemic stroke (AIS) etiology is fundamental to secondary stroke prevention efforts but can be diagnostically challenging. We trained and validated an automated classification tool, StrokeClassifier, using electronic health record (EHR) text from 2039 non-cryptogenic AIS patients at 2 academic hospitals to predict the 4-level outcome of stroke etiology adjudicated by agreement of at least 2 board-certified vascular neurologists' review of the EHR. StrokeClassifier is an ensemble consensus meta-model of 9 machine learning classifiers applied to features extracted from discharge summary texts by natural language processing. StrokeClassifier was externally validated in 406 discharge summaries from the MIMIC-III dataset reviewed by a vascular neurologist to ascertain stroke etiology. Compared with vascular neurologists' diagnoses, StrokeClassifier achieved the mean cross-validated accuracy of 0.74 and weighted F1 of 0.74 for multi-class classification. In MIMIC-III, its accuracy and weighted F1 were 0.70 and 0.71, respectively. In binary classification, the two metrics ranged from 0.77 to 0.96. The top 5 features contributing to stroke etiology prediction were atrial fibrillation, age, middle cerebral artery occlusion, internal carotid artery occlusion, and frontal stroke location. We designed a certainty heuristic to grade the confidence of StrokeClassifier's diagnosis as non-cryptogenic by the degree of consensus among the 9 classifiers and applied it to 788 cryptogenic patients, reducing cryptogenic diagnoses from 25.2% to 7.2%. StrokeClassifier is a validated artificial intelligence tool that rivals the performance of vascular neurologists in classifying ischemic stroke etiology. With further training, StrokeClassifier may have downstream applications including its use as a clinical decision support system.

Influence of Obstructive Sleep Apnea on the Risk of Dental Caries: Insights from a 13-Year Population-Based Retrospective Study.

KNOWLEDGE TRANSFER STATEMENT: Obstructive sleep apnea has been proven to have a great negative impact on patients, and the relationship between sleep apnea and dental caries is still inconclusive. Our study shows that patients with sleep apnea and those older than 45 y have a significant risk of dental caries.

Genomic sequencing surveillance of patients colonized with vancomycin-resistant Enterococcus (VRE) improves detection of hospital-associated transmission.

Background: Vancomycin-resistant enterococcal (VRE) infections pose significant challenges in healthcare. Transmission dynamics of VRE are complex, often involving patient colonization and subsequent transmission through various healthcare-associated vectors. We utilized a whole genome sequencing (WGS) surveillance program at our institution to better understand the contribution of clinical and colonizing isolates to VRE transmission. Methods: We performed whole genome sequencing on 352 VRE clinical isolates collected over 34 months and 891 rectal screening isolates collected over a 9-month nested period, and used single nucleotide polymorphisms to assess relatedness. We then performed a geo-temporal transmission analysis considering both clinical and rectal screening isolates compared with clinical isolates alone, and calculated 30-day outcomes of patients. Results: VRE rectal carriage constituted 87.3% of VRE acquisition, with an average monthly acquisition rate of 7.6 per 1000 patient days. We identified 185 genetically related clusters containing 2-42 isolates and encompassing 69.6% of all isolates in the dataset. The inclusion of rectal swab isolates increased the detection of clinical isolate clusters (from 53% to 67%, P<0.01). Geo-temporal analysis identified hotspot locations of VRE transmission. Patients with clinical VRE isolates that were closely related to previously sampled rectal swab isolates experienced 30-day ICU admission (17.5%), hospital readmission (9.2%), and death (13.3%). Conclusions: Our findings describe the high burden of VRE transmission at our hospital and shed light on the importance of using WGS surveillance of both clinical and rectal screening isolates to better understand the transmission of this pathogen. This study highlights the potential utility of incorporating WGS surveillance of VRE into routine hospital practice for improving infection prevention and patient safety.

Contemporary Prestroke Dual Antiplatelet Use and Symptomatic Intracerebral Hemorrhage Risk After Thrombolysis.

Importance: Intravenous alteplase (IV-tPA) can be administered to patients with acute ischemic stroke but is associated with symptomatic intracerebral hemorrhage (sICH). It is unclear if patients taking prestroke dual antiplatelet therapy (DAPT) are at higher risk of sICH. Objective: To determine the associated risk of sICH in patients taking prestroke dual antiplatelet therapy receiving alteplase for acute ischemic stroke using propensity score matching analysis. Design, Setting, and Participants: This cohort study used data from the American Heart Association and American Stroke Association Get With The Guidelines-Stroke (GWTG-Stroke) registry between 2013 and 2021. Data were obtained from hospitals in the GWTG-Stroke registry. This study included patients hospitalized with acute ischemic stroke and treated with IV-tPA. Data were analyzed from January 2013 to December 2021. Exposures: Prestroke DAPT before treatment with IV-tPA for acute ischemic stroke. Main Outcome Measures: sICH, In-hospital death, discharge modified Rankin scale score, and other life-threatening systemic hemorrhages. Results: Of 409 673 participants, 321 819 patients (mean [SD] age, 68.6 [15.1] years; 164 587 female [51.1%]) who were hospitalized with acute ischemic stroke and treated with IV-tPA were included in the analysis. The rate of sICH was 2.9% (5200 of 182 344), 3.8% (4457 of 117 670), and 4.1% (893 of 21 805) among patients treated with no antiplatelet therapy, single antiplatelet therapy (SAPT), and DAPT, respectively (P < .001). In adjusted analyses after propensity score subclassification, both SAPT (odds ratio [OR], 1.13; 95% CI, 1.07-1.19) and DAPT (OR, 1.28; 95% CI, 1.14-1.42) were associated with increased risks of sICH. Prestroke antiplatelet medications were associated with lower odds of discharge mRS score of 2 or less compared with no medication (SAPT OR, 0.92; 95% CI, 0.90-0.95; DAPT OR, 0.94; 95% CI, 0.88-0.98). Results of a subgroup analysis of patients taking DAPT exposed to aspirin-clopidogrel vs aspirin-ticagrelor combination therapy were not significant (OR, 1.35; 95% CI, 0.84-1.86). Conclusions and Relevance: Prestroke DAPT was associated with a significantly elevated risk of sICH among patients with ischemic stroke who were treated with thrombolysis; however, the absolute increase in risk was small. Patients exposed to antiplatelet medications did not have excess sICH compared with landmark trials, which demonstrated overall clinical benefit of thrombolysis therapy for acute ischemic stroke.

Twenty Years of Get With The Guidelines-Stroke: Celebrating Past Successes, Lessons Learned, and Future Challenges.

The Get With The Guidelines-Stroke program which, began 20 years ago, is one of the largest and most important nationally representative disease registries in the United States. Its importance to the stroke community can be gauged by its sustained growth and widespread dissemination of findings that demonstrate sustained increases in both the quality of care and patient outcomes over time. The objectives of this narrative review are to provide a brief history of Get With The Guidelines-Stroke, summarize its major successes and impact, and highlight lessons learned. Looking to the next 20 years, we discuss potential challenges and opportunities for the program.

Mapping the Ecological Terrain of Stroke Prehospital Delay: A Nationwide Registry Study.

BACKGROUND: Delays in hospital presentation limit access to acute stroke treatments. While prior research has focused on patient-level factors, broader ecological and social determinants have not been well studied. We aimed to create a geospatial map of prehospital delay and examine the role of community-level social vulnerability. METHODS: We studied patients with ischemic stroke who arrived by emergency medical services in 2015 to 2017 from the American Heart Association Get With The Guidelines-Stroke registry. The primary outcome was time to hospital arrival after stroke (in minutes), beginning at last known well in most cases. Using Geographic Information System mapping, we displayed the geography of delay. We then used Cox proportional hazard models to study the relationship between community-level factors and arrival time (adjusted hazard ratios [aHR] <1.0 indicate delay). The primary exposure was the social vulnerability index (SVI), a metric of social vulnerability for every ZIP Code Tabulation Area ranging from 0.0 to 1.0. RESULTS: Of 750 336 patients, 149 145 met inclusion criteria. The mean age was 73 years, and 51% were female. The median time to hospital arrival was 140 minutes (Q1: 60 minutes, Q3: 458 minutes). The geospatial map revealed that many zones of delay overlapped with socially vulnerable areas (https://harvard-cga.maps.arcgis.com/apps/webappviewer/index.html?id=08f6e885c71b457f83cefc71013bcaa7). Cox models (aHR, 95% CI) confirmed that higher SVI, including quartiles 3 (aHR, 0.96 [95% CI, 0.93-0.98]) and 4 (aHR, 0.93 [95% CI, 0.91-0.95]), was associated with delay. Patients from SVI quartile 4 neighborhoods arrived 15.6 minutes [15-16.2] slower than patients from SVI quartile 1. Specific SVI themes associated with delay were a community's socioeconomic status (aHR, 0.80 [95% CI, 0.74-0.85]) and housing type and transportation (aHR, 0.89 [95% CI, 0.84-0.94]). CONCLUSIONS: This map of acute stroke presentation times shows areas with a high incidence of delay. Increased social vulnerability characterizes these areas. Such places should be systematically targeted to improve population-level stroke presentation times.

Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease among children in the United States between 2010 and 2019: An indirect cohort study.

BACKGROUND: A U.S. case-control study (2010-2014) demonstrated vaccine effectiveness (VE) for ≥ 1 dose of the thirteen-valent pneumococcal conjugate vaccine (PCV13) against vaccine-type (VT) invasive pneumococcal disease (IPD) at 86 %; however, it lacked statistical power to examine VE by number of doses and against individual serotypes. METHODS: We used the indirect cohort method to estimate PCV13 VE against VT-IPD among children aged < 5 years in the United States from May 1, 2010 through December 31, 2019 using cases from CDC's Active Bacterial Core surveillance, including cases enrolled in a matched case-control study (2010-2014). Cases and controls were defined as individuals with VT-IPD and non-PCV13-type-IPD (NVT-IPD), respectively. We estimated absolute VE using the adjusted odds ratio of prior PCV13 receipt (1-aOR x 100 %). RESULTS: Among 1,161 IPD cases, 223 (19.2 %) were VT cases and 938 (80.8 %) were NVT controls. Of those, 108 cases (48.4 %; 108/223) and 600 controls (64.0 %; 600/938) had received > 3 PCV13 doses; 23 cases (17.6 %) and 15 controls (2.4 %) had received no PCV doses. VE ≥ 3 PCV13 doses against VT-IPD was 90.2 % (95 % Confidence Interval75.4-96.1 %), respectively. Among the most commonly circulating VT-IPD serotypes, VE of ≥ 3 PCV13 doses was 86.8 % (73.7-93.3 %), 50.2 % (28.4-80.5 %), and 93.8 % (69.8-98.8 %) against serotypes 19A, 3, and 19F, respectively. CONCLUSIONS: At least three doses of PCV13 continue to be effective in preventing VT-IPD among children aged < 5 years in the US. PCV13 was protective against serotypes 19A and 19F IPD; protection against serotype 3 IPD did not reach statistical significance.

Non-cardiac comorbid health outcomes and prevalence after myocardial infarction: an umbrella review.

OBJECTIVE: There exists limited comprehensive evidence on the potential association between non-cardiac comorbidities and myocardial infarction (MI). Thus, we conducted an umbrella review of existing meta-analyses to provide a broad understanding of non-cardiac health outcomes associated with MI. MATERIALS AND METHODS: The primary focus on the prevalence of related health outcomes in patients with MI was systemically searched. Each original meta-analysis that was included had its methodological quality evaluated by a Measurement Tool Assessment Systematic Reviews 2 (AMSTAR2). To evaluate the certainty in the evidence for each outcome, we employed GRADE and the Joanna Briggs Institute Prevalence Critical Appraisal Tool. The protocol was registered in PROSPERO (CRD42023458642). RESULTS: We identified seven meta-analyses comprising 126 studies with 336,581 participants from 22 countries and five continents. The pooled prevalence of comorbidities in patients with MI was 39% anxiety [95% confidence interval (CI), 30-48; GRADE, very low certainty], 29% depression (95% CI, 23-36; very low certainty), 39% frailty (95% CI, 24-55; very low certainty), and 23% failure of returning to work (95% CI, 16-29; very low certainty). The diagnosis of MI was associated with an increased risk of cognitive impairment (odds ratio, 1.45; 95% CI, 1.10-1.92; moderate certainty). Among frail patients, MI was associated with an increased risk of major bleeding (relative risk, 1.93; 95% CI, 1.08-3.45; low certainty) and mortality (relative risk, 2.29; 95% CI, 1.48-3.53; moderate certainty). However, we did not find any evidence of cancer risk associated with the development of MI. CONCLUSIONS: Our umbrella meta-analysis provided comprehensive evidence of the association between MI and several non-cardiac health conditions. The robustness of our study is attributed to the integration of evidence across several studies, thus, these insights offer valuable treatment options for policymakers and physicians to develop personalized health strategies.

Y chromosome damage underlies testicular abnormalities in ATR-X syndrome.

ATR-X (alpha thalassemia, mental retardation, X-linked) syndrome features genital and testicular abnormalities including atypical genitalia and small testes with few seminiferous tubules. Our mouse model recapitulated the testicular defects when Atrx was deleted in Sertoli cells (ScAtrxKO) which displayed G2/M arrest and apoptosis. Here, we investigated the mechanisms underlying these defects. In control mice, Sertoli cells contain a single novel "GATA4 PML nuclear body (NB)" that contained the transcription factor GATA4, ATRX, DAXX, HP1α, and PH3 and co-localized with the Y chromosome short arm (Yp). ScAtrxKO mice contain single giant GATA4 PML-NBs with frequent DNA double-strand breaks (DSBs) in G2/M-arrested apoptotic Sertoli cells. HP1α and PH3 were absent from giant GATA4 PML-NBs indicating a failure in heterochromatin formation and chromosome condensation. Our data suggest that ATRX protects a Yp region from DNA damage, thereby preventing Sertoli cell death. We discuss Y chromosome damage/decondensation as a mechanism for testicular failure.

Assisted reproductive techniques and subsequent risk of asthma and allergic rhinitis in offspring: a nationwide birth cohort study in South Korea.

OBJECTIVE: The relationship between assisted reproductive techniques (ART) and the risk of asthma and allergic rhinitis (AR) is controversial. Thus, we aimed to investigate the relationship between ART and the risk of asthma and AR in a nationwide, large-scale birth cohort. PATIENTS AND METHODS: This study utilized the National Health Insurance Service data in South Korea to conduct a nationwide, large-scale, population-based birth cohort. We included all infants born between 2017 and 2018. AR, asthma, food allergies, and atopic dermatitis were defined using the International Classification of Diseases tenth edition codes. Asthma was classified as allergic or non-allergic based on accompanying allergic diseases (AR, food allergy, or atopic dermatitis). Using 1:10 propensity score matching, we compared infants conceived through ART with those conceived naturally (non-ART). After matching, logistic regression was used to compare the hazard ratio for asthma and AR between the two groups. RESULTS: We included 543,178 infants [male infants, 280,194 (51.38%)]. After matching, 8,925 and 74,229 infants were selected for the ART and non-ART groups, respectively. The ART group showed a decreased risk of asthma in the offspring [adjusted hazard ratio (aHR), 0.45; 95% confidence interval (CI), 0.41-0.48]. Similarly, for AR, being conceived by ART was associated with a decreased risk of AR (aHR, 0.25; 95% CI, 0.12-0.37). ART offspring showed a decreased risk of asthma and AR in offspring compared to that observed in non-ART offspring. CONCLUSIONS: Our study offers important insights for clinicians, researchers, and parents regarding the health outcomes of ART-conceived infants and enhances our understanding of ART's impact on respiratory health.

Global health impacts of ambient fine particulate pollution associated with climate variability.

Air pollution is a key global environmental problem raising human health concern. It is essential to comprehensively assess the long-term characteristics of air pollution and the resultant health impacts. We first assessed the global trends of fine particulate matter (PM2.5) during 1980-2020 using a monthly global PM2.5 reanalysis dataset, and evaluated their association with three types of climate variability including El Niño-Southern Oscillation, Indian Ocean Dipole and North Atlantic Oscillation. We then estimated PM2.5-attributable premature deaths using integrated exposure-response functions. Results show a significant increasing trend of ambient PM2.5 during 1980-2020 due to increases in anthropogenic emissions. Ambient PM2.5 caused a total of âˆ¼ 135 million premature deaths globally during the four decades. Occurrence of air pollution episodes was strongly associated with climate variability, which were associated with up to 14 % increase in annual global PM2.5-attributable premature deaths.