Examination of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation in former elite American football players.

INTRODUCTION: Blood-based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players. METHODS: The sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45-74). Plasma assays were conducted for beta-amyloid (Aß) 40, Aß42, hyper-phosphorylated tau (p-tau) 181+231, total tau (t-tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), Aß42/p-tau181 and Aß42/Aß40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES). RESULTS: P-tau181 and p-tau231(padj = 0.016) were higher and Aß42/p-tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p-tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD-related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES-chronic traumatic encephalopathy (TES-CTE) Possible/Probable (padj = 0.008). DISCUSSION: Plasma p-tau181 and p-tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI-related neuropathologies. HIGHLIGHTS: Former football players had higher plasma p-tau181 and p-tau231 and lower Aß42/ptau-181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES-CTE possible/probable compared to TES-CTE no/suggestive.

Physical activity, metabolites, and breast cancer associations.

BACKGROUND: The effects of usual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites, and breast cancer risk. METHODS: Physical activity levels were assessed using doubly labeled water, accelerometers, and 24-hr recalls in the IDATA study (N = 707 participants, ages 50-74 years, 51% women), with 1-6 assessments over 12 months and two blood sample collections. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of metabolites with postmenopausal breast cancer in a nested case-control study (621 cases, 621 controls), all statistical tests were 2-sided. RESULTS: Physical activity was associated with 164 metabolites spanning numerous pathways, including amino acid and fatty acid metabolism. Twelve of these metabolites were also associated with breast cancer risk, ten of which supported a protective role of physical activity. Notably, higher physical activity was associated with lower 16alpha-hydroxy DHEA 3-sulfate (androgen) and adipoylcarnitine (fatty acid), both of which were associated with increased breast cancer risk (OR per 1 standard deviation (SD)=1.34, 95% CI = 1.16-1.55 and 1.26,1.11-1.42, respectively). Higher physical activity energy expenditure was also associated with lower sphingomyelin (d18:1/20:1, d18:2/20:0), which was associated with a reduced breast cancer risk (0.82,0.73-0.93). CONCLUSION: Physical activity is associated with a broad range of metabolites, many of which are consistent with a protective effect against breast cancer. Our findings highlight potential metabolic pathways for cancer prevention.

Increased Stillbirth Rates and Exposure to Environmental Risk Factors for Stillbirth in Counties with Higher Social Vulnerability: United States, 2015-2018.

INTRODUCTION: Exposure to unfavorable environmental conditions during pregnancy, such as extreme heat and air pollution, has been linked to increased risk of stillbirth, defined as fetal mortality at or after 20 weeks' gestation, however no studies have examined its association with social vulnerability. We examined associations between county-level stillbirth rates, environmental risk factors for stillbirth, and social vulnerability in the United States. METHODS: This ecologic study linked county-level data from three nationwide datasets on stillbirths (National Vital Statistics System), environmental conditions (North American Land Data Assimilation System and Environmental Protection Agency), and social vulnerability (Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry Social Vulnerability Index). Poisson and negative binomial models were fit to the variables and produced rate ratios to estimate associations among stillbirth rates, environmental risk factors, and social vulnerability. RESULTS: Social vulnerability was positively associated withn stillbirth rates, annual average number of extreme heat days, and ambient concentration of particulate matter ≤ 2.5 µm in diameter (PM2.5). The average number of days that ozone and PM2.5 each exceeded regulatory standards were not associated with stillbirth rates or social vulnerability. A positive association between average annual PM2.5 concentration and stillbirth rates was detected; no other significant associations between environmental risk factors and stillbirth rates were observed. DISCUSSION: We found evidence of associations between social vulnerability and stillbirth rates, and between social vulnerability and environmental risk factors for stillbirth at the county level. Further research could inform understanding of how social vulnerability impacts the relationship between environmental exposures and stillbirth risk.

Differential lipid signaling from CD4+ and CD8+ T cells contributes to type 1 diabetes development.

Introduction: We reported that Ca2+-independent phospholipase A2ß (iPLA2ß)-derived lipids (iDLs) contribute to type 1 diabetes (T1D) onset. As CD4+ and CD8+ T cells are critical in promoting ß-cell death, we tested the hypothesis that iDL signaling from these cells participates in T1D development. Methods: CD4+ and CD8+ T cells from wild-type non-obese diabetic (NOD) and NOD.iPLA2ß+/- (NOD.HET) mice were administered in different combinations to immunodeficient NOD.scid. Results: In mice receiving only NOD T cells, T1D onset was rapid (5 weeks), incidence 100% by 20 weeks, and islets absent. In contrast, onset was delayed 1 week and incidence reduced 40%-50% in mice receiving combinations that included NOD.HET T cells. Consistently, islets from these non-diabetic mice were devoid of infiltrate and contained insulin-positive ß-cells. Reduced iPLA2ß led to decreased production of proinflammatory lipids from CD4+ T cells including prostaglandins and dihydroxyeicosatrienoic acids (DHETs), products of soluble epoxide hydrolase (sEH), and inhibition of their signaling decreased (by 82%) IFNγ+CD4+ cells abundance. However, only DHETs production was reduced from CD8+ T cells and was accompanied by decreases in sEH and granzyme B. Discussion: These findings suggest that differential select iDL signaling in CD4+ and CD8+ T cells contributes to T1D development, and that therapeutics targeting such signaling might be considered to counter T1D.

Recent trends in GLP-1 RA and SGLT2i use among people with type 2 diabetes and atherosclerotic cardiovascular disease in the USA.

INTRODUCTION: This study aimed to assess recent trends in the US use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), including incident use following newly diagnosed ASCVD. RESEARCH DESIGN AND METHODS: This real-world, retrospective observational study used de-identified data from the TriNetX Dataworks-USA network. A longitudinal analysis of cross-sectional data (interval: January 01, 2018 to December 31, 2022) assessed the yearly prevalent use of GLP-1 RA and SGLT2i. A nested cohort study (January 01, 2017 to January 31, 2023) assessed the proportions of patients with T2D newly prescribed GLP-1 RAs and SGLT2is after incident ASCVD diagnosis. RESULTS: Prevalent use of GLP-1 RA and/or SGLT2i increased from 9.2% of patients in 2018 to 27.1% in 2022, with eligible annual patient numbers ranging from 279,474 to 348,997. GLP-1 RA-alone use rose from 5.2% to 9.9% and SGLT2i-alone use rose from 2.8% to 12.2% over this interval. Incident use of GLP-1 RA and/or SGLT2i within the year following ASCVD diagnosis increased from 5.9% to 17.0% (2018-2022). For GLP-1 RA alone, this increase was from 3.6% to 7.8%, while for SGLT2i alone, it was from 1.8% to 7.0%. CONCLUSIONS: Use of GLP-1 RAs/SGLT2is in patients with T2D and ASCVD has increased in recent years in the USA, but remains suboptimal given the prevalence of ASCVD and its high morbidity and mortality.

Automatic Enrollment in Patient Portal Systems Mitigates the Digital Divide in Healthcare: An Interrupted Time Series Analysis of an Autoenrollment Workflow Intervention.

PURPOSE: Racial and ethnic healthcare disparities require innovative solutions. Patient portals enable online access to health records and clinician communication and are associated with improved health outcomes. Nevertheless, a digital divide in access to such portals persist, especially among people of minoritized race and non-English-speakers. This study assesses the impact of automatic enrollment (autoenrollment) on patient portal activation rates among adult patients at the University of California, San Francisco (UCSF), with a focus on disparities by race, ethnicity, and primary language. MATERIALS AND METHODS: Starting March 2020, autoenrollment offers for patient portals were sent to UCSF adult patients aged 18 or older via text message. Analysis considered patient portal activation before and after the intervention, examining variations by race, ethnicity, and primary language. Descriptive statistics and an interrupted time series analysis were used to assess the intervention's impact. RESULTS: Autoenrollment increased patient portal activation rates among all adult patients and patients of minoritized races saw greater increases in activation rates than White patients. While initially not statistically significant, by the end of the surveillance period, we observed statistically significant increases in activation rates in Latinx (3.5-fold, p = < 0.001), Black (3.2-fold, p = 0.003), and Asian (3.1-fold, p = 0.002) patient populations when compared with White patients. Increased activation rates over time in patients with a preferred language other than English (13-fold) were also statistically significant (p = < 0.001) when compared with the increase in English preferred language patients. CONCLUSION: An organization-based workflow intervention that provided autoenrollment in patient portals via text message was associated with statistically significant mitigation of racial, ethnic, and language-based disparities in patient portal activation rates. Although promising, the autoenrollment intervention did not eliminate disparities in portal enrollment. More work must be done to close the digital divide in access to healthcare technology.

Stimulating Acidimicrobium sp. Strain A6 in iron-rich, acidic sediments from AFFF-impacted sites for PFAS defluorination.

Per- and polyfluoroalkyl substances (PFAS) are persistent and bioaccumulative contaminants that are widely used in industrial applications and consumer products and pose significant risks to ecosystems and human health. Acidimicrobium sp. Strain A6 (A6), which is common in acidic, and iron rich soils and sediments is capable of both anaerobic ammonium (NH4+) oxidation under iron reduction (Feammox) and defluorination of perfluorinated alkyl substances, such as perfluoroalkyl acids (PFAAs). This study investigates the potential for biostimulating A6 via the supply of NH4+ and ferric iron (Fe(III)) with the goal of defluorinating PFAAs. Sediment samples from acidic, iron-rich, AFFF (aqueous film forming foam) impacted sites were collected and incubated with added Fe(III) and NH4+. Quantitative PCR was used to track A6 numbers as well as dehalogenase and F- ion transporter genes during these incubations; changes in the microbial community structure were tracked through 16S rRNA gene sequencing. The findings reveal that the addition of Fe(III) and NH4+ stimulated the Feammox reaction and A6 growth and enhanced the degradation of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). Results also show a significant presence and activity of the above-mentioned genes in these incubations. The insights gained from this study could inform bioremediation strategies for PFAS-contaminated environments, especially in geochemical settings that favor the presence of A6.

A comparison of three methods for establishing an ACL reference length in vivo.

As anterior cruciate ligament (ACL) injuries are highly prevalent among active individuals, it is vital to better understand the loading conditions which lead to injury. One method for doing so is through measurement of dynamic, in vivo ACL strain. To measure strain, it is necessary to normalize elongation of the ACL to a 'reference length' which corresponds to the point at which the ligament transitions from being unloaded to carrying tension. The purpose of this study was to compare the length of the ACL in three different positions to evaluate their utility for establishing a reference (or zero-strain) length of the ACL. ACL reference length was determined using three different methods for each of ten healthy participants. Using magnetic resonance and biplanar radiographic imaging techniques, we measured the length of the ACL during supine resting, quiet standing, and anterior/posterior (AP) drawer testing. During the AP drawer testing, the slack-taut transition point was defined as the inflection point of the AP translation vs ACL elongation curve. There was good consistency between the three ACL length measurements (ICC=0.80). Differences in mean ACL length between the three methods were within 1 mm. While determining the precise zero-strain length of the ACL in vivo remains a challenge, the reference positions utilized in this study produce consistent measurements of ACL length. These findings are important because reliable measurements of in vivo ACL strain have the potential to serve as indicators of propensity for injury.

High-Frequency 10-kHz Spinal Cord Stimulation Provides Long-term (24-Month) Improvements in Diabetes-Related Pain and Quality of Life for Patients with Painful Diabetic Neuropathy.

BACKGROUND: The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes. METHODS: The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction. RESULTS: Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% (P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% (P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score (P < .001) and GAF score (P < .001), and 91.5% of participants reported satisfaction with treatment. CONCLUSIONS: High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN.

Co-Occurring Mental and Physical Health Conditions Among Older Adults With and Without Post-traumatic Stress Disorder: A Case Control Study.

OBJECTIVES: Rates of post-traumatic stress disorder (PTSD) among older adults range from 0.4%-4.5%. Research examining PTSD in adults has demonstrated numerous associations between physical and mental health conditions; however, these are less well characterized in older adults. The current study aimed to identify base rates of such conditions among older adults with and without a history of PTSD. METHOD: In a case control design using the National Alzheimer's Coordinating Center Uniform Data Set, adults 65 years or older from the United States who endorsed either the presence or absence of PTSD were matched by age to assess between-group differences (N = 472; 236 pairs). We examined differences across self-reported sociodemographics and physical health, mental health, and substance use histories. RESULTS: More participants with a history of PTSD identified as Hispanic, non-white, non-married, and functionally independent. Compared to individuals without a history of PTSD, significantly more individuals with a history of PTSD had histories of depression, anxiety, substance abuse, Parkinson's disease, seizures, insomnia, and TBI. Among participants without PTSD history, only 14.7% reported a history of TBI, compared to 41.1% of individuals with PTSD history. CONCLUSIONS: Findings showed expected trends toward worse physical and mental health among older adults with self-reported PTSD. There was a striking difference in the frequency of TBI history between participants with and without PTSD. These findings underscore a need to assess for PTSD among older adults, particularly those reporting a history of TBI.

Anaesthetic considerations for impacted fetal head at caesarean delivery: a focused review.

BACKGROUND: Impacted fetal head occurs when the fetal head is deeply engaged within the maternal pelvis and difficult to deliver during caesarean delivery. In order to deliver the fetal head, additional surgical manoeuvres and/or pharmacological tocolysis are needed. The aim of this focused review is to outline the incidence, risk factors, management and complications of this obstetric emergency from the perspective of the anaesthetist. METHODS: Databases were searched for free text headings and subject headings associated with different permutations of terms related to impacted fetal head and caesarean delivery. RESULTS: Impacted fetal head has been estimated to occur in 1.5 % of elective caesarean deliveries and 2.9-18.4% of all emergency caesarean deliveries at any cervical dilatation. Risk factors include advanced cervical dilatation, labour augmentation with oxytocin, prolonged second stage of labour, fetal malposition and junior grade of operating obstetrician. If impacted fetal head occurs, the anaesthetist in conjunction with the multidisciplinary team should consider decreasing the height of the operating table, providing a step for the obstetrician to stand on, placing the patient in the head down position, providing pharmacological tocolysis with glyceryl trinitrate (or nitroglycerin), beta-2 adrenoreceptor agonists or volatile anaesthetic agents, and managing complications such as postpartum haemorrhage. CONCLUSION: Impacted fetal head is an obstetric emergency that the anaesthetist should be familiar with and has a vital role in managing. We propose an algorithm for management that may serve as a clinical decision aid.

Risk and Protective Factors for Preterm Birth Among Racial, Ethnic, and Socioeconomic Groups in California.

Importance: Preterm birth (PTB) (gestational age <37 weeks) is a major cause of infant mortality and morbidity in the US and is marked by racial and ethnic and socioeconomic inequities. Further research is needed to elucidate the association of risk and protective factors with trends in PTB rates and with related inequities. Objective: To describe the association of PTB rates with inequities as well as related risk and protective factors over the past decade in a US population-based cohort. Design, Setting, and Participants: This retrospective cohort study of singleton live births in California from January 1, 2011, to December 31, 2022, was conducted using vital statistics records and hospital records. The cohort included births with a gestational age of 22 to 44 weeks. Main Outcomes and Measures: Preterm birth rates by racial and ethnic group and by public and nonpublic insurance (considered as a proxy for socioeconomic status) were studied across years. Log-linear regression (relative risks with 95% CIs) was used to evaluate risk and protective factors within groups. Associations of PTB rates with risk and protective factors were assessed. Results: This study included 5 431 018 singleton live births to individuals who identified as American Indian or Alaska Native (0.3%), Asian (14.2%), Black (4.9%), Hispanic (47.8%), or White (27.0%). A total of 43.1% of births were to individuals with public health insurance. From 2011 to 2022, the overall PTB rate increased from 6.8% to 7.5% (change [SE], 10.6% [0.6%]; z score of 18.5; P < .001). Differences in PTB rates and associated changes were observed for racial and ethnic groups and insurance groups. For example, 2022 PTB rates ranged from 5.8% among White individuals with nonpublic insurance to 11.3% among Black individuals with public health insurance. From 2011 to 2022, PTB rates decreased from 9.1% to 8.8% (change [SE], -3.5% [4.2]; z score of -0.8; P = .42) among Black individuals with nonpublic insurance, whereas they increased from 6.4% to 9.5% (change [SE], 49.8% [16.0%]; z score of 3.1; P = .002) among American Indian or Alaska Native individuals with nonpublic insurance. Increases in some risk factors (eg, preexisting diabetes, sexually transmitted infections, mental health conditions) were observed in most groups, and decreases in some protective factors (eg, participation in the California Women, Infants, and Children program) (P for trend < .001 from 2011 to 2021) were observed mostly in low-income groups. Conclusions and Relevance: In this cohort study of singleton live births in California, PTB rates increased in many groups. Persistent racial and ethnic and socioeconomic inequities were also observed. Changes in risk and protective factors provided clues to patterns of PTB. These data point to an urgent need to address factors associated with PTB at both the individual and population levels.

Plasminogen Activation Inhibitor-1 Promotes Resilience to Acute Oxidative Stress in Cerebral Arteries from Females.

Plasminogen activation inhibitor-1 (PAI-1) plays a central role in thrombus formation leading to stroke; however, the contributions of PAI-1 to cellular damage in response to reactive oxygen species which are elevated during reperfusion are unknown. Given that PAI-1 can limit apoptosis, we hypothesized that PAI increases the resilience of cerebral arteries to H2O2 (200 µM). Cell death, mitochondrial membrane potential, and mitochondrial ROS production were evaluated in pressurized mouse posterior cerebral arteries from males and females. The effects of pharmacological and genetic inhibition of PAI-1 signaling were evaluated with the inhibitor PAI-039 (10 µM) and PAI-1 knockout mice, respectively. During exposure to H2O2, PCAs from male mice lacking PAI-1 had reduced mitochondrial depolarization and smooth muscle cell death, and PAI-039 increased EC death. In contrast, mitochondrial depolarization and cell death were augmented in female PCAs. With no effect of PAI-1 inhibition on resting mitochondrial ROS production, vessels from female PAI-1 knockout mice had increased mitochondrial ROS generation during H2O2 exposure. During acute exposure to oxidative stress, protein ablation of PAI-1 enhances cell death in posterior cerebral arteries from females while limiting cell death in males. These findings provide important considerations for blood flow restoration during stroke treatment.

Molecular characterization of peste des petits ruminants virus and Mycoplasma capricolum subsp. capripneumoniae in small ruminants in northern Mauritania, 2023.

Global eradication of peste des petits ruminants (PPR) is planned for 2030 by international animal health organizations in collaboration with national partners. As the deadline approaches, it is fundamental that the PPR status in each country is determined. In addition, the identification of other pathogens of small ruminants that share common geographical locations and can produce similar clinical signs is also important for differential diagnosis. With this in mind, 37 samples collected from goats and sheep presenting respiratory symptoms in Mauritania in 2023 were screened for the presence of PPR virus, Capripoxvirus, Pasteurella multocida and Mycoplasma capricolum subspecies capripneumoniae (Mccp) using a one-step multiplex RT-qPCR assay. None of the samples were positive for Capripoxvirus or P. multocida. Nine of them were positive for PPRV and sequence analysis of a segment of the PPRV nucleoprotein revealed that they belonged to lineage IV and were similar to viruses recently identified in Côte D'Ivoire, Guinea, and Niger indicating transboundary movement. The full genome of one representative virus was also generated. Mccp was identified in eight samples and multi-locus sequence analysis (MLSA) identified them as belonging to MLSA Group 3 together with Mccps identified in China, Tajikistan, Turkey and the United Arab Emirates. This is the first time that such a study has been undertaken in Mauritania and the data generated should be of interest to those involved in the management of goat diseases in Mauritania and neighbouring countries.

Blackcurrant (Ribes nigrum L.) improves cholinergic signaling and protects against chronic Scopolamine-induced memory impairment in mice.

BACKGROUND: Blackcurrant (Ribes nigrum L.) is a berry rich in anthocyanins, bioactive compounds known for their antioxidant and neuroprotective properties that benefit human health. AIMS: This study aimed to investigate the effects of blackcurrant and its association with Donepezil on memory impairment, cholinergic neurotransmission, and antioxidant systems in a mouse model of amnesia induced by chronic administration of Scopolamine. METHODS: Adult male Swiss mice were given saline, blackcurrant (50 mg/kg, orally), and/or Donepezil (5 mg/kg, orally) and/or Scopolamine (1 mg/kg, intraperitoneally). RESULTS: Behavioral tests revealed that blackcurrant and/or Donepezil prevented the learning and memory deficits induced by Scopolamine. In the cerebral cortex and hippocampus, blackcurrant and/or Donepezil treatments prevented the increase in acetylcholinesterase and butyrylcholinesterase activities induced by Scopolamine. Scopolamine also disrupted the glutathione redox system and increased levels of reactive species; nevertheless, blackcurrant and/or Donepezil treatments were able to prevent oxidative stress. Furthermore, these treatments prevented the increase in gene expression and protein density of acetylcholinesterase and the decrease in gene expression of the choline acetyltransferase enzyme induced by Scopolamine. CONCLUSIONS: Findings suggest that blackcurrant and Donepezil, either alone or in combination, have anti-amnesic effects by modulating cholinergic system enzymes and improving the redox profile. Therefore, blackcurrant could be used as a natural supplement for the prevention and treatment of memory impairment in neurodegenerative diseases.

Concomitant Use of Oral Anticoagulants with Oral Dipeptidyl Peptidase-4 Inhibitors and Serious Bleeding Events.

In a prior screening study, saxagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP-4is and serious bleeding in a large US database, using self-controlled case series (SCCS) and case-crossover (CCO) designs. The study population was eligible Medicare beneficiaries co-exposed to a DPP-4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016-2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co-exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug-exposed cases over the ORs in negative object drug-exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05-1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29-9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00-0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74-12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.

Challenges in the Application of African Swine Fever Vaccines in Asia.

This paper explores the significance of quality vaccines in managing ASF in Asia, where it poses a substantial threat to the pork industry. It emphasizes the risks associated with substandard vaccines, including the emergence of new virus strains that complicate disease control. Highlighting recent advancements in vaccine deployment in Vietnam, the paper calls for rigorous testing and regulations to guarantee vaccine effectiveness and safety. The authors advocate for the implementation of vaccines with the inclusion of differentiating infected from vaccinated animals (DIVA), which enhances disease management strategies in both endemic and non-endemic regions. The conclusion underscores the necessity of stringent standards in vaccine development and strict adherence to regulatory guidelines to ensure successful ASF management and maintain public trust in the vaccines.