Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Bioluminescent Reporting of In Vivo IFN-γ Immune Responses during Infection and Autoimmunity.

IFN-γ is a key cytokine of innate and adaptive immunity. It is important to understand temporal changes in IFN-γ production and how these changes relate to the role of IFN-γ in diverse models of infectious and autoimmune disease, making the ability to monitor and track IFN-γ production in vivo of a substantial benefit. IFN-γ ELISPOTs have been a central methodology to measure T cell immunity for many years. In this study, we add the capacity to analyze IFN-γ responses with high sensitivity and specificity, longitudinally, in vitro and in vivo. This allows the refinement of experimental protocols because immunity can be tracked in real-time through a longitudinal approach. We have generated a novel murine IFN-γ reporter transgenic model that allows IFN-γ production to be visualized and quantified in vitro and in vivo as bioluminescence using an imaging system. At baseline, in the absence of an inflammatory stimulus, IFN-γ signal from lymphoid tissue is detectable in vivo. Reporter transgenics are used in this study to track the IFN-γ response to Pseudomonas aeruginosa infection in the lung over time in vivo. The longitudinal development of the adaptive T cell immunity following immunization with Ag is identified from day 7 in vivo. Finally, we show that we are able to use this reporter transgenic to follow the onset of autoimmune T cell activation after regulatory T cell depletion in an established model of systemic autoimmunity. This IFN-γ reporter transgenic, termed "Gammaglow," offers a valuable new modality for tracking IFN-γ immunity, noninvasively and longitudinally over time.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Zygomaticus major muscle bony attachment site: a Thiel-embalmed cadaver study.

OBJECTIVE: Thezygomaticus major is a principal muscle of facial expression which is engaged when smiling. The zygomaticus major origin of the zygomatic bone is often discussed relevant to its importance in the field of plastic surgery. In addition, the zygomaticus major attachment site is also significant for forensic craniofacial reconstruction, separating the cheek into frontal and lateral surfaces. However, there are discrepancies amongst published articles regarding the precise origin of the zygomaticus major muscle. The aim of this study is to investigate more distinctive and palpable landmarks as the bony attachment of the zygomaticus major. METHODS: This project is the first zygomaticus major dissection study utilising Thiel embalmed cadavers. Fifty-two facial dissections were investigated in 26 Thiel embalmed bodies, bequeathed to the Centre for Anatomy and Human Identification at The University of Dundee between 2013 and 2015. RESULTS: This study found that the origin of zygomaticus major muscle was located at the superior margin of the temporal process on the lateral surface of zygomatic bone. Moreover, the zygomaticus major muscle overlapped the anterosuperior border of the masseter muscle. One out of 52 zygomaticus major muscles presented bifurcation. CONCLUSION: The origin site of zygomaticus major is considered important to increase resemblance in forensic craniofacial reconstruction. Furthermore, since zygomaticus major is a salient muscle involved in facial expression, the potential effects for cosmetic/surgical procedures are also relevant to the medical field and successful surgical outcomes. The current study provided easily palpable landmarks of zygomaticus major origin site which is beneficial for both surgeons and forensic craniofacial reconstruction practitioners.

Investigation of the First Seven Reported Cases of Candida auris, a Globally Emerging Invasive, Multidrug-Resistant Fungus-United States, May 2013-August 2016.

November 11, 2016/65(44);1234-1237. What is already known about this topic? Candida auris is an emerging pathogenic fungus that has been reported from at least a dozen countries on four continents during 2009-2015. The organism is difficult to identify using traditional biochemical methods, some isolates have been found to be resistant to all three major classes of antifungal medications, and C. auris has caused health care-associated outbreaks. What is added by this report? This is the first description of C. auris cases in the United States. C. auris appears to have emerged in the United States only in the last few years, and U.S. isolates are related to isolates from South America and South Asia. Evidence from U.S. case investigations suggests likely transmission of the organism occurred in health care settings. What are the implications for public health practice? It is important that U.S. laboratories accurately identify C. auris and for health care facilities to implement recommended infection control practices to prevent the spread of C. auris. Local and state health departments and CDC should be notified of possible cases of C. auris and of isolates of C. haemulonii and Candida spp. that cannot be identified after routine testing.

Emergency medical service provider decision-making in out of hospital cardiac arrest: an exploratory study.

BACKGROUND: There are approximately 60,000 out-of-hospital cardiac arrests (OHCA) in the United Kingdom (UK) each year. Within the UK there are well-established clinical practice guidelines that define when resuscitation should be commenced in OHCA, and when resuscitation should cease. Background literature indicates that decision-making in the commencement and cessation of resuscitation efforts in OHCA is complex, and not comprehensively understood. No relevant research from the UK has been published to date and this research study seeks to explore the influences on UK Emergency Medical Service (EMS) provider decision-making when commencing and ceasing resuscitation attempts in OHCA. The aim of this research to explore the influences on UK Emergency Medical Services provider decision-making when commencing and ceasing resuscitation attempts in OHCA. METHODS: Four focus groups were convened with 16 clinically active EMS providers. Four case vignettes were discussed to explore decision-making within the focus groups. Thematic analysis was used to analyse transcripts. RESULTS: This research found that there are three stages in the decision-making process when EMS providers consider whether to commence or cease resuscitation attempts in OHCA. These stages are: the call; arrival on scene; the protocol. Influential factors present at each of the three stages can lead to different decisions and variability in practice. These influences are: factual information available to the EMS provider; structural factors such as protocol, guidance and research; cultural beliefs and values; interpersonal factors; risk factors; personal values and beliefs. CONCLUSIONS: An improved understanding of the circumstantial, individual and interpersonal factors that mediate the decision-making process in clinical practice could inform the development of more effective clinical guidelines, education and clinical decision support in OHCA. These changes have the potential to lead to greater consistency. and EMS provider confidence, with the potential for improved patient outcome from OHCA.

Personality diatheses and Hurricane Sandy: effects on post-disaster depression.

BACKGROUND: According to diathesis-stress models, personality traits, such as negative emotionality (NE) and positive emotionality (PE), may moderate the effects of stressors on the development of depression. However, relatively little empirical research has directly examined whether NE and PE act as diatheses in the presence of stressful life events, and no research has examined whether they moderate the effect of disaster exposure on depressive symptoms. Hurricane Sandy, the second costliest hurricane in US history, offers a unique opportunity to address these gaps. METHOD: A total of 318 women completed measures of NE and PE 5 years prior to Hurricane Sandy. They were also assessed for lifetime depressive disorders on two occasions, the latter occurring an average of 1 year before the hurricane. Approximately 8 weeks after the disaster (mean = 8.40, s.d. = 1.48 weeks), participants completed a hurricane stress exposure questionnaire and a measure of current depressive symptoms. RESULTS: Adjusting for lifetime history of depressive disorders, higher levels of stress from Hurricane Sandy predicted elevated levels of depressive symptoms, but only in participants with high levels of NE or low levels of PE. CONCLUSIONS: These findings support the role of personality in the development of depression and suggest that personality traits can be useful in identifying those most vulnerable to major stressors, including natural disasters.

Prospects for vaccination against pathogenic African trypanosomes.

African trypanosomes cause human and animal African trypanosomiases, which are chronic, debilitating and often fatal diseases of people and livestock in sub-Saharan Africa. The extracellular protozoan parasites are exemplars of antigenic variation. They direct host-protective B-cell and T-cell immune responses towards hypervariable components of their variable surface glycoprotein coat and evade immune elimination by generating new surface coat antigenic variants at a rate that supersedes immune destruction. This results in recurring waves of parasitemia, tissue invasion and escalating immunopathology in trypanosomiasis-susceptible hosts. Here, we discuss the possibility that host control of African trypanosomes might be improved by immunization with conserved VSG peptides and invariant surface glycoproteins. Infection-induced T-cell recall responses to these typically poorly expressed or nonimmunogenic parasite components induce tissue phagocytes to produce microbicidal materials that kill trypanosomes. Preliminary data that support this immune-enhancing vaccine strategy are discussed, as are host and parasite interactions that might downregulate the protective responses. These include infection-induced immunosuppression and increasing virulence of infecting parasites over time.

A laser driven pulsed X-ray backscatter technique for enhanced penetrative imaging.

X-ray backscatter imaging can be used for a wide range of imaging applications, in particular for industrial inspection and portal security. Currently, the application of this imaging technique to the detection of landmines is limited due to the surrounding sand or soil strongly attenuating the 10s to 100s of keV X-rays required for backscatter imaging. Here, we introduce a new approach involving a 140 MeV short-pulse (< 100 fs) electron beam generated by laser wakefield acceleration to probe the sample, which produces Bremsstrahlung X-rays within the sample enabling greater depths to be imaged. A variety of detector and scintillator configurations are examined, with the best time response seen from an absorptive coated BaF2 scintillator with a bandpass filter to remove the slow scintillation emission components. An X-ray backscatter image of an array of different density and atomic number items is demonstrated. The use of a compact laser wakefield accelerator to generate the electron source, combined with the rapid development of more compact, efficient and higher repetition rate high power laser systems will make this system feasible for applications in the field. Content includes material subject to Dstl (c) Crown copyright (2014). Licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: psi@ nationalarchives.gsi.gov.uk.

Endoscopic vein harvesting in lower extremity arterial bypass: a systematic review.

OBJECTIVE: Endoscopic vein harvesting (EVH) for arterial bypass surgery may be associated with lower wound complication rates than open vein harvesting (OVH), but other long-term outcomes remain controversial, and there are concerns that graft patency may be poorer after EVH compared with OVH. We conducted a systematic review of all available evidence for EVH in lower extremity arterial bypass (LEAB). METHODS: A literature search of Medline, Embase, Ovid and Cochrane databases between 1996 and 2013 was performed using the terms "endoscopic vein harvesting", "minimally invasive vein harvest", "peripheral bypass surgery", and "lower extremity bypass surgery", and detailed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Primary outcomes were graft patency and overall wound complication rates. Secondary outcomes were wound infection, length of hospital stay, and cost-effectiveness. Summary estimates were calculated by random effects meta-analysis if sufficient data were available. RESULTS: We identified 18 cohort studies and case series, with considerable clinical heterogeneity, including 2,343 patients. Meta-analysis of six studies revealed a significantly reduced rate of primary patency after EVH (hazard ratio 1.29, 95% confidence interval [CI] 1.03-1.63), with no significant difference between EVH and OVH with respect to wound infection in 12 studies (odds ratio 0.81, 95% CI 0.61-1.08). There was a lack of strong evidence to support the secondary outcomes of EVH. CONCLUSION: EVH reduces primary patency rates after LEAB, but does not demonstrate an advantage with respect to postoperative wound complications. However, the available data are heterogeneous, and uncertainty is introduced by both evolution in technology and increasing technical experience. EVH should be used with caution and in the context of formal research.

The incidence and position of melanocytic nevi for the purposes of forensic image comparison.

Expert witness opinion based on the comparison of images has been accepted by UK courts as admissible evidence in relation to issues of identity. Within images of the hand are a multiplicity of anatomical features of different aetiology, incidence and distribution patterns and this includes melanocytic nevi, referred to more colloquially as moles and/or birthmarks. The hand is not a common place for these isolated features to develop and so their presence in this anatomical region has the potential to be useful for issues of identity. The results of this study show that approximately 9 % of individuals in a sample of 476 hands, displayed at least one nevus on the back of their hand and, contrary to the literature, the incidence was found to be greater in females (15 % of female cohort) than males (7 % of male cohort). Almost a third of all nevi identified on the dorsum of the hand were abnormal or dysplastic. The most frequent location for these aggregations of melanocytes was in the central region of the dorsum of the hand or at the base of the index finger. The relevance of nevi identified in the image of a perpetrator's hand and also on that of a suspect/accused is discussed in relation to the issue of whether the images have originated from the same individual.

Safety, Efficacy and Clinical Applications of Focused Ultrasound-Mediated Blood Brain Barrier Opening in Alzheimer's Disease: A Systematic Review.

Alzheimer's disease is a neurodegenerative disorder marked by cognitive decline and brain pathology involving amyloid plaques and neurofibrillary tangles. Current drug development focuses on disease-modifying therapies, primarily antibodies targeting amyloid or tau. However, the blood-brain barrier (BBB) poses a challenge for drug delivery to the brain. Pre- and early clinical data suggests that Focused Ultrasound (FUS) technology safely enhances BBB permeability without damaging brain tissue, enabling drug delivery. This systematic review discusses the application of FUS to open the BBB for the treatment of Alzheimer's disease (AD). We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients.

Investigating the Factor Structure of the Preclinical Alzheimer Cognitive Composite and Cognitive Function Index across Racial/Ethnic, Sex, and Aß Status Groups in the A4 Study.

BACKGROUND: Disparities in Alzheimer's disease (AD) are well-documented among different racial/ethnic groups and between sex/genders. Neuropsychological assessment provides important information about cognitive changes and can offer valuable insights into disparities. However, neuropsychological measures must be comparable across racial/ethnic and sex/gender groups to accurately interpret disparities. OBJECTIVES: To evaluate measurement invariance (equivalence) of the Preclinical Alzheimer Cognitive Composite (PACC) and the Cognitive Function Index across racial/ethnic, sex/gender, and ß-amyloid (Aß) status groups. DESIGN, SETTING, PARTICIPANTS: Cross-sectional analysis of screening data from the Anti-Amyloid in Asymptomatic AD (A4) Study. The study enrolled participants aged 65-85 from sites across the United States, Canada, Australia, and Japan. MEASUREMENTS: Participants completed the PACC and the Cognitive Function Index. Participants classified as cognitively normal also underwent a Positron Emission Tomography (PET) scan to determine Aß status. RESULTS: Participants self-identified as non-Hispanic White (n=5241), non-Hispanic Black (n=267), Asian (n=228), or Hispanic White (n=225) as well as male (n=2885) or female (n=3076). Among those who underwent a PET scan, 3115 were classified as Aß- and 1309 were classified as Aß+. We found support for a one-factor model for both the PACC and Cognitive Function Index across the full sample and in samples stratified by race/ethnicity, sex/gender, and Aß status. The one-factor model of the PACC and Cognitive Function Index demonstrated scalar measurement invariance across racial/ethnic, sex/gender, and Aß status groups. CONCLUSIONS: Our findings suggest that performance on the PACC and Cognitive Function Index can be compared across the racial/ethnic, sex/gender, and Aß status groups examined in this study.

The accuracy of prehospital triage decisions in English trauma networks - a case-cohort study.

BACKGROUND: Care for injured patients in England is provided by inclusive regional trauma networks. Ambulance services use triage tools to identify patients with major trauma who would benefit from expedited Major Trauma Centre (MTC) care. However, there has been no investigation of triage performance, despite its role in ensuring effective and efficient MTC care. This study aimed to investigate the accuracy of prehospital major trauma triage in representative English trauma networks. METHODS: A diagnostic case-cohort study was performed between November 2019 and February 2020 in 4 English regional trauma networks as part of the Major Trauma Triage Study (MATTS). Consecutive patients with acute injury presenting to participating ambulance services were included, together with all reference standard positive cases, and matched to data from the English national major trauma database. The index test was prehospital provider triage decision making, with a positive result defined as patient transport with a pre-alert call to the MTC. The primary reference standard was a consensus definition of serious injury that would benefit from expedited major trauma centre care. Secondary analyses explored different reference standards and compared theoretical triage tool accuracy to real-life triage decisions. RESULTS: The complete-case case-cohort sample consisted of 2,757 patients, including 959 primary reference standard positive patients. The prevalence of major trauma meeting the primary reference standard definition was 3.1% (n=54/1,722, 95% CI 2.3 - 4.0). Observed prehospital provider triage decisions demonstrated overall sensitivity of 46.7% (n=446/959, 95% CI 43.5-49.9) and specificity of 94.5% (n=1,703/1,798, 95% CI 93.4-95.6) for the primary reference standard. There was a clear trend of decreasing sensitivity and increasing specificity from younger to older age groups. Prehospital provider triage decisions commonly differed from the theoretical triage tool result, with ambulance service clinician judgement resulting in higher specificity. CONCLUSIONS: Prehospital decision making for injured patients in English trauma networks demonstrated high specificity and low sensitivity, consistent with the targets for cost-effective triage defined in previous economic evaluations. Actual triage decisions differed from theoretical triage tool results, with a decreasing sensitivity and increasing specificity from younger to older ages.

COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. METHODS: Using a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. RESULTS: Participants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. CONCLUSION: This multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Cerebral small vessel disease in aging and Alzheimer's disease: a comparative study using MRI and SPECT.

BACKGROUND: White matter hyperintensities (WMH) are associated with aging and are prevalent in various brain pathologies. The purpose of the current study was to characterize WMH perfusion in age-matched elderly controls (ECs) and patients with Alzheimer's disease (ADs). METHODS: Fifty ECs (23 men) and 61 ADs (33 men) underwent magnetic resonance imaging (MRI), 99mTc-ECD single-photon emission computed tomography (SPECT) and cognitive testing. Brain tissue type was classified on T1 weighted images, and WMH were identified on interleaved proton density/T2 weighted images. Co-registered MR images were used to characterize SPECT perfusion patterns. RESULTS: WMH perfusion was lower than normal appearing white matter (NAWM) perfusion (P < 0.001) in both EC and AD groups. There was no WMH perfusion difference between groups when considering the mean perfusion from all WMH voxels (P > 0.43). However, locations that were likely to be considered WMH tended to have lower perfusion in ADs compared with ECs. Perfusion gradients along watershed white matter regions were significantly different between EC and AD groups (P < 0.05). A relationship was found between the volume of a WMH lesion and its mean perfusion (P < 0.001) in both ECs and ADs. CONCLUSION: Global WMH were hypoperfused compared with NAWM to the same degree in EC and AD participants, which suggests a common WMH etiology between groups. However, white matter locations that were likely to contain WMH tended to be hypoperfused in ADs compared with healthy aging. This finding is suggestive of AD-specific pathology that reduces the perfusion at anatomic locations susceptible to the formation of WMH through either the neurodegenerative process or AD-related vasculopathy or both.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM. METHODS: Patients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52). RESULTS: HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo. CONCLUSIONS: Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.

Background rates of adverse events of special interest for COVID-19 vaccines: A multinational Global Vaccine Data Network (GVDN) analysis.

BACKGROUND: The Global COVID Vaccine Safety (GCoVS) project was established in 2021 under the multinational Global Vaccine Data Network (GVDN) consortium to facilitate the rapid assessment of the safety of newly introduced vaccines. This study analyzed data from GVDN member sites on the background incidence rates of conditions designated as adverse events of special interest (AESI) for COVID-19 vaccine safety monitoring. METHODS: Eleven GVDN global sites obtained data from national or regional healthcare databases using standardized methods. Incident events of 13 pre-defined AESI were included for a pre-pandemic period (2015-19) and the first pandemic year (2020). Background incidence rates (IR) and 95% confidence intervals (CI) were calculated for inpatient and emergency department encounters, stratified by age and sex, and compared between pre-pandemic and pandemic periods using incidence rate ratios. RESULTS: An estimated 197 million people contributed 1,189,652,926 person-years of follow-up time. Among inpatients in the pre-pandemic period (2015-19), generalized seizures were the most common neurological AESI (IR ranged from 22.15 [95% CI 19.01-25.65] to 278.82 [278.20-279.44] per 100,000 person-years); acute disseminated encephalomyelitis was the least common (<0.5 per 100,000 person-years at most sites). Pulmonary embolism was the most common thrombotic event (IR 45.34 [95% CI 44.85-45.84] to 93.77 [95% CI 93.46-94.08] per 100,000 person-years). The IR of myocarditis ranged from 1.60 [(95% CI 1.45-1.76) to 7.76 (95% CI 7.46-8.08) per 100,000 person-years. The IR of several AESI varied by site, healthcare setting, age and sex. The IR of some AESI were notably different in 2020 compared to 2015-19. CONCLUSION: Background incidence of AESIs exhibited some variability across study sites and between pre-pandemic and pandemic periods. These findings will contribute to global vaccine safety surveillance and research.

Spontaneous autoimmune gastritis and hypochlorhydria are manifest in the ileitis-prone SAMP1/YitFcs mice.

SAMP1/YitFcs mice serve as a model of Crohn's disease, and we have used them to assess gastritis. Gastritis was compared in SAMP1/YitFcs, AKR, and C57BL/6 mice by histology, immunohistochemistry, and flow cytometry. Gastric acid secretion was measured in ligated stomachs, while anti-parietal cell antibodies were assayed by immunofluorescence and enzyme-linked immunosorbent spot assay. SAMP1/YitFcs mice display a corpus-dominant, chronic gastritis with multifocal aggregates of mononuclear cells consisting of T and B lymphocytes. Relatively few aggregates were observed elsewhere in the stomach. The infiltrates in the oxyntic mucosa were associated with the loss of parietal cell mass. AKR mice, the founder strain of the SAMP1/YitFcs, also have gastritis, although they do not develop ileitis. Genetic studies using SAMP1/YitFcs-C57BL/6 congenic mice showed that the genetic regions regulating ileitis had comparable effects on gastritis. The majority of the cells in the aggregates expressed the T cell marker CD3 or the B cell marker B220. Adoptive transfer of SAMP1/YitFcs CD4(+) T helper cells, with or without B cells, into immunodeficient recipients induced a pangastritis and duodenitis. SAMP1/YitFcs and AKR mice manifest hypochlorhydria and anti-parietal cell antibodies. These data suggest that common genetic factors controlling gastroenteric disease in SAMP1/YitFcs mice regulate distinct pathogenic mechanisms causing inflammation in separate sites within the digestive tract.