Gender and contemporary risk of adverse events in atrial fibrillation

Background and Aims: The role of gender in decision-making for oral anticoagulation in patients with atrial fibrillation (AF) remains controversial.Methods: Population cohort study using electronic healthcare records of 16,587,749 patients from UK primary care (2005-2020). Primary (composite of all-cause mortality, ischaemic stroke or arterial thromboembolism) and secondary outcomes were analysed using Cox hazard ratios (HR), adjusted for age, socioeconomic status and comorbidities.Results: 78,852 patients were included with AF, age 40-75 years, no prior stroke and no prescription of oral anticoagulants. 28,590 (36.3%) were women and 50,262 (63.7%) men. Median age was 65.7 years (interquartile range 58.5-70.9) with women being older and other differences in comorbidities. During total follow-up of 431,086 patient-years, women had a lower adjusted primary outcome rate with HR 0.89 vs men (95% CI 0.87-0.92; p&lt;0.001), and HR 0.87 after censoring for oral anticoagulation (95% CI 0.83-0.91; p&lt;0.001). This was driven by lower mortality in women (HR 0.86, 0.83-0.89; p&lt;0.001). No difference was identified between women and men for the secondary outcomes of ischaemic stroke or arterial thromboembolism (adjusted HR 1.00, 0.94-1.07; p=0.87), any stroke or any thromboembolism (1.02, 0.96-1.07; p=0.58), and incident vascular dementia (1.13, 0.97-1.32; p=0.11). Clinical risk scores were only modest predictors of outcomes, with CHA2DS2-VA (ignoring gender) superior to CHA2DS2-VASc for primary outcomes in this population (receiver operator curve area 0.651 vs 0.639; p&lt;0.001), and no interaction with gender (p=0.45).Conclusions: Removal of gender from clinical risk scoring could simplify the approach to which patients with AF should be offered oral anticoagulation.  <br/

Leishmania donovani: Immunostimulatory Cellular Responses of Membrane and Soluble Protein Fractions of Splenic Amastigotes in Cured Patient and Hamsters

Visceral leishmaniasis (VL), caused by the intracellular parasite Leishmania donovani, L. chagasi and L. infantum is characterized by defective cell-mediated immunity (CMI) and is usually fatal if not treated properly. An estimated 350 million people worldwide are at risk of acquiring infection with Leishmania parasites with approximately 500,000 cases of VL being reported each year. In the absence of an efficient and cost-effective antileishmanial drug, development of an appropriate long-lasting vaccine against VL is the need of the day. In VL, the development of a CMI, capable of mounting Th1-type of immune responses, play an important role as it correlate with recovery from and resistance to disease. Resolution of infection results in lifelong immunity against the disease which indicates towards the feasibility of a vaccine against the disease. Most of the vaccination studies in Leishmaniasis have been focused on promastigote- an infective stage of parasite with less exploration of pathogenic amastigote form, due to the cumbersome process of its purified isolation. In the present study, we have isolated and purified splenic amastigotes of L. donovani, following the traditional protocol with slight modification. These were fractionated into five membranous and soluble subfractions each i.e MAF1-5 and SAF1-5 and were subjected for evaluation of their ability to induce cellular responses. Out of five sub-fractions from each of membrane and soluble, only four viz. MAF2, MAF3, SAF2 and SAF3 were observed to stimulate remarkable lymphoproliferative, IFN-γ, IL-12 responses and Nitric Oxide production, in Leishmania-infected cured/exposed patients and hamsters. Results suggest the presence of Th-1 type immunostimulatory molecules in these sub-fractions which may further be exploited for developing a successful subunit vaccine from the less explored pathogenic stage against VL

In Vitro Evaluation of a Soluble Leishmania Promastigote Surface Antigen as a Potential Vaccine Candidate against Human Leishmaniasis

International audiencePSA (Promastigote Surface Antigen) belongs to a family of membrane-bound and secreted proteins present in severalLeishmania (L.) species. PSA is recognized by human Th1 cells and provides a high degree of protection in vaccinated mice.We evaluated humoral and cellular immune responses induced by a L. amazonensis PSA protein (LaPSA-38S) produced in aL. tarentolae expression system. This was done in individuals cured of cutaneous leishmaniasis due to L. major (CCLm) or L.braziliensis (CCLb) or visceral leishmaniasis due to L. donovani (CVLd) and in healthy individuals. Healthy individuals weresubdivided into immune (HHR-Lm and HHR-Li: Healthy High Responders living in an endemic area for L. major or L. infantuminfection) or non immune/naive individuals (HLR: Healthy Low Responders), depending on whether they produce high orlow levels of IFN-c in response to Leishmania soluble antigen. Low levels of total IgG antibodies to LaPSA-38S were detectedin sera from the studied groups. Interestingly, LaPSA-38S induced specific and significant levels of IFN-c, granzyme B and IL-10 in CCLm, HHR-Lm and HHR-Li groups, with HHR-Li group producing TNF-a in more. No significant cytokine response wasobserved in individuals immune to L. braziliensis or L. donovani infection. Phenotypic analysis showed a significant increasein CD4+ T cells producing IFN-c after LaPSA-38S stimulation, in CCLm. A high positive correlation was observed between thepercentage of IFN-c-producing CD4+ T cells and the released IFN-c. We showed that the LaPSA-38S protein was able toinduce a mixed Th1 and Th2/Treg cytokine response in individuals with immunity to L. major or L. infantum infectionindicating that it may be exploited as a vaccine candidate. We also showed, to our knowledge for the first time, the capacityof Leishmania PSA protein to induce granzyme B production in humans with immunity to L. major and L. infantum infectio

Guideline LDL-C Threshold Achievement in Acute Myocardial Infarction Patients: A Real-World Evidence Study Demonstrating the Impact of Treatment Intensification with PCSK9i

Abstract Introduction A high proportion of Canadian patients with acute myocardial infarction (AMI) do not achieve the threshold low-density lipoprotein cholesterol (LDL-C) levels recommended by the Canadian Cardiovascular Society in 2021. This increases the risk of subsequent atherosclerotic cardiovascular disease (ASCVD) events. Here, we assess LDL-C levels and threshold achievement among patients by lipid-lowering therapies (LLT) received post-AMI. Methods A retrospective cohort study of patients identified with AMI between 2015 and 2019 was conducted using administrative health databases in Alberta, Canada. Patients were grouped by their highest-intensity LLT post-AMI (proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) + another LLT; PCSK9i alone; ezetimibe + statin; statins (high, moderate, low intensity); or ezetimibe alone), and available LDL-C levels were examined in the year before and after LLT dispense date. Results The cohort included 15,283 patients. In patients on PCSK9i + LLT, the median [95% confidence interval (CI)] LDL-C levels decreased from 2.7 (2.3–3.4) before to 0.9 (0.5–1.2) mmol/l after treatment, the largest decrease among treatment groups. In the ezetimibe + statin and high-intensity statin groups, median (95% CI) values after treatment were 1.5 (1.5–1.6) and 1.4 (1.4–1.4) mmol/l, respectively. The proportion of patients below the 1.8 mmol/l threshold increased by 77.7% in the PSCK9i + LLT group after treatment, compared to 45.4 and 32.4% in the ezetimibe + statin and high-intensity statin groups, respectively. Conclusions Intensification with PCSK9i in AMI patients results in a greater proportion of patients achieving below the recommended LDL-C threshold versus statins and or ezetimibe alone. Increased focus on achieving below the LDL-C thresholds with additional LLT as required may benefit patient cardiovascular outcomes

Pentoxifylline treatment of mice with chronic pulmonary tuberculosis accelerates the development of destructive pathology

It is well established in animal models that production of the cytokine tumour necrosis factor-α (TNF-α) is essential to the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis. This gives rise to an apparent state of chronic disease which over the next 100–200 days is characterized by slowly worsening pathological changes in the lung. To determine whether continued TNF-α production was harmful during this phase mice were treated with a TNF-α inhibitor, pentoxifylline. It was observed that although this therapy did not alter the numbers of bacteria recovered from the lungs of the infected mice, tissue damage within the lung was accelerated. These data thus demonstrate that production of TNF-α, already known to be important during the early expression of resistance to tuberculosis, remains important and beneficial during the chronic stage of the disease