Going viral: HBV-specific CD8+ tissue-resident memory T cells propagate anti-tumor immunity.

The nature of the epitopes recognized by tumor-infiltrating T cells is not clearly defined. In this issue of Immunity, Cheng et al. demonstrate that tissue-resident memory CD8+ T cells specific for hepatitis B virus-derived antigens exhibit potent anti-tumor properties and correlate with relapse-free survival in patients with resected hepatocellular carcinoma.

Causal identification of single-cell experimental perturbation effects with CINEMA-OT.

Recent advancements in single-cell technologies allow characterization of experimental perturbations at single-cell resolution. While methods have been developed to analyze such experiments, the application of a strict causal framework has not yet been explored for the inference of treatment effects at the single-cell level. Here we present a causal-inference-based approach to single-cell perturbation analysis, termed CINEMA-OT (causal independent effect module attribution + optimal transport). CINEMA-OT separates confounding sources of variation from perturbation effects to obtain an optimal transport matching that reflects counterfactual cell pairs. These cell pairs represent causal perturbation responses permitting a number of novel analyses, such as individual treatment-effect analysis, response clustering, attribution analysis, and synergy analysis. We benchmark CINEMA-OT on an array of treatment-effect estimation tasks for several simulated and real datasets and show that it outperforms other single-cell perturbation analysis methods. Finally, we perform CINEMA-OT analysis of two newly generated datasets: (1) rhinovirus and cigarette-smoke-exposed airway organoids, and (2) combinatorial cytokine stimulation of immune cells. In these experiments, CINEMA-OT reveals potential mechanisms by which cigarette-smoke exposure dulls the airway antiviral response, as well as the logic that governs chemokine secretion and peripheral immune cell recruitment.

Eicosanoid and Specialized Proresolving Mediator Regulation of Lymphoid Cells.

Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and adaptive immune responses when lymphocytes interact with leukocytes. Receptors for leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and SPMs are expressed on lymphocytes. Evidence points toward an essential role of these lipid mediators (LMs) in direct regulation of lymphocyte functions. SPMs, which include lipoxins, demonstrate comprehensive protective actions with lymphocytes. LTB4 and PGE2 regulation of lymphocytes is diverse and depends on the interaction of lymphocytes with other cells. Importantly, both LTB4 and PGE2 are essential regulators of T cell antitumor activity. These LMs are attractive therapeutic targets to control dysregulated innate and adaptive immune responses, promote lymphocyte antitumor activity, and prevent tumor immune evasion.

Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer.

Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.

The origin and impact of bound water around intrinsically disordered proteins.

Proteins and water couple dynamically over a wide range of time scales. Motivated by their central role in protein function, protein-water dynamics and thermodynamics have been extensively studied for structured proteins, where correspondence to structural features has been made. However, properties controlling intrinsically disordered protein (IDP)-water dynamics are not yet known. We report results of megahertz-to-terahertz dielectric spectroscopy and molecular dynamics simulations of a group of IDPs with varying charge content along with structured proteins of similar size. Hydration water around IDPs is found to exhibit more heterogeneous rotational and translational dynamics compared with water around structured proteins of similar size, yielding on average more restricted dynamics around individual residues of IDPs, charged or neutral, compared with structured proteins. The on-average slower water dynamics is found to arise from excess tightly bound water in the first hydration layer, which is related to greater exposure to charged groups. The more tightly bound water to IDPs correlates with the smaller hydration shell found experimentally, and affects entropy associated with protein-water interactions, the contribution of which we estimate based on the dielectric measurements and simulations. Water-IDP dynamic coupling at terahertz frequencies is characterized by the dielectric measurements and simulations.

Paracrine Role for Somatostatin Interneurons in the Assembly of Perisomatic Inhibitory Synapses.

GABAergic interneurons represent a heterogenous group of cell types in neocortex that can be clustered based on developmental origin, morphology, physiology, and connectivity. Two abundant populations of cortical GABAergic interneurons include the low-threshold, somatostatin (SST)-expressing cells and the fast-spiking, parvalbumin (PV)-expressing cells. While SST+ and PV+ interneurons are both early born and migrate into the developing neocortex at similar times, SST+ cells are incorporated into functional circuits prior to PV+ cells. During this early period of neural development, SST+ cells play critical roles in the assembly and maturation of other cortical circuits; however, the mechanisms underlying this process remain poorly understood. Here, using both sexes of conditional mutant mice, we discovered that SST+ interneuron-derived Collagen XIX, a synaptogenic extracellular matrix protein, is required for the formation of GABAergic, perisomatic synapses by PV+ cells. These results, therefore, identify a paracrine mechanism by which early-born SST+ cells orchestrate inhibitory circuit formation in the developing neocortex.SIGNIFICANCE STATEMENT Inhibitory interneurons in the cerebral cortex represent a heterogenous group of cells that generate the inhibitory neurotransmitter GABA. One such interneuron type is the low-threshold, somatostatin (SST)-expressing cell, which is one of the first types of interneurons to migrate into the cerebral cortex and become incorporated into functional circuits. In addition, to contributing important roles in controlling the flow of information in the adult cerebral cortex, SST+ cells play important roles in the development of other neural circuits in the developing brain. Here, we identified an extracellular matrix protein that is released by these early-born SST+ neurons to orchestrate inhibitory circuit formation in the developing cerebral cortex.

Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus.

In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.

Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch.

Atopic dermatitis (AD) is the most common skin disease in children. It is characterized by relapsing inflammation, skin-barrier defects, and intractable itch. However, the pathophysiology of itch in AD remains enigmatic. Here, we examine the contribution of Tmem79, an orphan transmembrane protein linked to AD in both mice and humans. We show that Tmem79 is expressed by both keratinocytes and sensory neurons, but that loss of keratinocytic Tmem79 is sufficient to elicit robust scratching. Tmem79-/- mice demonstrate an accumulation of dermal mast cells, which are diminished following chronic treatment with cyclooxygenase inhibitors and an EP3 receptor antagonist. In Tmem79-/- mice, mast cell degranulation produces histaminergic itch in a histamine receptor 1/histamine receptor 4 (H4R/H1R)-dependent manner that may involve activation of TRPV1- afferents. TMEM79 has limited sequence homology to a family of microsomal glutathione transferases and confers protection from cellular accumulation of damaging reactive species, and may thus play a role in regulating oxidative stress. In any case, mechanistic insights from this model suggest that therapeutics targeting PGE2 and/or H1R/H4R histaminergic signaling pathways may represent useful avenues to treat Tmem79-associated AD itch. Our findings suggest that individuals with mutations in Tmem79 develop AD due to the loss of protection from oxidative stress.

Local TNFR1 Signaling Licenses Murine Neutrophils for Increased TLR-Dependent Cytokine and Eicosanoid Production.

Neutrophils are generally the first immune cells recruited during the development of sterile or microbial inflammation. As these cells express many innate immune receptors with the potential to directly recognize microbial or endogenous signals, we set out to assess whether their functions are locally influenced by the signals present at the onset of inflammation. Using a mouse model of peritonitis, we demonstrate that neutrophils elicited in the presence of C-type lectin receptor ligands have an increased ability to produce cytokines, chemokines, and lipid mediators in response to subsequent TLR stimulation. Importantly, we found that licensing of cytokine production was mediated by paracrine TNF-α-TNFR1 signaling rather than direct ligand sensing, suggesting a form of quorum sensing among neutrophils. Mechanistically, licensing was largely imparted by changes in the posttranscriptional regulation of inflammatory cytokines, whereas production of IL-10 was regulated at the transcriptional level. Altogether, our data suggest that neutrophils rapidly adapt their functions to the local inflammatory milieu. These phenotypic changes may promote rapid neutrophil recruitment in the presence of pathogens but limit inflammation in their absence.

Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy.

RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms. One candidate disease for RNAi therapy application is myotonic dystrophy type 1 (DM1), which results from toxicity of a mutant mRNA. DM1 is caused by expansion of a CTG repeat in the 3' UTR of the DMPK gene. The expression of DMPK mRNA containing an expanded CUG repeat (CUG(exp)) leads to defects in RNA biogenesis and turnover. We designed miRNA-based RNAi hairpins to target the CUG(exp) mRNA in the human α-skeletal muscle actin long-repeat (HSA(LR)) mouse model of DM1. RNAi expression cassettes were delivered to HSA(LR) mice using recombinant adeno-associated viral (rAAV) vectors injected intravenously as a route to systemic gene therapy. Vector delivery significantly reduced disease pathology in muscles of the HSA(LR) mice, including a reduction in the CUG(exp) mRNA, a reduction in myotonic discharges, a shift toward adult pre-mRNA splicing patterns, reduced myofiber hypertrophy and a decrease in myonuclear foci containing the CUG(exp) mRNA. Significant reversal of hallmarks of DM1 in the rAAV RNAi-treated HSA(LR) mice indicate that defects characteristic of DM1 can be mitigated with a systemic RNAi approach targeting the nuclei of terminally differentiated myofibers. Efficient rAAV-mediated delivery of RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies.

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis.

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven " in vivo perturbation " modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16 + monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4 + T cell populations, including increases in the frequency of TIGIT + regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4 + T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy.

Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.

Factors That Inform Individual Decision Making Between Active Surveillance, Hemithyroidectomy and Total Thyroidectomy for Low-Risk Thyroid Cancer: A Scoping Review.

Background: Due to the excellent prognosis and relatively high incidence of small low-risk thyroid cancers, more conservative management strategies such as active surveillance (AS) or hemithyroidectomy (HT) may be preferable to total thyroidectomy (TT) for patients seeking to balance long-term survival rates with the potential adverse effects of overtreatment. The aim of this review was to synthesize key factors or variables that inform patient decision making about treatment for low-risk thyroid cancer, from current primary investigations that presented participants with information facilitating this choice. Methods: Studies were identified from the Medline, Cochrane, and Embase databases up until March 2022. Study characteristics were extracted into a pre-piloted form. Factors were hypothesized to include treatment-related risks and possible outcomes and identified from a review of studies with consensus by discussion. Results: The search identified 444 unique studies: 397 were excluded on review of abstract and title with 47 studies undergoing a full text review and 6 studies identified to be eligible. Four were cross-sectional: one a prospective cohort study and one a mixed-methods study with both a prospective observational and qualitative component. The decisions addressed included: the choice between AS versus surgery (HT and/or TT) and HT versus TT and enrolled participants ranging from healthy volunteers to thyroid cancer patients. Treatment choice was the primary outcome in five studies. Across the studies, participants who were given the option of AS or surgery predominately chose the more conservative pathway, with a range of 70-84%. The major factors represented by information provision in the studies were risk of cancer recurrence or spread, need for hormone replacement therapy, and voice change. Conclusions: A framework of key factors informing patient treatment choice may be derived from current studies involving information provision for low-risk thyroid cancer management. Further research evaluating the efficacy and optimal timing for decision support interventions would help inform the design and clinical use of these tools to promote shared decision making.

A novel role for lipoxin A4 in driving a lymph node-eye axis that controls autoimmunity to the neuroretina.

The eicosanoid lipoxin A4 (LXA4) has emerging roles in lymphocyte-driven diseases. We identified reduced LXA4 levels in posterior segment uveitis patients and investigated the role of LXA4 in the pathogenesis of experimental autoimmune uveitis (EAU). Immunization for EAU with a retinal self-antigen caused selective downregulation of LXA4 in lymph nodes draining the site of immunization, while at the same time amplifying LXA4 in the inflamed target tissue. T cell effector function, migration and glycolytic responses were amplified in LXA4-deficient mice, which correlated with more severe pathology, whereas LXA4 treatment attenuated disease. In vivo deletion or supplementation of LXA4 identified modulation of CC-chemokine receptor 7 (CCR7) and sphingosine 1- phosphate receptor-1 (S1PR1) expression and glucose metabolism in CD4+ T cells as potential mechanisms for LXA4 regulation of T cell effector function and trafficking. Our results demonstrate the intrinsic lymph node LXA4 pathway as a significant checkpoint in the development and severity of adaptive immunity.

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

Electronic health records and outpatient cardiovascular disease care delivery: Insights from the American College of Cardiology's PINNACLE India Quality Improvement Program (PIQIP).

BACKGROUND: There has been a push toward implementation of electronic health records (EHRs) in federally-funded hospitals under the current policies initiated by the Indian government, with a lack of evidence supporting their adoption. We analyzed data from the American College of Cardiology's PINNACLE (Practice Innovation and Clinical Excellence) India Quality Improvement Program (PIQIP) to evaluate the association between EHR use and quality of cardiovascular disease care in India. METHODS AND RESULTS: Between 2011-2016, we collected data on performance measures for patients with coronary artery disease (CAD), heart failure (HF) and atrial fibrillation (AF) among 17 participating practices in PIQIP. There were 19,035 patients with CAD, 9,373 patients with HF, and 1,127 patients with AF. Documentation of co-morbidity burden in patients with CAD was lower among practices with EHR-hypertension (49.8% vs. 52.1%, p=0.003), diabetes (34.9% vs. 38.3%, p<0.001), and hyperlipidemia (0.2 vs. 3.9%, p<0.001). On the contrary, documentation of medication prescription was higher in CAD patients seen at practices with EHR-aspirin (63.2% vs. 17.8%, p<0.001), clopidogrel (41.7% vs. 27.4%, p<0.001), beta-blockers (61.4% vs. 9.8%, p<0.001), and ACE-i or ARBs (53.9% vs. 16.4%, p<0.001). Similarly, documentation of receipt of beta-blockers (43.8% vs. 10.7%, p<0.001), ACE-i or ARBs (40.8% vs. 16.1%, p<0.001), and beta-blockers+ACE-i or ARBs (36.4% vs. 3.6%, p<0.001) was also significantly higher in patients with HF seen at practices with EHR. Among patients with AF, documentation of oral anticoagulation use was significantly higher among EHR practices-warfarin (42.5% vs. 26.1%, p<0.001). CONCLUSIONS: Documentation of receipt of guideline-directed medical therapy in CAD, HF, and AF was significantly higher in practices with EHRs in India compared with sites without EHRs. Our findings shed a spotlight on the value of EHRs in future health care policy-making in India with regard to widespread adoption of EHRs in primary and advanced specialty care settings across public and private sectors.

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury.

Astrocytes perform critical non-cell autonomous roles following CNS injury that involve either neurotoxic or neuroprotective effects. Yet the nature of potential prosurvival cues has remained unclear. In the current study, we utilized the close interaction between astrocytes and retinal ganglion cells (RGCs) in the eye to characterize a secreted neuroprotective signal present in retinal astrocyte conditioned medium (ACM). Rather than a conventional peptide neurotrophic factor, we identified a prominent lipid component of the neuroprotective signal through metabolomics screening. The lipoxins LXA4 and LXB4 are small lipid mediators that act locally to dampen inflammation, but they have not been linked directly to neuronal actions. Here, we determined that LXA4 and LXB4 are synthesized in the inner retina, but their levels are reduced following injury. Injection of either lipoxin was sufficient for neuroprotection following acute injury, while inhibition of key lipoxin pathway components exacerbated injury-induced damage. Although LXA4 signaling has been extensively investigated, LXB4, the less studied lipoxin, emerged to be more potent in protection. Moreover, LXB4 neuroprotection was different from that of established LXA4 signaling, and therapeutic LXB4 treatment was efficacious in a chronic model of the common neurodegenerative disease glaucoma. Together, these results identify a potential paracrine mechanism that coordinates neuronal homeostasis and inflammation in the CNS.

Trends in U.S. Cardiovascular Care: 2016 Report From 4 ACC National Cardiovascular Data Registries.

Cardiovascular disease is a leading cause of death and disability in the United States. National programs, such as the National Cardiovascular Data Registry, facilitate assessments of the quality of care and outcomes for broad populations of patients with cardiovascular disease. This report provides data for 2014 from 4 National Cardiovascular Data Registry hospital quality programs: 1) CathPCI (Diagnostic Catheterization and Percutaneous Coronary Intervention) for coronary angiography and percutaneous coronary intervention (667,424 procedures performed in 1,612 hospitals); 2) ICD Registry for implantable cardioverter-defibrillators (158,649 procedures performed in 1,715 hospitals); 3) ACTION-GWTG (Acute Coronary Treatment and Intervention Outcomes Network-Get With The Guidelines) for acute coronary syndromes (182,903 patients admitted to 907 hospitals); and 4) IMPACT (Improving Pediatric and Adult Congenital Treatment) for cardiac catheterization and intervention for pediatric and adult congenital heart disease (20,169 procedures in 76 hospitals). The report provides perspectives on the demographic and clinical characteristics of enrolled patients, characteristics of participating centers, and selected measures of processes and outcomes of care in these programs.

Gender disparities in cardiovascular care access and delivery in India: Insights from the American College of Cardiology's PINNACLE India Quality Improvement Program (PIQIP).

BACKGROUND: Limited data are available to assess whether access to and quality of cardiovascular disease (CVD) care are comparable among men and women in India. We analyzed data from the American College of Cardiology's PINNACLE (Practice Innovation and Clinical Excellence) India Quality Improvement Program (PIQIP) to evaluate gender disparities in CVD care delivery. METHODS AND RESULTS: Between 2011 and 2015, we collected data on performance measures for patients with coronary artery disease (CAD) (n=14,010), heart failure (HF) (n=11,965) and atrial fibrillation (AF) (n=496) in PIQIP, among 17 participating practices. The total number of women was 31,796 (32.0%). Women had fewer total encounters compared to men during the study interval (mean number of encounters=2.59 vs. 2.82 for women and men, respectively, p≤0.001). Women were significantly younger (48.9years vs. 51.5years, p≤0.01), but had a higher co-morbidity burden compared to men - hypertension (62.0% vs. 45.6%, p≤0.01), diabetes (39.4% vs. 35%, p≤0.01), and hyperlipidemia (3.7% vs. 3.1%, p=0.19). On the contrary, the guideline-directed medication prescriptions were strikingly lower in women with CAD compared to men - aspirin (38% vs. 50.4%, p≤0.001), aspirin or thienopyridine combination (46.9% vs. 57.2%, p≤0.001), and beta-blockers (36.8% vs. 47.8%, p≤0.001). Similarly, among women with ejection fraction ≤40%, the use of guideline-directed medical therapy was significantly lower compared to men for beta-blockers (30.8% vs. 37.0%, p≤0.001), angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARBs) (29.3% vs. 34.9%, p≤0.001), and beta-blockers/ACE-i or ARBs (24.6% vs. 31.0%, p≤0.001). Among patients with atrial fibrillation and CHADS2 score≥2, more women were on oral anticoagulation (19.6% vs. 14.6%, p=0.34), although this was not significantly different, and the overall number of patients with atrial fibrillation was low. CONCLUSIONS: Despite a significantly higher co-morbidity burden in women, we found fewer women receiving guideline-directed medical therapy for CVD compared with men. If such disparities are confirmed in the larger Indian population, it is important to find potential causes for, and seek solutions to narrow this gap.

Guideline-Directed Medication Use in Patients With Heart Failure With Reduced Ejection Fraction in India: American College of Cardiology's PINNACLE India Quality Improvement Program.

Little is known about the use of guideline-directed medical therapy (GDMT) in outpatients with heart failure with reduced left ventricular ejection fraction (HFrEF; ≤40%) in India. Our objective was to understand the use of GDMT in outpatients with HFrEF in India. The Practice Innovation And Clinical Excellence (PINNACLE) India Quality Improvement Program (PIQIP) is a registry for cardiovascular quality improvement in India supported by the American College of Cardiology Foundation. Between January 2008 and September 2014, we evaluated documentation of use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and ß-blockers, or both, among outpatients with HFrEF seeking care in 10 centers enrolled in the PIQIP registry. Among 75 639 patients in the PIQIP registry, 34 995 had EF reported, and 15 870 had an EF ≤40%. The mean age was 56 years; 23% were female. Hypertension, diabetes, coronary artery disease, and myocardial infarction were present in 37%, 23%, 27%, and 17%, respectively. Use of ACEIs/ARBs, ß-blockers, and both were documented in 33.5%, 34.9%, and 29.6% of patients, respectively. The documentation of GDMT was higher in men, in patients age ≥65 years, and in those with presence of hypertension, diabetes, or coronary artery disease. Documentation of GDMT gradually increased over the study period. Among patients enrolled in the PIQIP registry, about two-thirds of patients with EF ≤40% did not have documented receipt of GDMT. This study is an initial step toward improving adherence to GDMT in India and highlights the feasibility of examining quality of care in HFrEF in a resource-limited setting.