Role of Platelet-rich Plasma in Unexplained Recurrent Implantation Failure - A Systematic Review and Meta-analysis of Randomised Control Trials.

Background: Recurrent implantation failure (RIF) is a challenging clinical situation and various strategies have been tried to improve the pregnancy rate in RIF. Platelet-rich plasma (PRP), which is obtained from the autologous blood samples of a person and is multiple times richer in platelets and other growth factors helps improve endometrial receptivity. Objective: This study has been conducted to summarise the evidence and quality of evidence available so far regarding the role of PRP in cases of unexplained RIF. Materials and Methods: An electronic database search for randomised clinical trials comparing PRP against routine care in women with unexplained RIF was performed on PubMed, EMBASE, SCOPUS and Cochrane Central. Two independent reviewers conducted a literature search and retrieved data using the predefined eligibility criteria. Bias assessment was done using the Cochrane Collaboration Network Risk of Bias Tool version 2. The quality of evidence was determined and a summary of the findings table was prepared for individual outcomes using GRADEpro software. Results: We identified 1146 records, and after removing duplicates, 531 records were screened. Out of these, 22 studies reached full-text screening and nine studies were included in the final review. We are uncertain about the effect of PRP due to the very low quality of evidence and we have little confidence that the administration of PRP had any significant effect on improving the live birth rate in women with RIF (odds ratio [OR]: 7.32, 95% confidence interval [CI]: 4.54-11.81, I2 = 40%). Similarly, the quality of evidence was low for the clinical pregnancy rate, so we are uncertain if the administration of PRP had any significant effect on the clinical pregnancy rate (OR: 3.20, 95% CI: 2.38-4.28, I2 = 0%). Interpretation: The current review suggests that there may be some beneficial effects of PRP in women with RIF, but the quality of evidence is very low and we are uncertain of the benefit and have little confidence in these findings. Limitations: Limitations are the small sample size of most studies, a short follow-up period, non-uniformity in the definition of outcomes and very low quality of evidence. Registration: The protocol was registered on PROSPERO (CRD42021292209).

Micro-RNAs With Prognostic Significance in Gallbladder Cancer: A Systematic Review and Meta-Analysis.

Gallbladder cancer (GBC) stands out as one of the most widespread malignancies impacting the biliary tract globally. Despite increasing interest, to the best of our knowledge, no meta-analysis has been undertaken to amalgamate the existing data concerning the prognostic significance of micro-RNAs (miRNAs) in GBC in comparison to studies on miRNAs in other cancers. Hence, this systematic review and meta-analysis aimed at determining the prognostic significance of miRNAs in GBC patients. Comprehensive literature searches were conducted across PubMed, Cochrane Library, Ovid, Scopus, and Science Direct databases. Studies that evaluated the association between miRNAs and overall survival in GBC patients were included. Random-effect meta-analysis was employed to pool hazard ratios (HRs) and their 95% confidence intervals (CIs) across studies. A total of 15 studies, encompassing 16 miRs, were included for our analysis. The pooled analysis revealed that a high expression of miR-204, miR-7-2-3p, miR-29c-3p, miR-125b, miR-20a, miR-139-5p, miR-141, miR-92b-3p, miR-335, and miR-372 was significantly associated with poor prognosis and increased risk (HR>1 and the upper bound of the 95% CI>1). Additionally, these miRNAs were associated with the overall survival (HR = 1.56, 95% CI = 0.91-2.20, I2 = 91.82%). Significant heterogeneity was observed and could be attributed to the limited number of studies available on the GBC and significant reliance on quantitative real-time PCR for the detection of miRNAs. In conclusion, specific miRNAs exhibit prognostic significance in GBC, with potential implications for patient stratification and targeted therapeutic interventions. However, due to the heterogeneity among studies, these findings should be interpreted cautiously and validated in larger cohorts.

Visceral Fat Predicts New-Onset Diabetes After Necrotizing Pancreatitis.

OBJECTIVES: We aimed to estimate the incidence of new-onset diabetes (NOD) and identify risk factors for NOD in patients with necrotizing pancreatitis (NP). METHODS: Necrotizing pancreatitis patients were reviewed for NOD, diagnosed >90 days after acute pancreatitis. Baseline demographics, comorbidities, clinical outcomes, computed tomography (CT) characteristics of necrotic collections, and CT-derived abdominal fat measurements were analyzed to identify predictors for NOD. RESULTS: Among 390 eligible NP patients (66% men; median age, 51 years; interquartile range [IQR], 36-64) with a median follow-up of 400 days (IQR, 105-1074 days), NOD developed in 101 patients (26%) after a median of 216 days (IQR, 92-749 days) from NP. Of the NOD patients, 84% required insulin and 69% developed exocrine pancreatic insufficiency (EPI). Age (odds ratio [OR], 0.98), male sex (OR, 2.7), obesity (OR, 2.1), presence of EPI (OR, 2.7), and diffuse pancreatic necrosis (OR, 2.4) were independent predictors. In a separate multivariable model assessing abdominal fat on CT, visceral fat area (highest quartile) was an independent predictor for NOD (OR, 3.01). CONCLUSIONS: New-onset diabetes was observed in 1 of 4 patients with NP, most within the first year and requiring insulin. Male sex, obesity, diffuse pancreatic necrosis, development of EPI, and high visceral adiposity identified those at highest risk.

Safety, efficacy and health impact of electronic nicotine delivery systems (ENDS): an umbrella review protocol.

BACKGROUND: Electronic nicotine delivery systems (ENDS), commonly known as e-cigarettes or vapes, have witnessed a rise in popularity, particularly among the youth. Although they were initially introduced as an alternative to traditional smoking, the design and function of ENDS vary. The potential health effects of ENDS, especially in comparison to traditional cigarettes, are a matter of ongoing debate. Given the increasing number of clinical studies and systematic reviews on this topic, there exists a demand for an umbrella review that offers a comprehensive assessment. The goal of this study is to perform an umbrella review of systematic reviews and meta-analyses to assess the safety, efficacy, health implications and potential gateway effect associated with ENDS. METHODS AND ANALYSIS: This umbrella review will adhere to the Joanna Briggs Institute (JBI) framework and the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. A planned literature search will be executed across databases such as OVID, PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science. The inclusion criteria are systematic reviews that discuss ENDS and e-liquids in the context of safety, efficacy and health outcomes. The exclusion criteria include narrative reviews, non-systematic reviews and studies not in English. Quality of the selected studies will be evaluated using the AMSTAR V.2 Scale. An overlap assessment will be done using the Corrected Covered Area, and data synthesis will be presented both narratively and in tabulated forms ETHICS AND DISSEMINATION: Ethics approval is not required for this study, as it does not involve the collection of original data. The results will be disseminated through peer-reviewed publication. The findings will offer crucial insights for stakeholders, policy-makers and the general public, underlining the health implications and the role of ENDS in tobacco cessation.

Polycyclic Pyrazoles from Alkynyl Cyclohexadienones and Nonstabilized Diazoalkanes via [3 + 2]-Cycloaddition/[1,5]-Sigmatropic Rearrangement/Aza-Michael Reaction Cascade.

An efficient method for the stereoselective synthesis of "all center substituted" polycyclic pyrazoles from alkynyl cyclohexa-2,5-dienones and nonstabilized diazoalkanes via sequential [3 + 2]-cycloaddition/[1,5]-sigmatropic rearrangement and aza-Michael reactions is reported. The developed process is highly regioselective and stereoselective. It employs a wide substrate scope to furnish structurally diverse linear and bridged [4.4.n.0] ring-fused pyrazoles in moderate to good yields. One-pot and gram-scale syntheses and synthetic transformations have also been showcased.

Platelet Metabolic Profiling Reveals Glycolytic and 1-Carbon Metabolites Are Essential for GP VI-Stimulated Human Platelets-Brief Report.

BACKGROUND: Evolving evidence suggests that besides signaling pathways, platelet activation involves a complex interplay between metabolic pathways to support thrombus growth. Selective targeting of metabolic checkpoints may inhibit platelet activation and provide a novel antiplatelet strategy. We, therefore, examined global metabolic changes that occur during the transition of human platelets from resting to an activated state to identify metabolites and associated pathways that contribute to platelet activation. METHODS: We performed metabolic profiling of resting and convulxin-stimulated human platelet samples. The differential levels, pathway analysis, and PCA (principal component analysis) were performed using Metaboanalyst. Metascape was used for metabolite network construction. RESULTS: Of the 401 metabolites identified, 202 metabolites were significantly upregulated, and 2 metabolites were downregulated in activated platelets. Of all the metabolites, lipids scored highly and constituted ≈50% of the identification. During activation, aerobic glycolysis supports energy demand and provides glycolytic intermediates required by metabolic pathways. Consistent with this, an important category of metabolites was carbohydrates, particularly the glycolysis intermediates that were significantly upregulated compared with resting platelets. We found that lysophospholipids such as 1-palmitoyl-GPA (glycero-3-phosphatidic acid), 1-stearoyl-GPS (glycero-3-phosphoserine), 1-palmitoyl-GPI (glycerophosphoinositol), 1-stearoyl-GPI, and 1-oleoyl-GPI were upregulated in activated platelets. We speculated that platelet activation could be linked to 1-carbon metabolism, a set of biochemical pathways that involve the transfer and use of 1-carbon units from amino acids, for cellular processes, including nucleotide and lysophospholipid synthesis. In alignment, based on pathway enrichment and network-based prioritization, the metabolites from amino acid metabolism, including serine, glutamate, and branched-chain amino acid pathway were upregulated in activated platelets, which might be supplemented by the high levels of glycolytic intermediates. CONCLUSIONS: Metabolic analysis of resting and activated platelets revealed that glycolysis and 1-carbon metabolism are necessary to support platelet activation.

Does SARS Cov-2 infection affect the IVF outcome - A systematic review and meta-analysis.

STUDY QUESTION: What is the effect of SARS Cov-2 on IVF outcome? SUMMARY ANSWER: Mild or asymptomatic Covid-19 infection does not appear to affect clinical or ongoing pregnancy rate after IVF. WHAT IS ALREADY KNOWN: Covid-19 has been shown to affect female and male fertility and reproductive function. Studies have shown variable results regarding impact of Covid-19 on IVF outcome with few reporting impaired ovarian reserve, oocyte and embryo quality, semen parameters, clinical pregnancy rate (CPR) and live birth rate (LBR) while others reported no effect on IVF outcome. STUDY DESIGN, SIZE, DURATION: An electronic database search of PubMed, EMBASE, SCOPUS, WHO Covid-19 database, Clinical trials.gov and Cochrane Central was performed for articles published in English language between 1st January 2020 and 15th October 2022 by two independent reviewers using predefined eligibility criteria We have included observational studies both prospective and retrospective, cohort studies, and case control studies and excluded narrative reviews, case studies, cost-effectiveness studies or diagnostic studies. Risk of bias was assessed using NOS and quality of evidence was graded by GRADE pro. PARTICIPANTS, SETTINGS, METHODS: Studies comparing women undergoing IVF and comparing Covid-19 affected with those unaffected by Covid-19 were included. Also, studies comparing immune group (infected or vaccinated) in the study group and unaffected as controls (historical controls, IVF cycles done prior to Covid-19 outbreak but matched with study group) were included. Those with no comparison group or published in language other than English language or duplicate studies were excluded. MAIN RESULTS AND ROLE OF CHANCE: We identified 5046 records and after full text screening of 82 studies, 12 studies were selected for final review. For the clinical pregnancy rate, there was no difference in the CPR in covid recovered or control patients (OR 0.90, 95 % CI = 0.67 to1.21; I2 = 29 %). Similarly, there was no significant effect on implantation rate (RR 0.92, 95 % CI = 0.68 to1.23; I2 = 31 %) and ongoing pregnancy rate (RR 0.96, 95 % CI = 0.79 to 1.15;I2 = 21 %). The mean number of the oocyte retrieved per patient was not significantly different in both the groups (mean difference 0.52, 95 % CI = -1.45 to 2.49; I2 = 75 %). The certainty of the evidence was low. LIMITATIONS: The meta-analysis is based on observational studies each involving small number of participants. Few studies reported outcomes as per patient while others reported as per cycle, for uniformity we have reported outcomes as per cycle. Sample size in most of studies was small. WIDER IMPLICATIONS OF FINDINGS: This systematic review has not shown any significant effect on the outcome of IVF cycles in patients post Covid-19 recovery compared to controls. But given the sample size, the findings should be considered with caution. REGISTRATION: The review protocol has been registered on PROSPERO (registration number CRD42022314515).

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research.

A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?

Current antithrombotic therapies used in clinical settings target either the coagulation pathways or platelet activation receptors (P2Y12 or GPIIb/IIIa), as well as the cyclooxygenase (COX) enzyme through aspirin. However, they are associated with bleeding risk and are not suitable for long-term use. Thus, novel strategies which provide broad protection against platelet activation with minimal bleeding risks are required. Regardless of the nature of agonist stimulation, platelet activation is an energy-intensive and ATP-driven process characterized by metabolic switching toward a high rate of aerobic glycolysis, relative to oxidative phosphorylation (OXPHOS). Consequently, there has been considerable interest in recent years in investigating whether targeting metabolic pathways in platelets, especially aerobic glycolysis and OXPHOS, can modulate their activation, thereby preventing thrombosis. This review briefly discusses the choices of metabolic substrates available to platelets that drive their metabolic flexibility. We have comprehensively elucidated the relevance of aerobic glycolysis in facilitating platelet activation and the underlying molecular mechanisms that trigger this switch from OXPHOS. We have provided a detailed account of the antiplatelet effects of targeting vital metabolic checkpoints such as pyruvate dehydrogenase kinases (PDKs) and pyruvate kinase M2 (PKM2) that preferentially drive the pyruvate flux to aerobic glycolysis. Furthermore, we discuss the role of fatty acids and glutamine oxidation in mitochondria and their subsequent role in driving OXPHOS and platelet activation. While the approach of targeting metabolic regulatory mechanisms in platelets to prevent their activation is still in a nascent stage, accumulating evidence highlights its beneficial effects as a potentially novel antithrombotic strategy.

Psychobiotics for Mitigation of Neuro-Degenerative Diseases: Recent Advancements.

Ageing is inevitable and poses a universal challenge for all living organisms, including humans. The human body experiences rapid cell division and metabolism until approximately 25 years of age, after which the accumulation of metabolic by-products and cellular damage leads to age-related diseases. Neurodegenerative diseases are of concern due to their irreversible nature, lack of effective treatment, and impact on society and the economy. Researchers are interested in finding drugs that can effectively alleviate ageing and age-related diseases without side-effects. Psychobiotics are a novel class of probiotic organisms and prebiotic interventions that confer mental health benefits to the host when taken appropriately. Psychobiotic strains affect functions related to the central nervous system (CNS) and behaviors mediated by the Gut-Brain-Axis (GBA) through various pathways. There is an increasing interest in researchers of these microbial-based psychopharmaceuticals. Psychobiotics have been reported to reduce neuronal ageing, inflammation, oxidative stress, and cortisol levels; increase synaptic plasticity and levels of neurotransmitters and antioxidants. The present review focuses on the manifestation of elderly neurodegenerative and mental disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), and depression, and the current status of their potential alleviation through psychobiotic interventions, highlighting their possible mechanisms of action.

Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia.

BACKGROUND: Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9ß1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. METHODS: α9Neu-KO (α9fl/flMRP8Cre+) and littermate control α9WT (α9fl/flMRP8Cre-) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1ß levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. RESULTS: Stroke upregulated neutrophil α9 expression more in obese mice (P<0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) (P<0.05 versus α9WT obese mice). Obese α9Neu-KO mice were less susceptible to thrombosis in FeCl3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti-integrin α9 exhibited improved functional outcomes up to 4 weeks (P<0.05 versus vehicle). CONCLUSIONS: Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.

US Quantification of Liver Fat: Past, Present, and Future.

Fatty liver disease has a high and increasing prevalence worldwide, is associated with adverse cardiovascular events and higher long-term medical costs, and may lead to liver-related morbidity and mortality. There is an urgent need for accurate, reproducible, accessible, and noninvasive techniques appropriate for detecting and quantifying liver fat in the general population and for monitoring treatment response in at-risk patients. CT may play a potential role in opportunistic screening, and MRI proton-density fat fraction provides high accuracy for liver fat quantification; however, these imaging modalities may not be suited for widespread screening and surveillance, given the high global prevalence. US, a safe and widely available modality, is well positioned as a screening and surveillance tool. Although well-established qualitative signs of liver fat perform well in moderate and severe steatosis, these signs are less reliable for grading mild steatosis and are likely unreliable for detecting subtle changes over time. New and emerging quantitative biomarkers of liver fat, such as those based on standardized measurements of attenuation, backscatter, and speed of sound, hold promise. Evolving techniques such as multiparametric modeling, radiofrequency envelope analysis, and artificial intelligence-based tools are also on the horizon. The authors discuss the societal impact of fatty liver disease, summarize the current state of liver fat quantification with CT and MRI, and describe past, currently available, and potential future US-based techniques for evaluating liver fat. For each US-based technique, they describe the concept, measurement method, advantages, and limitations. © RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Characterization of bleeding symptoms in Ehlers-Danlos syndrome.

BACKGROUND: Easy bruising is included as a major or minor criterion for the classification of multiple types of Ehlers-Danlos syndrome (EDS). Despite a longstanding recognition of the association between EDS and bleeding, we still lack a definitive understanding of the frequency, severity, and types of bleeding complications in patients with EDS. OBJECTIVES: To evaluate hemorrhagic symptoms using the International Society of Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) in a cohort of patients with defined types of EDS. METHODS: We utilized the ISTH-BAT to characterize hemorrhagic symptoms and their severity in a cohort of 52 patients with classical, classical-like, hypermobile, or vascular EDS and a matched group of 52 healthy control subjects. RESULTS: The mean ISTH-BAT score was 0.1 for healthy subjects and 9.1 for patients with EDS (p < .0001). An abnormal ISTH-BAT score was observed in 32 of 52 (62%) patients with EDS and 0 of 52 healthy controls (p < .0001). The most frequent bleeding symptoms were bruising, muscle hematomas, menorrhagia, epistaxis, bleeding from the oral cavity, and bleeding after tooth extraction. Menorrhagia that was life-threatening or required surgery was reported in 7 of 52 (14%) patients with EDS. CONCLUSION: Patients with multiple types of EDS exhibit a wide range of bleeding symptoms ranging from mild to life-threatening episodes.

Otitis Media Prevalence in Children Below 18 Years of Age of India and the Associated Risk Factors: A Systematic Review and Meta-Analysis.

Ear ailments in children are a major public health problem in India. This systematic review and meta-analysis aim to quantitatively pool the epidemiologic evidence on the prevalence of all forms of otitis media in children of India. In this review PRISMA guidelines (preferred reporting items for systematic reviews and meta-analysis) were followed. We did extensive literature search in PubMed, Embase, Cinahl and Web of Science to identify relevant community based cross sectional studies that investigated the prevalence of otitis media in children of India. We used STATA version 16.0 software to perform meta-analysis. Six studies reporting the prevalence of otitis media in children were included in the final analysis. Based on the results of the random-effects sub-group meta-analysis model, the pooled estimated prevalence of Chronic suppurative otitis media in children of India was 3.78% (95% CI 2.72-4.84), Otitis media with effusion was found to be 2.68% (95% CI 1.80, 3.55) and Acute suppurative otitis media to be 0.55 (95% CI 0.32, 0.78). This review suggests substantial otitis media related disease burden in children of India. But due to lack of epidemiological studies, the actual disease burden remains concealed. It is imperative to promote more epidemiological studies that will aid policy makers in recommendation of preventive, diagnostic and treatment strategies for this disease.

Catalyst-Controlled Diastereoselective Synthesis of Bridged [3.3.1] Bis(Indolyl)-Oxanes and Oxepanes via Desymmetrization of Bis(Indolyl)-Cyclohexadienones.

A catalyst-controlled divergent synthesis of bridged [3.3.1] bis(indolyl)-oxanes and cis-[6.7] fused bis(indolyl) oxepanes via diastereoselective desymmetrization of bis(indolyl)-cyclohexadienones is presented for the first time. The reaction is highly atom- and step-economic, furnishing sp3-rich functionalized bis(indolyl) derivatives in good to excellent yields with wide substrate scope. The reaction proceeds through Friedel-Crafts alkylation followed by catalyst-controlled selective C-C bond formation/rearrangement. Gram scale synthesis and synthetic utility to generate bis(indolyl) alkaloid-like molecular diversity were also illustrated.

Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis.

BACKGROUND: Mitochondrial calcium uniporter b (MCUb) is a negative regulator of the mitochondrial calcium uniporter (MCU) and is known to limit mitochondrial calcium ion (Ca2+) uptake. The role of MCUb in platelet function remains unclear. OBJECTIVES: Utilizing MCUb-/- mice, we examined the role of MCUb in regulating platelet function and thrombosis. METHODS: Platelet activation was evaluated in agonist-induced standardized in vitro assays. Susceptibility to arterial thrombosis was evaluated in FeCl3 injury-induced carotid artery and laser injury-induced mesenteric artery thrombosis models. The glycolytic proton efflux rate and oxygen consumption rate were measured to evaluate aerobic glycolysis. RESULTS: Upon stimulation, MCUb-/- platelets exhibited reduced cytoplasmic Ca2+ responses concomitant with increased mitochondrial Ca2+ uptake. MCUb-/- platelets displayed reduced agonist-induced platelet aggregation and spreading on fibrinogen and decreased α and dense-granule secretion and clot retraction. MCUb-/- mice were less susceptible to arterial thrombosis in FeCl3 injury-induced carotid and laser injury-induced mesenteric thrombosis models with unaltered tail bleeding time. In adoptive transfer experiments, thrombocytopenic hIL-4Rα/GPIbα-transgenic mice transfused with MCUb-/- platelets were less susceptible to FeCl3 injury-induced carotid thrombosis compared with hIL-4Rα/GPIbα-Tg mice transfused with wild type platelets, suggesting a platelet-specific role of MCUb in thrombosis. MCUb-/- stimulated platelets exhibited reduced glucose uptake, decreased glycolytic rate, and lowered pyruvate dehydrogenase phosphorylation, suggesting that mitochondrial Ca2+ mediates bioenergetic changes in platelets. CONCLUSION: Our findings suggest that mitochondrial Ca2+ signaling and glucose oxidation are functionally linked in activated platelets and reveal a novel role of MCUb in platelet activation and arterial thrombosis.

Cost-Effectiveness of Currently Available Diagnostic Tools for Diagnosis of Pediatric Tuberculosis Under National Tuberculosis Elimination Program.

In India, children do not get diagnosed with tuberculosis (TB) for reasons such as lack of screening modality at the health-care settings, inadequate sputum sample, and low detection rate. This study aims to assess various modalities for diagnosis of pediatric TB and their cost-effectiveness. Cost-effectiveness was found for various diagnostic modalities for TB diagnosis in children of India below 15 years of age. TrueNat MTB was the intervention being compared to GeneXpert MTB and sputum microscopy. Evidence pertinent to effectiveness and cost per test, and health benefits in terms of disability adjusted life years were researched and documented. Modeling a cohort of children through a decision tree and assimilating costs and disability-adjusted life years (DALYs) at each step gave results in the form of cost-effectiveness. Interventions were compared by calculating the cost-effectiveness ratio. The results revealed that TrueNat is more cost effective (Rs. 9450/DALY averted) compared to GeneXpert MTB/RIF (Rs. 9750/DALY averted). The incremental cost effectiveness ratio of TrueNat with respect to GeneXpert was found to be Rs. 5925 per DALY averted. Diagnosis through TrueNat point of care (POC) will avert 962 more DALYs compared to GeneXpert. As is evident from the results, TrueNat does alleviate disability caused by TB in children as more DALYs are averted. At an additional cost of Rs. 5925 to avert one DALY, which is below the gross domestic product (GDP) per capita for India (for 2021, it was $2277), TrueNat can have significant health benefits.