Thromboelastography-guided vs. standard-of-care or on-demand platelet transfusion in patients with cirrhosis and thrombocytopenia undergoing procedures: A randomized controlled trial.

PURPOSE: To compare the efficacy and safety of a thromboelastography (TEG)-guided platelet transfusion strategy to empirical or on-demand transfusions in patients with cirrhosis and severe thrombocytopenia (platelet counts <50 x109/L) undergoing high-risk invasive procedures. MATERIALS AND METHODS: This was a single-center, single-blinded, randomized controlled trial. Patients with cirrhosis and severe thrombocytopenia undergoing high-risk invasive procedures were randomized into three groups- TEG group: transfusions based on TEG parameters; SOC group: 3 units of random donor platelets pre-procedure; On-demand group: transfusions based on procedural adverse effects /clinician's discretion. The primary outcome was periprocedural platelet transfusion in each arm. RESULTS: Eighty-seven patients were randomized (29 in each group) with no significant differences in demographics/coagulation profile/procedures. The median platelet count was 33 x109/L (IQR: 26-43). Percutaneous liver biopsy was the most common procedure (46, 52.9%). Significantly lower number of patients in the TEG group received platelets (4 cases, 13.8%; 95%CI: 3.9-31.7) compared to SOC (100%; 95%CI: 88.1-100) (p<0.001). Four patients in the on-demand group received platelets (13.8%; 95%CI: 3.9-31.7). Minor (WHO grade 2) procedure-related bleeding occurred in 3 (10%; 95%CI: 2.2-27.4) patients in the TEG-guided transfusion group, compared to 1 (3.4%; 95%CI: 0.1-17.8) each in SOC and on-demand groups, respectively (p=0.43) although our sample size was underpowered for comparison of outcomes such as post-procedural bleeding. No bleeding-related mortality was observed in any of the three groups. CONCLUSION: Thromboelastography-guided transfusion reduces prophylactic transfusions in patients with cirrhosis and severe thrombocytopenia undergoing high-risk invasive procedures. (CTRI/2021/05/033464).

Comparison of Sub-Ppm Instrument Response Suggests Higher Detection Limits Could Be Used to Quantify Methane Emissions from Oil and Gas Infrastructure.

Quantifying and controlling fugitive methane emissions from oil and gas facilities remains essential for addressing climate goals, but the costs associated with monitoring millions of production sites remain prohibitively expensive. Current thinking, supported by measurement and simple dispersion modelling, assumes single-digit parts-per-million instrumentation is required. To investigate instrument response, the inlets of three trace-methane (sub-ppm) analyzers were collocated on a facility designed to release gas of known composition at known flow rates between 0.4 and 5.2 kg CH4 h-1 from simulated oil and gas infrastructure. Methane mixing ratios were measured by each instrument at 1 Hertz resolution over nine hours. While mixing ratios reported by a cavity ring-down spectrometer (CRDS)-based instrument were on average 10.0 ppm (range 1.8 to 83 ppm), a mid-infrared laser absorption spectroscopy (MIRA)-based instrument reported short-lived mixing ratios far larger than expected (range 1.8 to 779 ppm) with a similar nine-hour average to the CRDS (10.1 ppm). We suggest the peaks detected by the MIRA are likely caused by a micrometeorological phenomenon, where vortex shedding has resulted in heterogeneous methane plumes which only the MIRA can observe. Further analysis suggests an instrument like the MIRA (an optical-cavity-based instrument with cavity size ≤10 cm3 measuring at ≥2 Hz with air flow rates in the order of ≤0.3 slpm at distances of ≤20 m from the source) but with a higher detection limit (25 ppm) could detect enough of the high-concentration events to generate representative 20 min-average methane mixing ratios. Even though development of a lower-cost, high-precision, high-accuracy instrument with a 25 ppm detection threshold remains a significant problem, this has implications for the use of instrumentation with higher detection thresholds, resulting in the reduction in cost to measure methane emissions and providing a mechanism for the widespread deployment of effective leak detection and repair programs for all oil and gas infrastructure.

ECG manifestations of occlusion of septal perforator of left anterior descending artery.

The fourth universal definition of MI defines requires presence of j point elevation in two contiguous leads except v2-3 where the elevation should be equal to or >2 mm in men (2.5 mm in <40 years) and 1.5 mm in women.(1) We present two cases of patients who presented with electrocardiographic manifestations of occlusion of septal perforator of left anterior descending artery and discuss the salient feature of ECG in such patients. We also present the limitations of STEMI criteria given the dynamic nature of acute coronary occlusion and stress on early recognition of this MI.

Temporary pacing through umbilical venous route for neonatal heart failure due to complete atrioventricular block.

We present a case of a neonate who presented with worsening heart failure due to congenital complete atrioventricular (AV) block, secondary to maternal anti Ro/SSA and anti-LA/SSB antibodies. The patient was implanted a temporary pacemaker in view of hemodynamic deterioration and subsequently was weaned off ionotropic support and referred for permanent epicardial pacemaker implantation. We report temporary pacemaker implantation in a neonate with hemodynamic instability as a stabilizing measure and discuss technical challenges for the same.

Crazy accessory pathway- going round the bend!

A 15-year-old boy with manifest preexcitation and recurrent palpitations had undergone an unsuccessful ablation procedure elsewhere and was subsequently referred to us. The ECG suggested a left free wall pathway but there was a pattern break in lead V2. This helped localise the accessory pathway to the summit region and achieve success.

Methane emissions from abandoned oil and gas wells in Colorado.

Recent studies indicate emission factors used to generate bottom-up methane inventories may have considerable regional variability. The US's Environmental Protection Agency's emission factors for plugged and unplugged abandoned oil and gas wells are largely based on measurement of historic wells and estimated at 0.4 g and 31 g CH4 well-1 h-1, respectively. To investigate if these are representative of wells more recently abandoned, methane emissions were measured from 128 plugged and 206 unplugged abandoned wells in Colorado, finding the first super-emitting abandoned well (76 kg CH4 well-1 h-1) and average emissions of 0 and 586 g CH4 well-1 h-1, respectively. Combining these with other states' measurements, we update the US emission factors to 1 and 198 g CH4 well-1 h-1, respectively. Correspondingly, annual methane emissions from the 3.4 million abandoned wells in the US are estimated at between 2.6 Tg, following current methodology, and 1.1 Tg, where emissions are disaggregated for well-type. In conclusion, this study identifies a new abandoned well-type, recently-producing orphaned, that contributes 74 % to the total abandoned wells methane emissions. Including this new well-type in the bottom-up inventory suggests abandoned well emissions equate to between 22 and 49 % of total emissions from US active oil and gas production operations.

Comparison of 1-day versus 3-day intravenous terlipressin in cirrhosis patients with variceal bleeding: A pilot randomised controlled trial.

BACKGROUND: In cirrhosis patients with acute variceal bleeding (AVB), the optimal duration of vasoconstrictor therapy after endoscopic haemostasis is unclear. AIMS: We aimed to compare efficacy of 1-day versus 3-day terlipressin therapy in cirrhosis patients with AVB post-endoscopic intervention. The primary objective was to compare rebleeding at 5 days between the two arms. Secondary objectives included rebleeding and mortality rates at 6 weeks. METHODS: In this open-label, randomised controlled trial, cirrhosis patients with AVB were randomised to either 1-day or 3-day terlipressin therapy. RESULTS: A total of 150 cirrhosis patients with AVB were recruited to receive either 1 day (n = 75) or 3 days (n = 75) of terlipressin therapy. One patient from 1-day arm was excluded. Modified intention-to-treat analysis included 149 patients. Baseline characteristics were comparable between the two groups. Rebleeding at 5 days: 3 (4.1%; 95% confidence interval [CI]: 0.4-9.0) versus 4 (5.3%; 95% CI: 2.0-10.0), risk difference (RD) p = 0.726 and 5-day mortality rates: 1 (1.4%; 95% CI: 0-7.3) versus 1 (1.3%; 95% CI: 0.2-7.0), RD p = 0.960 were similar. Rebleeding at 42 days: 9 (12.2%; 95% CI: 7.0-20.0) versus 10 (13.3%; 95% CI: 7.0-20.0), RD p = 0.842 and mortality at 42 days: 5 (6.8%; 95% CI: 3.0-10.0) versus 4 (5.3%; 95% CI: 2.0-10.0), RD p = 0.704 were also similar. Patients in the 1-day terlipressin therapy arm experienced significantly fewer adverse effects compared with those receiving 3 days of terlipressin therapy: 28 (37.8%) versus 42 (56%), p = 0.026. CONCLUSIONS: Our results suggest that 1 day of terlipressin therapy is associated with similar 5-day and 42-day rebleeding rates, 42-day mortality and an overall superior safety profile compared with 3-day of terlipressin therapy. These findings require to be validated in double-blinded, larger, multiethnic and multicentre studies across the various stages of cirrhosis (CTRI/2019/10/021771).

Opposing roles for TGFß- and BMP-signaling during nascent alveolar differentiation in the developing human lung.

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFß- and BMP-signaling, where inhibition of TGFß- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFß-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFß- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.

ABDA Score: A Non-invasive Model to Identify Subjects with Fibrotic Non-alcoholic Steatohepatitis in the Community.

Background: Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are prevalent in the community, especially among those with metabolic syndrome. Patients with fibrotic NASH are at increased risk of liver-related-events. Currently available non-invasive tests have not been utilized for screening for fibrotic NASH among the community. We aimed to develop a screening tool for fibrotic NASH among community members. Methods: We included two large cohorts aimed at assessing cardiovascular disease among community members. Fibrotic NASH was defined using the FibroScan-aspartate aminotransferase score of ≥0.67 that identifies ≥F2 fibrosis and a non-alcoholic fatty liver disease activity score ≥4 with a specificity of 90%. Metabolic parameters, biochemical tests and anthropometry were used to develop a multivariate model. Results: The derivation cohort (n = 1660) included a population with a median age 45 years, 42.5% males, metabolic syndrome in 66% and 2.7% (n = 45) with fibrotic NASH. Multivariate analysis identified the four significant variables (Age, body mass index , Diabetes and alanine aminotransferas levels) used to derive an ABDA score. The score had high diagnostic accuracy (the area under receiver-operating characteristic curve, 0.952) with adequate internal validity. An ABDA score ≥-3.52 identified fibrotic NASH in the derivation cohort with a sensitivity and specificity of 88.9% and 88.3%. The score was validated in a second cohort (n = 357) that included 21 patients (5.9%) with fibrotic NASH, where it demonstrated a high area under receiver-operating characteristic curve (0.948), sensitivity (81%) and specificity (89.3%). Conclusions: ABDA score utilizes four easily available parameters to identify fibrotic NASH with high accuracy in the community.

Hepatic Venous Pressure Gradient Predicts Further Decompensation in Cirrhosis Patients with Acute Esophageal Variceal Bleeding.

BACKGROUND: The role of hepatic venous pressure gradient (HVPG) in predicting further decompensation in cirrhosis patients with acute variceal bleeding (AVB) is not known. We aimed to evaluate the role of HVPG in predicting further decompensation in cirrhosis patients with AVB Methods: In this prospective study, 145 patients with cirrhosis with esophageal or gastric AVB were included. HVPG was measured on the day of the AVB. Decompensating events occurring after 42-days of AVB were considered further decompensation. RESULTS: The median age of the study cohort was 44 years; 88.3% males. The predominant etiology of cirrhosis was alcohol (46.2%). Overall, 40 (27.6%) patients developed further decompensation during median follow-up of 296 days following AVB. Gastro intestinal bleeding n = 27 (18.6%) and new-onset/worsening ascites n = 20 (13.8%) were the most common decompensating events. According to the multivariate model, HVPG was an independent predictor of any further decompensation in esophageal AVB patients but not in gastric variceal bleeding patients. HVPG cut-off of ≥16 mmHg predicted further decompensation in the esophageal AVB. However, HVPG was not an independent predictor of mortality. CONCLUSION: HVPG measured during an episode of acute variceal hemorrhage from esophageal varices predicts further decompensating events in cirrhosis patients.

Partitioning Quantum Chemistry Simulations with Clifford Circuits.

Current quantum computing hardware is restricted by the availability of only few, noisy qubits which limits the investigation of larger, more complex molecules in quantum chemistry calculations on quantum computers in the near term. In this work, we investigate the limits of their classical and near-classical treatment while staying within the framework of quantum circuits and the variational quantum eigensolver. To this end, we consider naive and physically motivated, classically efficient product ansatz for the parametrized wavefunction adapting the separable-pair ansatz form. We combine it with post-treatment to account for interactions between subsystems originating from this ansatz. The classical treatment is given by another quantum circuit that has support between the enforced subsystems and is folded into the Hamiltonian. To avoid an exponential increase in the number of Hamiltonian terms, the entangling operations are constructed from purely Clifford or near-Clifford circuits. While Clifford circuits can be simulated efficiently classically, they are not universal. In order to account for missing expressibility, near-Clifford circuits with only few, selected non-Clifford gates are employed. The exact circuit structure to achieve this objective is molecule-dependent and is constructed using simulated annealing and genetic algorithms. We demonstrate our approach on a set of molecules of interest and investigate the extent of our methodology's reach.

Regionally distinct progenitor cells in the lower airway give rise to neuroendocrine and multiciliated cells in the developing human lung.

Using scRNA-seq and microscopy, we describe a cell that is enriched in the lower airways of the developing human lung and identified by the unique coexpression of SCGB3A2/SFTPB/CFTR. To functionally interrogate these cells, we apply a single-cell barcode-based lineage tracing method, called CellTagging, to track the fate of SCGB3A2/SFTPB/CFTR cells during airway organoid differentiation in vitro. Lineage tracing reveals that these cells have a distinct differentiation potential from basal cells, giving rise predominantly to pulmonary neuroendocrine cells and a subset of multiciliated cells distinguished by high C6 and low MUC16 expression. Lineage tracing results are supported by studies using organoids and isolated cells from the lower noncartilaginous airway. We conclude that SCGB3A2/SFTPB/CFTR cells are enriched in the lower airways of the developing human lung and contribute to the epithelial diversity and heterogeneity in this region.

The multifactorial role of vanillin in amelioration of aluminium chloride and D-galactose induced Alzheimer's disease in mice.

The onset and progression of Alzheimer's disease (AD) are influenced by a variety of factors. These include oxidative stress, overexpression of acetylcholinesterase (AChE), depletion of acetylcholine levels, increased beta-secretase mediated conversion of Amyloid Precursor Protein (APP) to Amyloid Beta (Abeta), accumulation of Abeta oligomers, decrease in Brain Derived Neurotrophic factor (BDNF) and accelerated neuronal apoptosis due to elevated levels of caspase-3. The currently available therapeutic approaches are inadequate in affecting these pathological processes except maybe the overexpression of AChE (AChE inhibitors like donepezil, rivastigmine). There is an urgent need to develop disease modifying pharmacotherapeutic interventions which have appreciable safety and cost effectiveness. From previously reported in vitro studies and a preliminary assessment of neuroprotective effect in scopolamine induced dementia-like cognitive impairment in mice, vanillin has been used as the compound of interest in the present study. Vanillin, a phytoconstituent, has been used in humans, safely, in the form of a flavouring agent for various foods, beverages, and cosmetics. Owing to its chemical nature i.e. being a phenolic aldehyde, it has an additional antioxidant property that is congruent to the desirable characteristics that are sought in a suitable novel anti-AD agent. In our study, vanillin proved to have a nootropic effect in healthy Swiss albino mice as well as an ameliorative effect in aluminium chloride and D-galactose induced AD model in mice. Apart from tackling oxidative stress, vanillin was found to reduce the levels of AChE, beta secretase, caspase-3, enhance degradation of Abeta plaques and elevate the levels of BDNF, in cortical and hippocampal regions. Vanillin is a promising candidate for being incorporated into the search for safe and effective anti-AD molecules. However, further research might be needed to warrant its application clinically.

Chronic Mania: Diagnostic Dilemma and the Need for Addition in Nosology.

Chronic mania is a mental health disorder that has been described by various psychiatrists in the past but currently is not a part of nosology. Robust epidemiological data for chronic mania are lacking with regard to its prevalence and clinical features. The present case report is of a 48-year-old male with a six-year history of mood and psychotic symptoms, based on which differential diagnoses of schizoaffective disorder (manic type), schizophrenia, and mania with psychotic symptoms (with chronic course) were made. The diagnosis of chronic mania was confirmed considering the predominance of fluctuating mood symptoms along with psychotic symptoms, lack of remission, and chronic course of illness. Antipsychotics were initially started for six weeks, to which the patient demonstrated a minimal response. A mood stabilizer was added to the regimen, leading to significant improvement, and the patient was discharged. According to existing literature, patients with chronic mania present with severe illness, the presence of psychotic symptoms, and socio-occupational impairment, which was also noticed in this case. The prevalence of chronic mania among patients with bipolar disorder is approximately 13-15%, which constitutes a significant proportion of known mental illnesses. Therefore, chronic mania should be added as a distinct clinical entity in the existing nosological systems.

Opposing roles for TGFß- and BMP-signaling during nascent alveolar differentiation in the developing human lung.

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFß- and BMP-signaling, where inhibition of TGFß- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro . AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFß-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFß- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro .

Pregnancy outcomes in patients with Budd-Chiari syndrome: A tertiary care experience.

BACKGROUND: Budd-Chiari syndrome (BCS) is associated with infertility and adverse pregnancy outcomes in affected females. Scant literature is available on the effect of an endovascular intervention on fertility and the outcome of future pregnancies in these patients. AIMS: To assess the infertility rates, maternal and fetal outcomes of pregnancy and effect of endovascular intervention in women with BCS. METHODS: In this retrospective analysis, 121 female patients with BCS attending our liver clinic from 2017 to 2020 were included. Demographic details, intervention details, pregnancies - pre- and post-intervention - and fetal outcomes were noted. RESULTS: BCS was diagnosed pre-conception in 58 women (group 1; median age: 22 years), during/after pregnancy, but before completion of family in 39 (group 2; median age: 27 years), and after completion of family in 24 (group 3; median age: 34 years). Median Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores were 7 and 12, respectively. The primary infertility rate was 19.8% (24/121). In group 1, 15 women with primary infertility underwent endovascular intervention with 5/15 (33%) women conceiving subsequently, resulting in four live births and seven abortions. In group 2, five women developed BCS during pregnancy and 11 postpartum; 11/39 had a history of one or more abortions. Overall, 8/34 (23.5%) who underwent endovascular intervention had 4/8 (50%) successful pregnancies. In group 3, no patient had any major complications during past pregnancies. The mode of delivery was vaginal in 88% of cases. No congenital anomaly/major bleeding episodes/decompensation/maternal mortality occurred. CONCLUSIONS: Infertility is common in patients with BCS. Pregnancy is well-tolerated in those with compensated liver disease.

Compensated Advanced Chronic Liver Disease in Nonalcoholic Fatty Liver Disease: Two-Step Strategy is Better than Baveno Criteria.

BACKGROUND: Advanced fibrosis and cirrhosis (compensated advanced chronic liver disease [cACLD]) are clinically indistinguishable and increase risk of developing clinically significant portal hypertension. Baveno VII recommends using elastography to rule out and diagnose cACLD with liver stiffness measurement (LSM) cut-offs of 10/15 kPa. METHODS: In a retrospective analysis of 330 nonalcoholic fatty liver disease (NAFLD) patients, performance of the Baveno VII cut-offs for diagnosing cACLD was compared with newly suggested lower cut-offs (8/12 kPa). A model for detecting cACLD among those with LSM between 8 and 12 kPa was developed and compared with recently published models. RESULTS: Seventy (21.2%) of the 330 NAFLD patients had biopsy-proven cACLD. The Baveno VII cut-offs (10/15 kPa) had a lower sensitivity of 72.8% (60.9-82.8%) and a specificity of 93.4% (89.7-96.1%). Sensitivity and specificity of lower cut-offs (8/12 kPa) were 91.4% (82.3-96.8%) and 88.5% (83.9-92.1%), respectively. Modeling based on the presence of diabetes (odds ratio [OR] 3.625[1.161-11.320], p = 0.027) and serum aspartate aminotransferase (AST) levels (OR 1.636[1.098-2.436], p = 0.015) correctly identified 75.7% of patients with LSM between 8 and 12 kPa. Our model performed best with an area under receiver operator curve (AUROC) of 0.725 (95%CI 0.609-0.822), compared to Papatheodoridi (AUROC 0.626, CI 0.506-.736) and Zhou (AUROC 0.523, CI 0.403-0.640) models. A two-step strategy comprising application of lower LSM cut-offs followed by the predictive model correctly identified the presence of cACLD in 83% of the patients as compared to 75% by the Baveno VII cut-offs. CONCLUSION: A two-step strategy employing lower LSM cut-offs and modeling based on diabetes and AST levels outperforms Baveno VII cut-offs for identifying cACLD in NAFLD patients.