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Methane is a powerful greenhouse gas with a 25 times higher 100-year warming potential than carbon dioxide and is a target for mitigation to achieve climate goals. To control and curb methane emissions, estimates are required from the sources and sectors which are typically generated using bottom-up methods. However, recent studies have shown that national and international bottom-up approaches can significantly underestimate emissions. In this study, we present three bottom-up approaches used to estimate methane emissions from all emission sectors in the Denver-Julesburg basin, CO, USA. Our data show emissions generated from all three methods are lower than historic measurements. A Tier 1/2 approach using IPCC emission factors estimated 2022 methane emissions of 358 Gg (0.8% of produced methane lost by the energy sector), while a Tier 3 EPA-based approach estimated emissions of 269 Gg (0.2%). Using emission factors informed by contemporary and region-specific measurement studies, emissions of 212 Gg (0.2%) were calculated. The largest difference in emissions estimates were a result of using the Mechanistic Air Emissions Simulator (MAES) for the production and transport of oil and gas in the DJ basin. The MAES accounts for changes to regulatory practice in the DJ basin, which include comprehensive requirements for compressors, pneumatics, equipment leaks, and fugitive emissions, which were implemented to reduce emissions starting in 2014. The measurement revealed that normalized gas loss is predicted to have been reduced by a factor of 20 when compared to 10-year-old normalization loss measurements and a factor of 10 less than a nearby oil and production area (Delaware basin, TX); however, we suggest that more measurements should be made to ensure that the long-tail emission distribution has been captured by the modeling. This study suggests that regulations implemented by the Colorado Department of Public Health and Environment could have reduced emissions by a factor of 20, but contemporary regional measurements should be made to ensure these bottom-up calculations are realistic.

Due to the risk of releasing carcinogenic nickel ions from conventional 316L stainless steel under a corrosive human body environment, a new variant of steel termed nickel-free stainless steel (NiFSS) has been investigated. The present study investigates the tribological properties and biocompatibility of NiFSS manufactured via laser powder bed fusion (PBF-LB/M). The ferritic NiFSS exhibited significantly lower coefficient of friction (0.08 to 0.28) and wear rate (1.60 × 10-6 mm3/Nm to 6.60 × 10-6 mm3/Nm) compared to reported values for austenitic 316L SS, under both dry and simulated body fluid (SBF) conditions and various sliding geometries. This improvement is attributed to the superior hardness (3.394 ± 0.1340 GPa) and elastic modulus (238 ± 9.0797 GPa) of NiFSS. To assess the biocompatibility, the viability of mouse pre-osteoblastic MC3T3-E1 cells was evaluated with an Alamar Blue assay when the cells were cultured on top of PBF-LB/M built NiFSS and 316L SS samples. The results indicated that even though cell growth was most optimal on regular cell culture plastic, cell viability was better maintained on PBF-LB/M built NiFSS compared to 316L SS. Therefore, the results of the present study propose that PBF-LB/M fabricated NiFSS holds promise for application in biomedical devices for joint arthroplasty.

Abstract 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 TGFβ- and BMP-signaling, where inhibition of TGFβ- 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 TGFβ-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 TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.

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.

Inflammatory bowel disease (IBD), once considered a disease of the Western hemisphere, has emerged as a global disease. As the disease prevalence is on a steady rise, management of IBD has come under the spotlight. 5-Aminosalicylates, corticosteroids, immunosuppressive agents and biologics are the backbone of treatment of IBD. With the advent of biologics and small molecules, the need for surgery and hospitalization has decreased. However, economic viability and acceptability is an important determinant of local prescription patterns. Nearly one-third of the patients in West receive biologics as the first/initial therapy. The scenario is different in developing countries where biologics are used only in a small proportion of patients with IBD. Increased risk of reactivation of tuberculosis and high cost of the therapy are limitations to their use. Thiopurines hence become critical for optimal management of patients with IBD in these regions. However, approximately one-third of patients are intolerant or develop adverse effects with their use. This has led to suboptimal use of thiopurines in clinical practice. This review article discusses the clinical aspects of thiopurine use in patients with IBD with the aim of optimizing their use to full therapeutic potential.

BackgroundAlzheimer’s disease (AD) is the most common form of dementia, which is among the top five causes of death in the United States. It is a neurodegenerative disorder that causes permanent loss of memory and cognition. The current pharmacotherapy for AD is based on providing symptomatic relief only and has many side effects. There is a need for a safer, disease-modifying drug for the treatment of AD.Experimental approachThe PASS online software was used to screen phytoconstituents based on their predicted effects on various AD-related targets. Vanillin was selected as the compound of interest, as it has not been researched elaborately on any animal model of AD. The acetylcholinesterase inhibitory activity of vanillin was established in vitro. Thereafter, ameliorative effect of vanillin was evaluated using the exteroceptive memory model in scopolamine-induced cognitive impairment mice model.ResultsVanillin showed an acetylcholinesterase inhibitory activity in vitro, and the IC50 value was calculated to be 0.033 mM. Vanillin significantly reversed the memory and behavioral deficits caused by scopolamine as demonstrated by significant improvement in memory in negative reinforcement, elevated plus maze, and spatial learning paradigms. Vanillin also proved to have a nootropic effect. Also, vanillin proved to have significantly better antioxidant and acetylcholinesterase inhibitory effects in vivo than donepezil hydrochloride. The potential anti-AD activity of vanillin was also confirmed by the reduction in IL-6 levels and TNF-α levels.ConclusionOur results suggest that vanillin is a safe and effective natural drug candidate having a great potential for the treatment of AD. However, more research is required to evaluate its effect on A beta plaques and Tau neurofibrillary tangles in vivo.

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.

Abstract Background and Aims Decompensated cirrhosis in autoimmune hepatitis has poor prognosis. Besides liver transplant, treatment for this entity is undefined. We explored the outcomes of autoimmune hepatitis (AIH)‐related decompensated cirrhosis with active disease on treatment with steroids. Methods In this retrospective analysis, clinical data, laboratory parameters, and prognostic scores, such as baseline model for end‐stage liver disease (MELD) scores, were compared among patients of AIH with decompensated cirrhosis with mild/no ascites (n = 38), gross ascites (n = 24), and compensated cirrhosis (n = 32) when administered steroids. The primary outcome was transplant‐free survival at 12 months. Biochemical remission rates and other adverse events were also assessed and compared between these groups. Results Steroids were initiated at lower doses (25 mg/day‐mild/no ascites, 20 mg/day‐gross ascites) in patients with decompensated cirrhosis and at 40 mg/day in those with compensated cirrhosis. Transplant‐free survival was 25.4%, 74.6%, and 96.9% (P = 0.001), and biochemical remission occurred in 5.1%, 49.0%, and 64.1% (P = 0.001) at 12 months in patients with gross ascites, mild/no ascites, and compensated cirrhosis, respectively. Infections were seen more frequently in decompensated cirrhosis, while other adverse events were comparable. Among decompensated cirrhosis, those with mild/no ascites had better prognostic scores, fewer posttreatment infections, and more frequent biochemical remission than those with gross ascites, achieving rates comparable to compensated cirrhosis. On multivariate analysis, the MELD score (subdistributional hazards ratio [sHR]; 95% confidence interval: 1.153 [1.07–1.24]; P = 0.001) and ascites (sHR: 2.556 [1.565–5.65]; P = 0.020) predicted survival. Conclusion Type and severity of decompensation affect outcomes in patients with AIH‐related cirrhosis. Those with mild/no ascites have comparable outcomes to those with compensated cirrhosis upon treatment with low‐dose steroids.

Abstract Background and Aim Hepatic venous pressure gradient (HVPG), although an important determinant in predicting rebleeding after an episode of acute variceal bleed (AVB), is seldom utilized in clinical practice. We aimed to study the role of liver stiffness measurement (LSM) after variceal bleeding as a potential noninvasive predictor of rebleed. Methods This was a post hoc analysis of clinical trial of patients undergoing HVPG (postbleed HVPG) and LSM (postbleed LSM) assessment within 3–5 days of index AVB. HVPG response was assessed after 4 weeks of pharmacotherapy. Comparative assessment of long‐term rebleeding rates stratified using postbleed LSM, postbleed HVPG, and HVPG response was performed. Decision curve analysis (DCA) was conducted to identify the most appropriate tool for routine use. Results Long‐term clinical and HVPG response data were available for 48 patients post‐AVB, of whom 45 patients had valid postbleed LSM. Rebleeding occurred in 13 (28%) patients over a median follow‐up of 4 years with no early rebleeds. Postbleed LSM >30 kPa and baseline HVPG >15 mm Hg were optimal cutoffs for identifying patients at high risk of rebleeding. Time‐dependent receiver operating characteristic curves and competing risk analysis accounting for death showed similar discriminative values for all three stratification tools. At usual risk thresholds, HVPG response had maximum benefit on DCA followed by postbleed LSM. On DCA, 50–60 additional HVPGs were required to detect one additional patient at high risk of rebleed. Conclusion Liver stiffness measurement during AVB can potentially be used as an alternative to portal pressure indices in decompensated cirrhosis to identify those at high risk of late‐onset rebleed.

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Near-term quantum computation holds potential across multiple application domains. However, imperfect preparation and evolution of states due to algorithmic and experimental shortcomings, characteristic in the near-term implementation, would typically result in measurement outcomes deviating from the ideal setting. It is thus crucial for any near-term application to quantify and bound these output errors. We address this need by deriving robustness intervals which are guaranteed to contain the output in the ideal setting. The first type of interval is based on formulating robustness bounds as semidefinite programs, and uses only the first moment and the fidelity to the ideal state. Furthermore, we consider higher statistical moments of the observable and generalize bounds for pure states based on the non-negativity of Gram matrices to mixed states, thus enabling their applicability in the NISQ era where noisy scenarios are prevalent. Finally, we demonstrate our results in the context of the variational quantum eigensolver (VQE) on noisy and noiseless simulations.

Objective: To determine the presentation, anatomical distribution, diagnostic method, management and outcome of hollow viscus injury (HVI) from blunt abdominal trauma. Methods: This was a retrospective cross-sectional study including patients with blunt abdominal trauma leading to HVI admitted at Rajendra Institute of Medical Sciences, Ranchi, over a period of 4.5 years (January 2009 to July 2014). Data were retrieved from patients’ medical records. Total 173 patients with HVI due to blunt abdominal trauma, who underwent laparotomy at our institute, were reviewed. Data regarding clinical presentation, anatomical distribution, management and outcome were recorded and analysed. Results: Out of 173 patients 87.1% were men and 12.9% were women. Mean age of patients was 29±14.02 years. The most common site of injury was ileum (46.2%) followed by jejunum (44.5%). There were 5 gastric perforations (2.9%), 2 (1.15%) duodenal, 2 (1.15%) colonic, 2 (1.15%) sigmoidal and 2 (1.15%) rectal injuries. One caecal injury was also recorded. Road traffic accident was the most common mechanism of injury (57.2%) followed by fall from height (36.4%) and assault (6.4%). Free gas under diaphragm on erect abdomen radiography was seen in 85.5% of cases while preoperative CT Abdomen was done in 11.6% of cases. Treatment consisted of simple closure of the perforation (66.5%), resection and anastomosis (11.0%) and stoma (22.5%). Major complication was anastamotic leak which was recorded in 6.4% cases and 15.6% patients developed burst abdomen. Average hospital stay was 13±6 days. Overall mortality rate was 12.7%. Conclusion: Although early recognition of intestinal injuries from blunt abdominal trauma may be difficult in all cases, it is very important due to its tremendous life threatening potential. Age of the patient, anatomical site and time of presentation are probably main prognostic factors.