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.

Thromboelastography-Guided versus Standard-of-Care or On-Demand Platelet Transfusion in Patients with Cirrhosis and Thrombocytopenia Undergoing Procedures: A Randomized Controlled Trial.

PURPOSE: To determine the rate of platelet transfusion in patients with cirrhosis and severe thrombocytopenia (platelet counts <50 × 109/L) undergoing high-risk invasive procedures when prescribed by thromboelastography (TEG) compared with empirical and on-demand transfusion strategies. 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 3 groups: TEG group, transfusions based on TEG parameters; standard of care (SOC) group, 3 units of random donor platelets before procedure; and on-demand group, transfusions based on procedural adverse events/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 × 109/L (interquartile range, 26-43 × 109/L). 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 with SOC group (100%; 95% CI, 88.1-100; P < .001). Four patients in the on-demand group received platelets (13.8%; 95% CI, 3.9-31.7). Minor (World Health Organization [WHO] Grade 2) procedure-related bleeding occurred in 3 (10%; 95% CI, 2.2-27.4) patients in the TEG-guided transfusion group compared with 1 (3.4%; 95% CI, 0.1-17.8) patient each in the SOC and on-demand groups (P = .43), although the study was not powered for comparison of bleeding rates. No bleeding-related mortality was observed in any of the 3 groups. CONCLUSIONS: TEG-prescribed transfusion reduced prophylactic transfusions in patients with cirrhosis and severe thrombocytopenia undergoing high-risk invasive procedures.

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.

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.

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.

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.

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.

A quantum computing view on unitary coupled cluster theory.

We present a review of the Unitary Coupled Cluster (UCC) ansatz and related ansätze which are used to variationally solve the electronic structure problem on quantum computers. A brief history of coupled cluster (CC) methods is provided, followed by a broad discussion of the formulation of CC theory. This includes touching on the merits and difficulties of the method and several variants, UCC among them, in the classical context, to motivate their applications on quantum computers. In the core of the text, the UCC ansatz and its implementation on a quantum computer are discussed at length, in addition to a discussion on several derived and related ansätze specific to quantum computing. The review concludes with a unified perspective on the discussed ansätze, attempting to bring them under a common framework, as well as with a reflection upon open problems within the field.

Optical and Scintillation Properties of Record-Efficiency CdTe Nanoplatelets toward Radiation Detection Applications.

Colloidal CdTe nanoplatelets featuring a large absorption coefficient and ultrafast tunable luminescence coupled with heavy-metal-based composition present themselves as highly desirable candidates for radiation detection technologies. Historically, however, these nanoplatelets have suffered from poor emission efficiency, hindering progress in exploring their technological potential. Here, we report the synthesis of CdTe nanoplatelets possessing a record emission efficiency of 9%. This enables us to investigate their fundamental photophysics using ultrafast transient absorption, temperature-controlled photoluminescence, and radioluminescence measurements, elucidating the origins of exciton- and defect-related phenomena under both optical and ionizing excitation. For the first time in CdTe nanoplatelets, we report the cumulative effects of a giant oscillator strength transition and exciton fine structure. Simultaneously, thermally stimulated luminescence measurements reveal the presence of both shallow and deep trap states and allow us to disclose the trapping and detrapping dynamics and their influence on the scintillation properties.

Clinical Utility of Transient Elastography in the Management of Patients with Budd-Chiari Syndrome Undergoing Endovascular Intervention.

PURPOSE: To quantify liver stiffness measurement (LSM) changes after endovascular intervention for Budd-Chiari syndrome (BCS) and evaluate whether LSM changes predict restenosis after endovascular intervention. MATERIALS AND METHODS: Patients with BCS who underwent endovascular intervention and had at least 2 LSM values available after the intervention were included. ΔLSM was the difference between LSMs estimated at the last and second last hospital visits. In patients with restenosis, 2 LSM values before restenosis were included. ΔLSM% was calculated as the ratio of ΔLSM to the LSM at the second last visit and expressed as a percentage. Odds ratio (OR) with confidence interval (CI) and area under the receiver operating characteristic curves (AUROCs) were calculated for the predictors of restenosis. RESULTS: The median baseline and postinterventional 1-week, 3-month, 6-month, and 12-month LSM values were 47.2 kPa (33.8-68.4 kPa), 29.2 kPa (24.5-43.0 kPa), 26.2 kPa (18.6-38.9 kPa), 20.9 kPa (13.3-29.8 kPa), and 17.3 kPa (11.8-25.4 kPa), respectively. Of the 118 patients, including 67 men, restenosis developed in 10 patients after a median (interquartile range) duration of 19 months (11-46 months). ΔLSM% was higher (more positive) in patients with restenosis than in those without restenosis (44.7 [8.3-134.3] vs -6.6 [-19.4 to 14.9], P = .001). ΔLSM% was a significant predictor of restenosis with an OR of 1.032 (95% CI, 1.015-1.050; P < .001). The AUROC for ΔLSM% was 0.831 (95% CI, 0.750-0.893; P = .001), and a ΔLSM% increment of 13.2% predicted restenosis with a sensitivity and specificity of 80.0% and 74.1%, respectively. CONCLUSIONS: LSM gradually decreases after endovascular intervention, and transient elastography is a promising test for detecting restenosis after the endovascular treatment of patients with BCS.

Real-world re-treatment outcomes of direct-acting antiviral therapy failure in patients with chronic hepatitis C.

Direct-acting antiviral (DAA) drugs are associated with high (>95%) sustained virological response at 12 weeks (SVR12) in chronic hepatitis C (CHC) patients. There is a paucity of data regarding the characteristics and re-treatment outcomes of DAA treatment failure patients. In a retrospective analysis of the prospectively collected database, we assessed the outcomes of re-treatment among patients with previous DAA failure. Patients' characteristics, viral characteristics, including resistance-associated substitutions (RAS) in a subgroup of patients, SVR12, and clinical outcomes were studied. Of 40 patients with DAA failure, among whom 36 were retreated, mean age was 45.7 years, 63.9% (n = 23) were male, 63.9% (n = 23) had a genotype-3 infection and 63.9% (n = 23) were cirrhotic. The re-treatment regimens included a combination of pan-genotypic DAA, mainly sofosbuvir and velpatasvir with or without ribavirin. Three patients who declined retreatment and one who was still on treatment was excluded. For patients who completed re-treatment, SVR12 was 100% irrespective of genotypes. SVR12 among genotype 3 was 75% (15 of 20) when lost to follow-up was considered a treatment failure. Six patients died due to liver-related causes, including five (83.3%) with hepatocellular carcinoma. RAS analysis in 17 randomly selected patients did not reveal any dominant substitutions in NS5A or NS5B region affecting SVR12, though several novel mutations were observed. In conclusion, re-treatment of CHC patients with prior DAA failure using pan-genotypic DAA is associated with high SVR12 rates irrespective of genotype or the presence of RAS.

FibroScan-aspartate aminotransferase score in an Asian cohort of non-alcoholic fatty liver disease and its utility in predicting histological resolution with bariatric surgery.

BACKGROUND AND AIM: The FibroScan-aspartate aminotransferase (FAST) score was developed for identifying patients with non-alcoholic steatohepatitis, who also have an elevated non-alcoholic fatty liver disease (NAFLD) activity score (NAS) ≥ 4 and significant fibrosis (F ≥ 2). We aimed to validate it in our NAFLD cohort and assess if it correlates with the histological changes after bariatric surgery. METHODS: Patients with NAFLD, including those undergoing bariatric surgery, were included. The FAST score was calculated using liver stiffness measure, controlled attenuation parameter, and aspartate aminotransferase. Calibration and discrimination of the model were assessed by calibration plots and area under the receiver operating characteristic curve, respectively. Sensitivity and specificity were assessed at the rule-out and rule-in cutoffs (≤0.35 and ≥0.67), respectively. Changes in the NAS and FAST scores were compared in the bariatric cohort 1 year after surgery. RESULTS: The cohort composed of 309 patients, of which 48 patients underwent repeat liver biopsy at 1 year. The model showed good discrimination with area under the receiver operating characteristic curve of 0.79 (0.74-0.84); however, it was not satisfactorily calibrated (Hosmer-Lemeshow test, P = 0.008). The sensitivity and specificity at the rule-out and rule-in cutoffs were 0.90 and 0.84, respectively. A significant correlation was seen between the 1-year reduction in the NAS and FAST scores (r = 0.38, P = 0.009). A significant reduction in the median FAST score was seen in patients who had ≥2-point reduction in NAS after bariatric surgery. CONCLUSION: FibroScan-aspartate aminotransferase score demonstrated good discrimination for fibrotic non-alcoholic steatohepatitis in our cohort. However, a miscalibration resulted in overprediction. The score correlated well with the histological response to interventions for NAFLD.

Deciding Among Noninvasive Tools for Predicting Varices Needing Treatment in Chronic Liver Disease: An Analysis of Asian Cohort.

INTRODUCTION: Both transient elastography (TE)-based and non-TE-based criteria exist for detection of varices needing treatment (VNT) in patients with asymptomatic advanced chronic liver disease (CLD). However, their performance in clinical settings at different risk thresholds of detection of VNT and in regions where elastography is not widely available is unknown. We aimed to validate existing noninvasive criteria in our patients with CLD and identify best TE- and non-TE-based criteria for VNT screening at usual risk thresholds. METHODS: Patients with compensated advanced CLD (cACLD) who underwent esophagogastroduodenoscopy and TE within 3 months were included. Diagnostic performance of Baveno VI, expanded Baveno VI, platelet-model for end-stage liver disease, and platelet-albumin (Rete Sicilia Selezione Terapia-hepatitis C virus) criteria were estimated. Decision curve analysis was conducted for different predictors across range of threshold probabilities. A repeat analysis including all patients with compensated CLD (cACLD and non-cACLD) was performed to simulate absence of TE. RESULTS: A total of 1,657 patients (cACLD, 895; non-cACLD, 762) related to hepatitis B virus (38.2%), hepatitis C virus (33.4%), nonalcoholic steatohepatitis (14.7%), and alcohol (11.8%) were included. Baveno VI identified maximum VNT (97.3%) and had best negative predictive value (96.9%), followed by platelet-albumin criteria. Expanded Baveno VI and platelet-model for end-stage liver disease had intermediate performance. At threshold probability of 5%, Baveno VI criteria showed maximum net benefit, and platelet-albumin criteria was next best, with need for 95 additional elastographies to detect 1 additional VNT. Similar results were obtained on including all patients with compensated CLD irrespective of TE. DISCUSSION: Baveno VI criteria maximizes VNT yield at 5% threshold probability. An acceptable alternative is the platelet-albumin criteria in resource-limited settings.

Natural course of chronic pancreatitis and predictors of its progression.

BACKGROUND: The natural course of chronic pancreatitis(CP) and its complications has been inadequately explored. We aimed to describe the natural history and factors affecting the progression of alcoholic(ACP), idiopathic juvenile(IJCP) and idiopathic senile(ISCP) variants of CP. METHODS: This study was a retrospective analysis from a prospectively maintained database of patients with CP following up at a tertiary care centre from 1998 to 2019. Cumulative rates of pain resolution, diabetes, steatorrhea, pseudocysts and pancreatic cancer were computed using Kaplan-Meier analysis, and the factors affecting their incidence were identified on multivariable-adjusted Cox-proportional-hazards model. RESULTS: A total of 1415 patients were included, with 540(38.1%) ACP, 668(47.2%) IJCP and 207(14.6%) ISCP with a median follow-up of 3.5 years(Inter-quartile range: 1.5-7.5 years). Diabetes occurred at 11.5, 28 and 5.8 years(p < 0.001) while steatorrhea occurred at 16, 24 and 18 years(p = 0.004) after onset for ACP, IJCP and ISCP respectively. Local complications including pseudocysts occurred predominantly in ACP(p < 0.001). Ten-year risk of pancreatic cancer was 0.9%, 0.2% and 5.2% in ACP, IJCP and ISCP, respectively(p < 0.001). Pain resolution occurred more frequently in patients with older age of onset[Multivariate Hazard Ratio(HR):1.7(95%CI:1.4-2.0; p < 0.001)], non-smokers[HR:0.51(95%CI:0.34-0.78); p = 0.002] and in non-calcific CP[HR:0.81(0.66-1.0); p = 0.047]. Occurrence of steatorrhea[HR:1.3(1.03-1.7); p = 0.028] and diabetes[HR:2.7(2.2-3.4); p < 0.001] depended primarily on age at onset. Occurrence of pancreatic cancer depended on age at onset[HR:12.1(4.7-31.2); p < 0.001], smoking-history[HR:6.5(2.2-19.0); p < 0.001] and non-alcoholic etiology[HR:0.14(0.05-0.4); p < 0.001]. CONCLUSION: ACP, IJCP and ISCP represent distinct entities with different natural course. Age at onset of CP plays a major prognostic role in all manifestations, with alcohol predominantly causing local inflammatory complications.

Vascular complications of chronic pancreatitis: A tertiary center experience.

INTRODUCTION: Vascular complications such as venous thrombosis (VT) and pseudoaneurysm are not uncommon in patients with chronic pancreatitis (CP). The aim of this study to was to evaluate the prevalence and risk factors for vascular complications in patients with CP. METHODS: A retrospective analysis of a prospectively maintained database of patients with CP presenting from January 2002 to August 2019 was performed. Venous thrombosis and pseudoaneurysm were identified using radiological imaging, and their risk factors were identified using multivariate Cox-proportional hazards. RESULTS: Of 1363 patients with CP, 166 (12.2%) had vascular complications. Isolated VT was present in 132, pseudoaneurysm in 17, and both in 17 patients. They were more commonly seen in males and alcoholic CP (ACP), and less commonly in patients with pancreatic atrophy and calcification. It involved the vessels in the closest proximity to the pancreas, VT most commonly involving the splenic vein whereas pseudoaneurysm most commonly involved the splenic artery. Alcoholic CP [odds ratio (OR) 2.1, p = 0.002], pseudocyst (OR 4.6, p < 0.001) and inflammatory head mass (OR 3.1, p = 0.006) were independent risk factors for VT, whereas ACP (OR 3.49, p = 0.006) and pseudocyst (OR 3.2, p = 0.002) were independent risk factors for pseudoaneurysm. Gastrointestinal bleed occurred in 3.5% patients, and more commonly in patients with pseudoaneurysm than VT (64.7% vs 15.9%), and in patients with ACP in comparison to other etiologies (p < 0.001). CONCLUSION: Vascular complications are a common complication of CP, VT being more frequent than pseudoaneurysm. Pseudocyst and ACP are independent risk factors for the development of vascular complications.

Quantized Electronic Doping towards Atomically Controlled "Charge-Engineered" Semiconductor Nanocrystals.

"Charge engineering" of semiconductor nanocrystals (NCs) through so-called electronic impurity doping is a long-standing challenge in colloidal chemistry and holds promise for ground-breaking advancements in many optoelectronic, photonic, and spin-based nanotechnologies. To date, our knowledge is limited to a few paradigmatic studies on a small number of model compounds and doping conditions, with important electronic dopants still unexplored in nanoscale systems. Equally importantly, fine-tuning of charge engineered NCs is hampered by the statistical limitations of traditional approaches. The resulting intrinsic doping inhomogeneity restricts fundamental studies to statistically averaged behaviors and complicates the realization of advanced device concepts based on their advantageous functionalities. Here we aim to address these issues by realizing the first example of II-VI NCs electronically doped with an exact number of heterovalent gold atoms, a known p-type acceptor impurity in bulk chalcogenides. Single-dopant accuracy across entire NC ensembles is obtained through a novel non-injection synthesis employing ligand-exchanged gold clusters as "quantized" dopant sources to seed the nucleation of CdSe NCs in organic media. Structural, spectroscopic, and magneto-optical investigations trace a comprehensive picture of the physical processes resulting from the exact doping level of the NCs. Gold atoms, doped here for the first time into II-VI NCs, are found to incorporate as nonmagnetic Au+ species activating intense size-tunable intragap photoluminescence and artificially offsetting the hole occupancy of valence band states. Fundamentally, the transient conversion of Au+ to paramagnetic Au2+ (5d9 configuration) under optical excitation results in strong photoinduced magnetism and diluted magnetic semiconductor behavior revealing the contribution of individual paramagnetic impurities to the macroscopic magnetism of the NCs. Altogether, our results demonstrate a new chemical approach toward NCs with physical functionalities tailored to the single impurity level and offer a versatile platform for future investigations and device exploitation of individual and collective impurity processes in quantum confined structures.

Emerging treatments for the behavioral and psychological symptoms of dementia.

Dementia is referred to a loss of memory and decline in other mental abilities at levels critical enough to hinder performance of daily activities. It can be of several types, depending on the underlying pathophysiology. The behavioral and psychological symptoms of dementia (BPSD) are various, but the most clinically significant are depression, apathy, and anxiety. Other BPSD include agitation, aberrant motor behavior, elation, hallucinations, and alterations in sleep and appetite. About 90% of sufferers of dementia are affected by BPSD during the course of the illness. These symptoms occur in demented patients irrespective of the dementia subtype. However, there has not been significant development in the areas of disease-modifying pharmacotherapeutics for dementia. Therefore, tackling BPSD has emerged as a research avenue in the recent past. Existing antidepressants, antipsychotics, and cholinergic agents have been extensively used in the treatment of BPSD, independently and in different combinations. However, these agents have not successful in completely alleviating such symptoms. Research in this field is going on globally, but it is still limited by various factors. There is a strong need to develop new entities and test them clinically. This review focuses on emerging treatments for the management of clinically significant BPSD.