Van Gogh-like 2 is essential for the architectural patterning of the mammalian biliary tree.

BACKGROUND & AIMS: In the developing liver, bipotent epithelial progenitor cells undergo lineage segregation to form hepatocytes, which constitute the bulk of the liver parenchyma, and biliary epithelial cells (cholangiocytes), which comprise the bile duct (a complex tubular network that is critical for normal liver function). Notch and TGFß signalling promote the formation of a sheet of biliary epithelial cells, the ductal plate, that organises into discontinuous tubular structures. How these structures elongate and connect to form a continuous duct remains undefined. We aimed to define the mechanisms by which the ductal plate transitions from a simple sheet of epithelial cells into a complex and connected bile duct. METHODS: By combining single-cell RNA sequencing of embryonic mouse livers with genetic tools and organoid models we functionally dissected the role of planar cell polarity in duct patterning. RESULTS: We show that the planar cell polarity protein VANGL2 is expressed late in intrahepatic bile duct development and patterns the formation of cell-cell contacts between biliary cells. The patterning of these cell contacts regulates the normal polarisation of the actin cytoskeleton within biliary cells and loss of Vangl2 function results in the abnormal distribution of cortical actin remodelling, leading to the failure of bile duct formation. CONCLUSIONS: Planar cell polarity is a critical step in the post-specification sculpture of the bile duct and is essential for establishing normal tissue architecture. IMPACT AND IMPLICATIONS: Like other branched tissues, such as the lung and kidney, the bile ducts use planar cell polarity signalling to coordinate cell movements; however, how these biochemical signals are linked to ductular patterning remains unclear. Here we show that the core planar cell polarity protein VANGL2 patterns how cell-cell contacts form in the mammalian bile duct and how ductular cells transmit confluent mechanical changes along the length of a duct. This work sheds light on how biological tubes are patterned across mammalian tissues (including within the liver) and will be important in how we promote ductular growth in patients where the duct is mis-patterned or poorly formed.

Stratified analysis in comparative effectiveness studies that emulate randomized trials.

PURPOSE: For observational cohort studies that employ matching by propensity scores (PS), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre-stratification in two real-life examples. For both, prior evidence from placebo-controlled randomized clinical trials (RCTs) suggested small or no risk reduction, but observational analysis suggested protection, presumably the result of confounding bias. STUDY DESIGN AND SETTING: The study populations consisted of Medicare beneficiaries (2014-18) with type 2 diabetes initiating either (i) empagliflozin versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or (ii) empagliflozin versus glucagon-like peptide-1 receptor agonists (GLP-1RA). The outcome was myocardial infarction or stroke. We estimated hazard ratios (HR) and rate differences (RD) after controlling for 143 pre-exposure covariates via 1:1 PS matching after (1) PS estimation in the total cohort (total-cohort PS-matching) and (2) PS estimation separately by baseline cardiovascular disease (stratified PS matching). RESULTS: Stratified PS matching resulted in HRs that exceeded those from total-cohort PS-matching by 13% and 9%, respectively, for the comparisons of empagliflozin to DPP-4i and GLP-1RA. Against both comparators, HRs and RDs after stratified PS matching were closer to the null, with slightly higher variances (2%-3%) than those after total-cohort PS matching. CONCLUSION: Stratified PS matching produced effect estimates closer to the expected trial findings than total-cohort PS matching. The price paid in increased variance was minimal.

Semiparametric Allocation of Subjects to Cohort Strata.

BACKGROUND: We illustrate a method for stratum assignment in small cohort studies that avoids modeling assumptions. METHODS: Off-the-shelf software ( rgenoud ) made stratum assignments to minimize a loss function built on within-stratum and population-adjusted Euclidean distances. RESULTS: In 100 trials using simulated data of 300 records with a binary treatment and four dissimilar covariate treatment predictors, minimizing a loss based on Euclidean distance reduced covariate imbalance by a median of 99%. Stratification by propensity score and weighting records by the inverse of their probability of treatment reduced imbalance by 76%-89% and 83%-94%, respectively. Loss minimization applied to a cohort of 361 children undergoing immunotherapy achieved nearly complete elimination of covariate differences for important treatment predictors. CONCLUSION: With the availability of semiparametric stratum-assignment algorithms, analysts can tailor loss functions to meet design goals. Here, a loss function that emphasized covariate balance performed well under limited testing.

A TGFß-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-ß (TGFß) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFß signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery.

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)-induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

Trends in pulmonary tuberculosis mortality between 1985 and 2018: an observational analysis.

BACKGROUND: Pulmonary tuberculosis (TB) is a major source of global morbidity and mortality. Latent infection has enabled it to spread to a quarter of the world's population. The late 1980s and early 1990s saw an increase in the number of TB cases related to the HIV epidemic, and the spread of multidrug-resistant TB. Few studies have reported pulmonary TB mortality trends. Our study reports and compares trends in pulmonary TB mortality. METHODS: We utilized the World Health Organization (WHO) mortality database from 1985 through 2018 to analyze TB mortality using the International Classification of Diseases-10 codes. Based on the availability and quality of data, we investigated 33 countries including two countries from the Americas; 28 countries from Europe; and 3 countries from the Western Pacific region. Mortality rates were dichotomized by sex. We computed age-standardized death rates per 100,000 population using the world standard population. Time trends were investigated using joinpoint regression analysis. RESULTS: We observed a uniform decrease in mortality in all countries across the study period except the Republic of Moldova, which showed an increase in female mortality (+ 0.12 per 100,000 population). Among all countries, Lithuania had the greatest reduction in male mortality (-12) between 1993-2018, and Hungary had the greatest reduction in female mortality (-1.57) between 1985-2017. For males, Slovenia had the most rapid recent declining trend with an estimated annual percentage change (EAPC) of -47% (2003-2016), whereas Croatia showed the fastest increase (EAPC, + 25.0% [2015-2017]). For females, New Zealand had the most rapid declining trend (EAPC, -47.2% [1985-2015]), whereas Croatia showed a rapid increase (EAPC, + 24.9% [2014-2017]). CONCLUSIONS: Pulmonary TB mortality is disproportionately higher among Central and Eastern European countries. This communicable disease cannot be eliminated from any one region without a global approach. Priority action areas include ensuring early diagnosis and successful treatment to the most vulnerable groups such as people of foreign origin from countries with a high burden of TB and incarcerated population. Incomplete reporting of TB-related epidemiological data to WHO excluded high-burden countries and limited our study to 33 countries only. Improvement in reporting is crucial to accurately identify changes in epidemiology, the effect of new treatments, and management approaches.

Management of Lobular Neoplasia Diagnosed by Core Biopsy.

Lobular neoplasia (LN) involves proliferative changes within the breast lobules. LN is divided into lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LCIS can be further subdivided into three subtypes: classic LCIS, pleomorphic LCIS, and LCIS with necrosis (florid type). Because classic LCIS is now considered as a benign etiology, current guidelines recommend close follow-up with imaging versus surgical excision. The goal of our study was to determine if the diagnosis of classic LN on core needle biopsy (CNB) merits surgical excision. This is a retrospective, observational study conducted at Mount Auburn Hospital, Cambridge, MA, from May 17, 2017, through June 30, 2020. We reviewed the data of breast biopsies conducted at our hospital over this period and included patients who were diagnosed with classic LN (LCIS and/or ALH) and excluded patients having any other atypical lesions on CNB. All known cancer patients were excluded. Of the 2707 CNBs performed during the study period, we identified 68 women who were diagnosed with ALH or LCIS on CNB. CNB was performed for an abnormal mammogram in the majority of patients (60; 88%) while 7(10.3%) had an abnormal breast magnetic resonance imaging study (MRI), and 1 had an abnormal ultrasound (US). A total of 58 patients (85%) underwent excisional biopsy, of which 3 (5.2%) showed malignancy, including 2 cases of DCIS and 1 invasive carcinoma. In addition, there was 1 case (1.7%) with pleomorphic LCIS and 11 cases with ADH (15.5%). The management of LN found on core biopsy is evolving, with some advocating surgical excision and others recommending observation. Our data show a change in diagnosis with excisional biopsy in 13 (22.4%) of patients with 2 cases of DCIS, 1 invasive carcinoma, 1 pleomorphic LCIS, and 9 cases of ADH, diagnosed on excisional biopsy. While ALH and classic LCIS are considered benign, the choice of ongoing surveillance versus excisional biopsy should be made with shared decision making with the patient, with consideration of personal and family history, as well as patient preferences.

Push Outcomes Bias Perceptions of Scratch Card Games.

In the domain of scratch card gambling, "pushes" refer to outcomes in which a prize is won that is equal to the cost of a scratch card game. Despite resulting in no net monetary gain, these outcomes are categorized as wins by lottery operators, effectively inflating published scratch card information (e.g., posted odds of winning). Additionally, the experience of obtaining a push shares similarities (e.g., the revealing of matching symbols) with the experience of obtaining a win and thus may be experienced similarly to wins by gamblers. Across four studies (N = 1502), we examined the impact of push outcomes on participants' perceptions of scratch card games. In Studies 1 and 2, participants reported feeling more likely to win, more excitement to play, and a stronger urge to gamble when presented with a scratch card that categorized push outcomes as wins compared to when presented a scratch card that did not categorize these outcomes as wins. In Study 3, participants experiencing a push outcome prior to a loss reported feeling more likely to win compared to those not experiencing a push outcome yet experiencing the same net monetary loss. In Study 4, push outcomes were found to elicit more excitement and a stronger urge to gamble compared to losses but less excitement and a weaker urge to gamble compared to wins. Overall, the present investigation suggests that push outcomes, a prevalent feature of scratch card games, can bias gambling-related judgments and increase the appeal of scratch card games.

Using Icon Arrays to Communicate Gambling Information Reduces the Appeal of Scratch Card Games.

Past work has demonstrated that presenting statistical information in a foreground-background icon array can improve risk understanding, reduce decision-making biases, and decrease the salience of low-probability risks. In the present study, we assess whether presenting readily available gambling information within a foreground-background icon array influences individuals' gambling-related judgments (e.g., their perceived likelihood of winning a prize). Across two experiments (N = 1151), we find that using icon arrays to present gambling information reduces the appeal of scratch card games. That is, participants presented with gambling information in a foreground-background icon array, as opposed to a non-graphical numerical format, reported feeling less likely to win a prize, less excitement to play, and less urge to gamble on a scratch card game presented in a hypothetical gambling task. Overall, we conclude that presenting gambling information in an icon array format represents a simple yet promising tool for correcting gamblers' often overly-optimistic perceptions and reducing the appeal of negative expected value scratch card games.

Increased risk of type 3c diabetes mellitus after acute pancreatitis warrants a personalized approach including diabetes screening.

BACKGROUND: Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a personalized medicine approach. METHODS: Using a longitudinal electronic healthcare record-linkage analysis, all patients admitted to hospital in Scotland with a first episode of AP between 1 April 2009 and 31 March 2012 and followed for a minimum of 5 years after their index AP admission were identified. All new-onset morbidity with specific focus on type 3c DM were analysed and, using time-split multiple regression. RESULTS: A total of 2047 patients were included. AP requiring critical care was followed by 2 years of heightened risk (HR 5.24) of developing type 3c DM, increased risk of new-onset cardiac disease (HR 1.61), and renal disease (HR 2.96). The additional risk conferred by critical care AP had a negative interaction with time, whereas additional risk associated with male sex and a non-gallstone aetiology was long lasting. CONCLUSION: Based on these findings, a personalized approach to include type 3c DM screening for a minimum of 2 years for individuals who required critical care when hospitalized with AP is recommended.

Antibiotic prescribing patterns among patients admitted to an academic teaching hospital for COVID-19 during the first wave of the pandemic in Toronto: A retrospective, controlled study.

BACKGROUND: Empirical antibiotics are not recommended for coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, patients admitted to Toronto General Hospital's general internal medicine from the emergency department for COVID-19 between March 1 and August 31, 2020 were compared with those admitted for community-acquired pneumonia (CAP) in 2020 and 2019 in the same months. The primary outcome was antibiotics use pattern: prevalence and concordance with COVID-19 or CAP guidelines. The secondary outcome was antibiotic consumption in days of therapy (DOT)/100 patient-days. We extracted data from electronic medical records. We used logistic regression to model the association between disease and receipt of antibiotics, linear regression to compare DOT. RESULTS: The COVID-19, CAP 2020, and CAP 2019 groups had 67, 73, and 120 patients, respectively. Median age was 71 years; 58.5% were male. Prevalence of antibiotic use was 70.2%, 97.3%, and 90.8% for COVID-19, CAP 2020, and CAP 2019, respectively. Compared with CAP 2019, the adjusted odds ratio (aOR) for receiving antibiotics was 0.23 (95% CI 0.10 to 0.53, p = 0.001) and 3.42 (95% CI 0.73 to 15.95, p = 0.117) for COVID-19 and CAP 2020, respectively. Among patients receiving antibiotics within 48 hours of admission, compared with CAP 2019, the aOR for guideline-concordant combination regimens was 2.28 (95% CI 1.08 to 4.83, p = 0.031) for COVID-19, and 1.06 (95% CI 0.55 to 2.05, p = 0.856) for CAP 2020. Difference in mean DOT/100 patient-days was -24.29 (p = 0.009) comparing COVID-19 with CAP 2019, and +28.56 (p = 0.003) comparing CAP 2020 with CAP 2019. CONCLUSIONS: There are opportunities for antimicrobial stewardship to address unnecessary antibiotic use.

HISTORIQUE: L'antibiothérapie empirique n'est pas recommandée pour le traitement de la maladie à coronavirus 2019 (COVID-19). MÉTHODOLOGIE: Dans cette étude rétrospective, les chercheurs ont comparé les patients atteints de COVID-19 hospitalisés au département de médecine interne générale du Toronto General Hospital entre le 1er mars et le 31 août 2020 après être passés par l'urgence à ceux hospitalisés à cause d'une pneumonie d'origine communautaire (POC) au cours des mêmes mois en 2020 et 2019 (POC-20 et POC-19). Le résultat primaire était le schéma d'utilisation des antibiotiques, c'est-à-dire la prévalence et le respect des lignes directrices sur la COVID-19 ou la POC. Le résultat secondaire correspondait à la consommation d'antibiotiques pendant les jours de traitement (JdT)/100 jours-patients. Les chercheurs ont puisé les données dans les dossiers médicaux électroniques. Ils se sont servi de la régression logistique pour modéliser l'association entre la maladie et la réception des antibiotiques, et de la régression linéaire pour comparer les JdT. RÉSULTATS: Le groupe COVID-19, le groupe POC-20 et le groupe POC-19 étaient composés de 67, 73 et 120 patients, respectivement. Ils avaient un âge médian de 71 ans, et 58,5 % étaient de sexe masculin. La prévalence d'utilisation d'antibiotiques s'élevait à 70,2 %, 97,3 % et 90,8 % dans les groupes COVID-19, POC-20 et POC-19, respectivement. Par rapport au groupe POC-19, le rapport de cotes rajusté (RCr) relatif à la réception d'antibiotiques s'élevait à 0,23 (IC à 95 %, 0,10 à 0,53, p = 0,001) et 3,42 (IC à 95 %, 0,73 à 15,95, p = 0,117) dans les groupes COVID-19 et POC-20, respectivement. Chez les patients qui avaient reçu des antibiotiques dans les 48 heures suivant leur hospitalisation par rapport au POC-19, le RCr relatif à la posologie d'association conforme aux lignes directrices était de 2,28 (IC à 95 %, 1,08 à 4,83, p = 0,031) et de 1,06 (IC à 95 %, 0,55 à 2,05, p = 0,856) dans le groupe POC-20. La différence quant au nombre moyen de JdT/100 jours-patients correspondait à ­24,29 (p = 0,009) lorsqu'on comparait le groupe COVID-19 au groupe POC-19, et à +28,56 (p = 0,003) lorsqu'on comparait le groupe POC-20 au groupe POC-19. CONCLUSIONS: L'utilisation inutile d'antibiotiques pourrait très bien être prise en charge par la gérance des antimicrobiens.

Patent Foramen Ovale and Ascending Aortic Dilatation Causing Platypnea-Orthodeoxia Syndrome.

Platypnea-orthodeoxia syndrome (POS) is an underdiagnosed clinical syndrome characterized by dyspnea (platypnea) and hypoxemia (orthodeoxia) in the upright position that resolves when recumbent. POS is often due to an underlying right-to-left shunt. Four broad mechanisms for the shunt have been described: intracardiac shunts, intrapulmonary shunts, hepatopulmonary syndrome, and pulmonary ventilation-perfusion mismatch. A 68-year-old male with a past medical history of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, ascending aortic dilation (3.9 cm), myelofibrosis, and status post stem cell transplant complicated by graft versus host disease was found hypoxemic (oxygen saturation: 82%) on routine visit prompting hospitalization. Hypoxemia initially responded to 40% FiO2 but subsequently progressed to refractory hypoxemia on 100% FiO2. A chest computed tomography (CT) scan showed evidence of multiple segmental pulmonary emboli with patent central pulmonary arteries. Hypoxemia out of proportion to pulmonary embolism clot burden and examination findings consistent with orthodeoxia prompted further investigations. Nuclear medicine scan showed radiotracer activity in both brain and kidneys consistent with a small right-to-left shunt (5.9%). Transesophageal echocardiography (TEE) revealed a patent foramen ovale (PFO) with a right-to-left shunt across the atrial septum, with a maximum opening of 3.5 mm and tunnel length of 25 mm. Right heart catheterization (RHC) is consistent with the right-to-left shunt and normal right heart pressures. The degree of the shunt was not significant enough to explain the degree of hypoxemia, but all the diagnostic studies were performed in a supine position, possibly underestimating the degree of the shunt. PFO closure with transcatheter 30-mm Gore device (GORE® CARDIOFORM, Arizona, USA) decreased supplemental oxygen requirement from 75% high-flow nasal cannula (NC) to room air (RA) immediately after the procedure. The patient was subsequently discharged home on a baseline oxygen requirement of 2 L NC at nighttime. POS should be suspected when a patient develops severe hypoxemia after changing from a recumbent position to a sitting or standing position. The identification and correction of the shunting or mismatch often allow complete resolution of POS. Transthoracic echocardiography with agitated saline, TEE, and RHC are the diagnosis modalities of choice. Left heart cardiac catheterization remains the gold standard, which would demonstrate a mismatch in oxygen saturation between the pulmonary vein and the aorta. Our patient's PFO was successfully closed by a percutaneous transcatheter closure device leading to the complete resolution of hypoxemia immediately.

The acute effects of azithromycin use on cardiovascular mortality as compared with amoxicillin-clavulanate in US Veterans.

PURPOSE: Azithromycin is a common first-line antibiotic for respiratory infection; however, there is conflicting evidence regarding risk of cardiovascular death. We assessed cardiovascular and noncardiovascular mortality associated with azithromycin versus amoxicillin-clavulanate among US Veterans treated for nonear-nose-throat respiratory infection ("respiratory") or ear-nose-throat infection indication. METHODS: Electronic health record data from the US Veterans Health Administration database were used to identify Veterans (30-74 years) with outpatient dispensings of oral azithromycin versus amoxicillin-clavulanate for respiratory or ear-nose-throat infection (January 01, 2000-December 31, 2014). Outcomes assessed were risk of cardiovascular death and noncardiovascular death within 1-5 and 6-10 days postdispensing. Inverse probability of treatment-weighted proportional hazards models and binomial regression models were used to estimate hazard ratios (HRs) and compute risk differences (RD) per million courses of therapy. Cardiac death (subset of cardiovascular death) was assessed in sensitivity analyses. RESULTS: There were 629 345 azithromycin and 168 429 amoxicillin-clavulanate dispensings for respiratory indications, 143 783 azithromycin, and 203 142 amoxicillin-clavulanate dispensings for ear-nose-throat indications. For respiratory indications, azithromycin was not associated with a significantly different risk of cardiovascular death versus amoxicillin-clavulanate within 1-5 days postdispensing (HR [95% confidence interval (CI)]: 1.12 [0.63, 2.00]; RD [95% CI]: 11 [-43, 64] deaths/million courses of therapy). No elevated risk for azithromycin was found for ear-nose-throat indications. Pooled results for both indications via meta-analysis showed no association between antibiotics and cardiovascular mortality. There was no significant difference in risk of noncardiovascular or cardiac death between antibiotics postdispensing. CONCLUSION: Azithromycin was not associated with elevated risk of cardiovascular or noncardiovascular death versus amoxicillin-clavulanate among US Veterans.

Beauty and truth, truth and beauty: Chiastic structure increases the subjective accuracy of statements.

The Keats heuristic suggests that people find esthetically pleasing expressions more accurate than mundane expressions. We test this notion with chiastic statements. Chiasmus is a stylistic phenomenon in which at least two linguistic constituents are repeated in reverse order, conventionally represented by the formula A-B-B-A. Our study focuses on the specific form of chiasmus known as antimetabole, in which the reverse-repeated constituents are words (e.g., All for one and one for all; A = all, B = one). In three out of four experiments (N = 797), we find evidence that people judge antimetabolic statements (e.g., Success is getting what you want. Happiness is wanting what you get.) as more accurate than semantically equivalent nonantimetabolic statements (e.g., Success is getting what you wish. Happiness is wanting what you receive.). Furthermore, we evaluate fluency as a potential mechanism explaining the observed accuracy benefit afforded to antimetabolic statements, finding that the increased speed (i.e., fluency) with which antimetabolic statements were processed predicted judgments of accuracy. Overall, the present work is consistent with the growing literature on stylistic factors biasing assessments of truth, using the distinctive stylistic pattern of antimetabole. We find that information communicated using an antimetabolic structure is judged to be more accurate than nonantimetabolic paraphrases. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

An Evaluation of the Effect of the OxyContin Reformulation on Unintentional Fatal and Nonfatal Overdose.

OBJECTIVES: OxyContin was reformulated with a polyethylene oxide matrix in August 2010 to reduce the potential for intravenous abuse and for abuse by insufflation. The objective of this study was to evaluate the impact of OxyContin's reformulation on overdose (OD) risk for individuals dispensed OxyContin in comparison to those dispensed other opioids under regular care. MATERIALS AND METHODS: Three national insurance databases with National Death Index linkage identified OD in individuals with any dispensing of OxyContin or a primary comparator opioid (extended release morphine, transdermal fentanyl, or methadone) between July 2008 through September 2015. A difference-in-differences design was used to compare the pre-post reformulation changes in OD rates for OxyContin versus comparators. RESULTS: A total of 297,836 individuals were dispensed OxyContin and 659,673 individuals were dispensed a primary comparator across the 3 databases. Overall, there was little or no difference in the temporal change in OD incidence in comparators versus OxyContin (Medicaid: adjusted ratio-of-rate-ratios (aRoRs) ranging from 0.90 to 1.05; MarketScan/HIRD: aRoR ranging from 1.10 to 1.22). However, restriction to person-time without concomitant opioid use revealed a modestly greater reduction in OD incidence over time during OxyContin use, as the aRoRs comparing the primary comparators to OxyContin ranged from 1.06 to 1.30 in Medicaid and from 1.64 to 1.85 in MarketScan/HIRD. DISCUSSION: This study did not detect an overall effect of the OxyContin reformulation on OD in insured patients under regular medical care. There is a suggestion of a modestly reduced OxyContin-associated OD risk following the reformulation but only in commercially insured individuals receiving single-opioid regimens.

Longstanding Phenytoin Use as a Cause of Progressive Dyspnea.

CASE PRESENTATION: A 54-year-old South African man with a medical history of type 2 diabetes mellitus, seizure disorder, OSA, and latent TB presented to the ER with gradually progressive dyspnea over months. He also reported occasional dry cough and fatigue at presentation but denied fever, chills, chest pain, leg swelling, palpitations, or lightheadedness. He was treated with a course of levofloxacin for presumed community-acquired pneumonia as an outpatient without improvement and had tested negative for COVID-19. He denied occupational or environmental exposures or sick contacts, though he had traveled back to South Africa 1 year before presentation. He had complex partial seizures for the past 22 years, which had been well controlled on phenytoin (300 mg daily). His other home medications included dulaglutide, sertraline, and atorvastatin and had no recent changes. He quit smoking 30 years ago after smoking one pack per day for 10 years.

Culture as a Moderator of Epistemically Suspect Beliefs.

A consistent finding reported in the literature is that epistemically suspect beliefs (e.g., paranormal beliefs) are less frequently endorsed by individuals with a greater tendency to think analytically. However, these results have been observed predominantly in Western participants. In the present work, we explore various individual differences known to predict epistemically suspect beliefs across both Western and Eastern cultures. Across four studies with Japanese (n = 666) and Western (n = 650) individuals, we find that the association between thinking style and beliefs varied as a function of culture. Specifically, while Westerners who scored higher on measures of Type-2 analytic thinking tended to endorse epistemically suspect beliefs less, this association was not observed in Japanese samples, suggesting that the often-observed negative association between analytic thinking and epistemically suspect beliefs may be exclusive to Western individuals. Additionally, we demonstrate that a tendency to think holistically (specifically with regards to causality) is positively associated with the endorsement of epistemically suspect beliefs within both samples. Overall, we discuss how various individual differences predict the endorsement of epistemically suspect beliefs across cultures.

Mapping inhibitory sites on the RNA polymerase of the 1918 pandemic influenza virus using nanobodies.

Influenza A viruses cause seasonal epidemics and global pandemics, representing a considerable burden to healthcare systems. Central to the replication cycle of influenza viruses is the viral RNA-dependent RNA polymerase which transcribes and replicates the viral RNA genome. The polymerase undergoes conformational rearrangements and interacts with viral and host proteins to perform these functions. Here we determine the structure of the 1918 influenza virus polymerase in transcriptase and replicase conformations using cryo-electron microscopy (cryo-EM). We then structurally and functionally characterise the binding of single-domain nanobodies to the polymerase of the 1918 pandemic influenza virus. Combining these functional and structural data we identify five sites on the polymerase which are sensitive to inhibition by nanobodies. We propose that the binding of nanobodies at these sites either prevents the polymerase from assuming particular functional conformations or interactions with viral or host factors. The polymerase is highly conserved across the influenza A subtypes, suggesting these sites as effective targets for potential influenza antiviral development.

Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.