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Abstract Background and Aim This review investigates the role of gastrointestinal and hepatic manifestations in COVID‐19, particularly with regard to the prevalence of isolated gastrointestinal (GI) symptoms. Methods We searched PubMed, Embase, and Cochrane library for COVID‐19 publications from 1 December 2019 to 18 May 2020. We included any study that reported the presence of GI symptoms in a sample of >5 COVID‐19 patients. Data collection and risk of bias assessment were performed independently by two reviewers. Where ≥3 studies reported data sufficiently similar to allow calculation of a pooled prevalence, we performed random effects meta‐analysis. Results This review included 17 776 COVID‐19 patients from 108 studies. Isolated GI symptoms only occurred in 1% (95% confidence interval [CI] 0–6%) of patients. GI symptoms were reported in 20% (95% CI 15–24%) of patients. The most common were anorexia (21%, 95% CI 15–27%), diarrhea (13%, 95% CI 11–16%), nausea or vomiting (8%, 95% CI 6–11%), and abdominal pain (4%, 95% CI 2–6%). Transaminase elevations were present in 24% (95% CI 17–31%) of patients. Higher prevalence of GI symptoms were reported in studies published after 1st April, with prevalence of diarrhea 16% (95% CI 13–20), nausea or vomiting 12% (95% CI 8–16%), and any GI symptoms 24% (95% CI 18–34%). GI symptoms were associated with severe COVID‐19 disease (odds ratio [OR] 2.1, 95% CI 1.3–3.2), but not mortality (OR 0.90, 95% CI 0.52–1.54). Conclusions Patients with isolated GI symptoms may represent a small but significant portion of COVID‐19 cases. When testing resources are abundant, clinicians should still consider testing patients with isolated GI symptoms or unexplained transaminase elevations for COVID‐19. More recent studies estimate higher overall GI involvement in COVID‐19 than was previously recognized.

Background: Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for patients with BA. Preliminary data suggests that measurement of direct bilirubin (DB) in newborns may be an effective screening tool for neonatal cholestasis, particularly BA, allowing for early referral and diagnosis. The objective of our study was to establish a cutoff DB value to predict diagnosis of cholestatic liver disease (CLD) with high sensitivity and specificity, as well as, to evaluate whether newborns with elevated DB received appropriate follow-up in our health system., Methods: Baseline data were collected on infants born between 2016 and 2019 who had serum total bilirubin and DB drawn in the nursery, and who continued to follow in our health system. Sensitivity, specificity, and positive and negative predictive values were examined using cutoff values of 0.5, 0.6, and 0.7 mg/dL for identifying infants at risk for CLD. Patients' charts were reviewed to note whether they had follow-up levels drawn by their pediatrician or by the hepatology team within 2 months of age and whether they were diagnosed with CLD., Results: Serum total bilirubin and DB levels were drawn from 11 965 infants during their hospitalizations. Three infants from this cohort were diagnosed with CLD: 2 with BA and 1 with Alagille syndrome. DB cutoff values of 0.5, 0.6, and 0.7 mg/dL had sensitivity of 100% and specificity of 96.83% (95% confidence interval [CI], 96.69%-97.53%), 99.08% (95% CI, 98.81%-99.30%), and 99.63% (95% CI, 99.4%-99.7%), respectively. Given that a DB of 0.6 mg/dL had a sensitivity of 100% and specificity of 99%, this value was chosen as the cutoff value to monitor for DB follow-up and diagnosis of CLD. Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD., Conclusions: A DB cutoff value of 0.6 mg/dL yielded high sensitivity and specificity for identifying patients with CLD. All 3 patients diagnosed with CLD had elevated DB at hospital discharge. The data revealed that the majority (75%) of eligible newborns did not receive follow-up for their elevated DB in the outpatient setting., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Population annealing is a recent addition to the arsenal of the practitioner in computer simulations in statistical physics and it proves to deal well with systems with complex free-energy landscapes. Above all else, it promises to deliver unrivaled parallel scaling qualities, being suitable for parallel machines of the biggest caliber. Here we study population annealing using as the main example the two-dimensional Ising model, which allows for particularly clean comparisons due to the available exact results and the wealth of published simulational studies employing other approaches. We analyze in depth the accuracy and precision of the method, highlighting its relation to older techniques such as simulated annealing and thermodynamic integration. We introduce intrinsic approaches for the analysis of statistical and systematic errors and provide a detailed picture of the dependence of such errors on the simulation parameters. The results are benchmarked against canonical and parallel tempering simulations.

Background. Caffeine is widely used to treat apnea of prematurity. Here, we evaluated the efficacy of early caffeine (1-2 DOL) in decreasing the incidence of adverse neonatal outcomes. Methods. A retrospective cohort was used to compare the neonatal morbidity of 150 preterm neonates with gestational age ≤29 weeks. Infants were divided into 3 groups based on the initiation timing of caffeine therapy; (1) early caffeine (1-2 DOL), (2) late caffeine (3-7 DOL), and (3) very late caffeine (≥8 DOL). Results. The neonatal outcomes of early caffeine were comparable with those of the late caffeine group. Moreover, when comparing the neonatal morbidity of the very late caffeine group with that of the early caffeine group, multivariable logistic regression analyses were performed. We found that the timing of caffeine did not influence the risk of BPD (OR, 0.393; CI, 0.126-1.223; p = 0.107), but birthweight did (OR, 0.996; CI, 0.993-0.999; p = 0.018) in these infants. Conclusion. Neonatal outcomes of preterm infants were comparable whether caffeine was administered early or late in the first 7 DOL. The risk of BPD in infants receiving caffeine after 8 DOL was irrespective of delayed treatment with caffeine. Our results clearly demonstrate the need for further studies before caffeine prophylaxis can be universally recommended.

We propose methods for constructing high-quality pseudorandom number generators (RNGs) based on an ensemble of hyperbolic automorphisms of the unit two-dimensional torus (Sinai-Arnold map or cat map) while keeping a part of the information hidden. The single cat map provides the random properties expected from a good RNG and is hence an appropriate building block for an RNG, although unnecessary correlations are always present in practice. We show that introducing hidden variables and introducing rotation in the RNG output, accompanied with the proper initialization, dramatically suppress these correlations. We analyze the mechanisms of the single-cat-map correlations analytically and show how to diminish them. We generalize the Percival-Vivaldi theory in the case of the ensemble of maps, find the period of the proposed RNG analytically, and also analyze its properties. We present efficient practical realizations for the RNGs and check our predictions numerically. We also test our RNGs using the known stringent batteries of statistical tests and find that the statistical properties of our best generators are not worse than those of other best modern generators.

Substituted 5-amino-4-carbamoyl-1,2,3-triazoles 3a-w were prepared by two synthetic schemes and evaluated in vivo for anticoccidial activity. Both schemes proceeded by brominating appropriately substituted toluenes 4a-s,v to 5a-s,v. In Scheme I, the brominated benzyl analogues 5 were converted to the corresponding benzyl azides 6, which were treated with cyanoacetamide to yield 1-substituted-5-amino-4-carbamoyl-1,2,3-triazoles 3. In Scheme II, the benzyl halides 5 were employed to alkylate the sodium salt of 5-amino-4-carbamoyl-1,2,3-triazole (7). Preliminary screening data against Eimeria acervulina and E. tenella in chickens suggested structural requirements for maximizing activity. Further evaluation against a relatively resistant series of eight Eimeria field isolates revealed L-651,582 (3a) to be a highly effective coccidiostat. However, unacceptable tissue residues precluded further development. Mechanistic studies on this series of 5-amino-4-carbamoyl-1,2,3-triazoles and, in particular, on L-651,582 (3a) revealed that its mode of action does not involve inhibition of IMP dehydrogenase, but probably interferes with host cell calcium entry. In addition, L-651,582 has been found to have antiproliferative activity in several disease models and was recently reported to possess antimetastatic activity in a model of ovarian cancer progression.

The title enzyme deactivates the potent carbapenem antibiotic imipenem in the kidney, producing low antibiotic levels in the urinary tract. A series of (Z)-2-(acylamino)-3-substituted-propenoic acids (3) are specific, competitive inhibitors of the enzyme capable of increasing the urinary concentration of imipenem in vivo. Many of the compounds were prepared in one step from an alpha-keto acid and a primary amide. The optimum R2 groups are 2,2-dimethyl, -dichloro, and -dibromocyclopropyl. With R2 = 2,2-dimethylcyclopropyl (DMCP), a wide variety of R3 groups including alkyl, oxa- and thiaalkyl, and alkyl groups containing acidic, basic, and neutral substituents give effective inhibitors with Ki values of 0.02-1 microM and a range of pharmacokinetic properties. By resolution of enantiomers and X-ray crystallography, the enzyme-inhibitory activity of the DMCP group was found to reside with the 1S isomer. The cysteinyl compound 176 (cilastatin, MK-0791) has the desired pharmacological properties and has been chosen for combination with imipenem.