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In sickle cell anemia, deoxygenation causes erythrocytes to distort, while reoxygenation permits them to recover a normal biconcave disk shape. Irreversibly sickled cells (ISCs) remain distorted when reoxygenated and have been thought to have among the highest intracellular hemoglobin concentrations of the sickle red cell population and therefore the greatest vulnerability to vasoocclusion. Using a new optical method, which we describe, we have made precise measurements of the intracellular hemoglobin concentration, and intracellular O 2 saturation, of ISCs, as well as oxygenated sickle cells with a normal biconcave disc shape, and cells with shapes distorted by the sickle fibers they contain. This method also provides good estimates of cell volumes, and hemoglobin per red cell. The concentration distribution of the ISCs is found to be similar to normal, discoid cells. Average ISC volumes exceed their discoid counterparts, with a much broader distribution, arguing against dehydration as their origin. The concentration distribution of the polymer-laden sickled cells is significantly higher in mean value, and their volume distributions indicate some dehydration. Previous assumptions about ISCs may have thus been colored by the presence of sickle cells that did contain polymer, and true ISCs may be much more benign than once thought, which underscores the importance of accurate measurement on individual cells. This method could be used to follow changes in individual cell properties under various specific perturbations, and where characterization by flow cytometry is infeasible., Competing Interests: Declaration of interests All authors declare no conflicts of interest., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Nascent polypeptide chains (NCs) are extruded from the ribosome through an exit tunnel (ET) traversing the large ribosomal subunit. The ET's irregular and chemically complex wall allows for various NC-ET interactions. Translational arrest peptides (APs) bind in the ET to induce translational arrest, a property that can be exploited to study NC-ET interactions by Force Profile Analysis (FPA). We employed FPA and molecular dynamics (MD) simulations to investigate how individual residues placed in a glycine-serine repeat segment within an AP-stalled NC interact with the ET to exert a pulling force on the AP and release stalling. Our results indicate that large and hydrophobic residues generate a pulling force on the NC when placed ≳10 residues away from the peptidyl transfer center (PTC). Moreover, an asparagine placed 12 residues from the PTC makes a specific stabilizing interaction with the tip of ribosomal protein uL22 that reduces the pulling force on the NC, while a lysine or leucine residue in the same position increases the pulling force. Finally, the MD simulations suggest how the Mannheimia succiniproducens SecM AP interacts with the ET to promote translational stalling., Competing Interests: Conflict of interest The authors declare no competing interests.

Background: Endovascular thrombectomy(EVT) is the standard of care for large vessel occlusion(LVO) stroke. Data on technical and clinical outcome in proximal medium vessel occlusions(pMeVOs) comparing frontline techniques remain limited., Methods: We report an international multicenter retrospective study of patients undergoing EVT for stroke at 32 centers between 2015-2021. Patients were divided into LVOs(ICA/M1/Vertebrobasilar) or pMeVOs(M2/A1/P1) and categorized by thrombectomy technique. Primary outcome was 90-day good functional outcome(mRS ≤ 2). Multivariate logistic regressions were used to evaluate the impact of technical variables on clinical outcomes. Propensity score matching was used to compare outcome in patients with pMeVO treated with aspiration versus stent-retriever., Results: In the cohort of 5977 LVO and 1287 pMeVO patients, pMeVO did not independently predict good-outcome(p  =  0.55). In pMeVO patients, successful recanalization irrespective of frontline technique(aOR = 3.2,p < 0.05), procedure time ≤ 1-h(aOR = 2.2,p < 0.05), and thrombectomy attempts ≤ 4(aOR =  2.8,p < 0.05) were independent predictors of good-outcomes.In a propensity-matched cohort of aspiration versus stent-retriever pMeVO patients, there was no difference in good-outcomes. The rates of hemorrhage were higher(9%vs.4%,p < 0.01) and procedure time longer(51-min vs. 33-min,p < 0.01) with stent-retriever, while the number of attempts was higher with aspiration(2.5vs.2,p < 0.01). Rates of hemorrhage and good-outcome showed an exponential relationship to procedural metrics, and were more dependent on time in the aspiration group compared to attempts in the stent-retriever group., Conclusions: Clinical outcomes following EVT for pMeVO are comparable to those in LVOs. The golden hour or 3-pass rules in LVO thrombectomy still apply to pMeVO thrombectomy. Different techniques may exhibit different futility metrics; SR thrombectomy was more influenced by attempts whereas aspiration was more dependent on procedure time., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We model the autoionization of water by determining the free energy of hydration of the major intermediate species of water ions. We represent the smallest ions─the hydroxide ion OH - , the hydronium ion H 3 O + , and the Zundel ion H 5 O 2 + ─by bonded models and the more extended ionic structures by strong nonbonded interactions (e.g., the Eigen H 9 O 4 + = H 3 O + + 3(H 2 O) and the Stoyanov H 13 O 6 + = H 5 O 2 + + 4(H 2 O)). Our models are faithful to the precise QM energies and their components to within 1% or less. Using the calculated free energies and atomization energies, we compute the p K a of pure water from first principles as a consistency check and arrive at a value within 1.3 log units of the experimental one. From these calculations, we conclude that the hydronium ion, and its hydrated state, the Eigen cation, are the dominant species in the water autoionization process.

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members towards one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but non-financial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analysing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated towards COVID-19 elimination (zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases towards advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multiple myeloma (MM), a malignancy involving plasma cells, disproportionately affects older adults with an average age of diagnosis of about 70 years. Oftentimes, the therapies used in the treatment of MM are associated with a risk for immunotoxicity, lowering the ability of the immune system to fight off opportunistic infections. This is an important relationship for clinicians to realize as the incidence of opportunistic infections in myeloma patients is increasing. As an example, we present a case of a patient with MM who subsequently developed a cryptococcal infection. Our paper will highlight the key details of the case as well as shed light on the importance of understanding the immunodeficiencies in this patient population. We highlight important aspects of the current literature related to MM and relate them to the associated case., Competing Interests: None to declare., (Copyright 2024, Nightingale et al.)

Introduction: The study examined whether increased physical activity (PA) in nonmetropolitan cancer survivors was maintained 12 weeks following the PPARCS intervention., Methods: PA outcomes were assessed using an accelerometer at baseline, end of the intervention, and at 24 weeks. Linear mixed models were used to examine between-group changes in PA outcomes., Results: The increased moderate-to-vigorous PA (MVPA) following intervention was maintained with significantly higher MVPA in the intervention group at 24 weeks (vs. controls) compared to baseline nett change of 52.5 min/week (95% CI 11.0-94.0.4)., Conclusions: Distance-based interventions using wearables and health coaching may produce MVPA maintenance amongst nonmetropolitan cancer survivors., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Objective: Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion., Methods: The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs., Results: Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment., Conclusions: Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

We incorporate nuclear quantum effects (NQE) in condensed matter simulations by introducing short-range neural network (NN) corrections to the ab initio fitted molecular force field ARROW. Force field NN corrections are fitted to average interaction energies and forces of molecular dimers, which are simulated using the Path Integral Molecular Dynamics (PIMD) technique with restrained centroid positions. The NN-corrected force field allows reproduction of the NQE for computed liquid water and methane properties such as density, radial distribution function (RDF), heat of evaporation (HVAP), and solvation free energy. Accounting for NQE through molecular force field corrections circumvents the need for explicit computationally expensive PIMD simulations in accurate calculations of the properties of chemical and biological systems. The accuracy and locality of pairwise NN NQE corrections indicate that this approach could be applicable to complex heterogeneous systems, such as proteins.

We present a formalism of a neural network encoding bonded interactions in molecules. This intramolecular encoding is consistent with the models of intermolecular interactions previously designed by this group. Variants of the encoding fed into a corresponding neural network may be used to economically improve the representation of torsional degrees of freedom in any force field. We test the accuracy of the reproduction of the ab initio potential energy surface on a set of conformations of two dipeptides, methyl-capped ALA and ASP, in several scenarios. The encoding, either alone or in conjunction with an analytical potential, improves agreement with ab initio energies that are on par with those of other neural network-based potentials. Using the encoding and neural nets in tandem with an analytical model places the agreements firmly within "chemical accuracy" of ±0.5 kcal/mol.

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood, and its treatment is unsatisfactory. Na + , K + -ATPase is a major plasma membrane transporter and signal transducer. The catalytic α subunit of this enzyme is the binding site for cardiac steroids. Three α isoforms of the Na + , K + -ATPase are present in the brain. Previous studies have supported the involvement of the Na + , K + -ATPase and endogenous cardiac steroids (ECS) in the etiology of BD. Decreased brain ECS has been found to elicit anti-manic and anti-depressive-like behaviors in mice and rats. However, the identity of the specific α isoform involved in these behavioral effects is unknown. Here, we demonstrated that decreasing ECS through intracerebroventricular (i.c.v.) administration of anti-ouabain antibodies (anti-Ou-Ab) decreased the activity of α1 +/- mice in forced swimming tests but did not change the activity in wild type (wt) mice. This treatment also affected exploratory and anxiety behaviors in α1 +/- but not wt mice, as measured in open field tests. The i.c.v. administration of anti-Ou-Ab decreased brain ECS and increased brain Na + , K + -ATPase activity in wt and α1 +/- mice. The serum ECS was lower in α1 +/- than wt mice. In addition, a study in human participants demonstrated that serum ECS significantly decreased after treatment. These results suggest that the Na + , K + -ATPase α1 isoform is involved in depressive- and manic-like behaviors and support that the Na + , K + -ATPase/ECS system participates in the etiology of BD.

Background: Physical activity (PA) is important for cancer survivors. Trials of remotely delivered interventions are needed to assist in reaching under-served non-metropolitan cancer survivors. The objective of this study was to ascertain whether wearable technology, coupled with health coaching was effective in increasing PA in breast and colorectal cancer survivors living in regional and remote areas in Australia., Methods: Cancer survivors from 5 states were randomized to intervention and control arms. Intervention participants were given a Fitbit Charge 2 TM and received up to 6 telephone health coaching sessions. Control participants received PA print materials. Accelerometer assessments at baseline and 12 weeks measured moderate-to-vigorous PA (MVPA), light PA, and sedentary behavior., Results: Eighty-seven participants were recruited (age = 63 ± 11 years; 74 (85%) female). There was a significant net improvement in MVPA of 49.8 min/week, favoring the intervention group (95% confidence interval (95%CI): 13.6-86.1, p = 0.007). There was also a net increase in MVPA bouts of 39.5 min/week (95%CI: 11.9-67.1, p = 0.005), favoring the intervention group. Both groups improved light PA and sedentary behavior, but there were no between-group differences., Conclusion: This is the first study to demonstrate that, when compared to standard practice (i.e., PA education), a wearable technology intervention coupled with distance-based health coaching, improves MVPA in non-metropolitan cancer survivors. The results display promise for the use of scalable interventions using smart wearable technology in conjunction with phone-based health coaching to foster increased PA in geographically disadvantaged cancer survivors., (Copyright © 2023. Production and hosting by Elsevier B.V.)

Excess deaths provide total impact estimates of major crises, such as the COVID-19 pandemic. We evaluated excess death trajectories across countries with accurate death registration and population age structure data and assessed relationships with vulnerability indicators. Using the Human Mortality Database on 34 countries, excess deaths were calculated for 2020-2023 (to week 29, 2023) using 2017-2019 as reference, with adjustment for 5 age strata. Countries were divided into less and more vulnerable; the latter had per capita nominal GDP < $30,000, Gini > 0.35 for income inequality and/or at least ≥2.5% of their population living in poverty. Excess deaths (as proportion of expected deaths, p%) were inversely correlated with per capita GDP ( r = -0.60), correlated with proportion living in poverty ( r = 0.66), and modestly correlated with income inequality ( r = 0.45). Incidence rate ratio for deaths was 1.062 (95% CI, 1.038-1.087) in more versus less vulnerable countries. Excess deaths started deviating in the two groups after the first wave. Between-country heterogeneity diminished gradually within each group. Less vulnerable countries had mean p% = -0.8% and 0.4% in 0-64 and >65-y-old strata. More vulnerable countries had mean p% = 7.0% and 7.2%, respectively. Lower death rates were seen in children of age 0-14 y during 2020-2023 versus prepandemic years. While the pandemic hit some countries earlier than others, country vulnerability dominated eventually the cumulative impact. Half the analyzed countries witnessed no substantial excess deaths versus prepandemic levels, while the others suffered major death tolls., Competing Interests: Competing interests statement:The authors declare no competing interest.

Excess death estimates have great value in public health, but they can be sensitive to analytical choices. Here we propose a multiverse analysis approach that considers all possible different time periods for defining the reference baseline and a range of 1 to 4 years for the projected time period for which excess deaths are calculated. We used data from the Human Mortality Database on 33 countries with detailed age-stratified death information on an annual basis during the period 2009-2021. The use of different time periods for reference baseline led to large variability in the absolute magnitude of the exact excess death estimates. However, the relative ranking of different countries compared to others for specific years remained largely unaltered. The relative ranking of different years for the specific country was also largely independent of baseline. Averaging across all possible analyses, distinct time patterns were discerned across different countries. Countries had declines between 2009 and 2019, but the steepness of the decline varied markedly. There were also large differences across countries on whether the COVID-19 pandemic years 2020-2021 resulted in an increase of excess deaths and by how much. Consideration of longer projected time windows resulted in substantial shrinking of the excess deaths in many, but not all countries. Multiverse analysis of excess deaths over long periods of interest can offer an approach that better accounts for the uncertainty in estimating expected mortality patterns, comparative mortality trends across different countries, and the nature of observed mortality peaks., (© 2023. The Author(s).)

A key goal of molecular modeling is the accurate reproduction of the true quantum mechanical potential energy of arbitrary molecular ensembles with a tractable classical approximation. The challenges are that analytical expressions found in general purpose force fields struggle to faithfully represent the intermolecular quantum potential energy surface at close distances and in strong interaction regimes; that the more accurate neural network approximations do not capture crucial physics concepts, e.g., nonadditive inductive contributions and application of electric fields; and that the ultra-accurate narrowly targeted models have difficulty generalizing to the entire chemical space. We therefore designed a hybrid wide-coverage intermolecular interaction model consisting of an analytically polarizable force field combined with a short-range neural network correction for the total intermolecular interaction energy. Here, we describe the methodology and apply the model to accurately determine the properties of water, the free energy of solvation of neutral and charged molecules, and the binding free energy of ligands to proteins. The correction is subtyped for distinct chemical species to match the underlying force field, to segment and reduce the amount of quantum training data, and to increase accuracy and computational speed. For the systems considered, the hybrid ab initio parametrized Hamiltonian reproduces the two-body dimer quantum mechanics (QM) energies to within 0.03 kcal/mol and the nonadditive many-molecule contributions to within 2%. Simulations of molecular systems using this interaction model run at speeds of several nanoseconds per day.

Introduction/background: Although the combination of bladder dysfunction and upper tract anomalies puts patient with cloaca at risk for renal disease, the rarity of this condition makes it difficult to study empirically. As a high-volume center, we uniquely capture bladder function outcomes following our growing number of cloacal repairs., Objective: 1) Describe the rates of incomplete bladder emptying following primary cloacal repair (at 2-3 months after repair and last follow up), and 2) identify clinical factors associated with assisted bladder emptying., Study Design: We performed a prospective cohort study of patients undergoing primary cloaca repair by our Children's National Colorectal Center team between 2020 and 2021. The primary outcome was assisted bladder emptying at 2-3 months postoperatively and last visit. Covariables included preoperative characteristics (cloacagram measurements), ARM complexity (moderate = common channel [CC] <3-cm, severe = CC ≥ 3-cm), vesicoureteral reflux (VUR) status, sacral ratio (good ≥0.7, intermediate 0.7-0.4, poor ≤0.4), spinal cord status, means of preoperative bladder emptying, and operative details (age at repair, repair type, & concomitant laparotomy)., Results: Eighteen participants were eligible. A majority had moderate cloaca (78%), VUR (67%), spinal cord abnormalities (89%), and good sacral ratios (56%). Preoperatively, 10 patients were diapered for urine and 8 had assisted bladder emptying. Surgical repairs were performed at a median age of 8 months (range 4-46). Nine (50%) patients underwent urogenital separation (UGS), eight (44%) total urogenital mobilization, and 1 (6%) perineal sparing posterior sagittal anorectoplasty with introitoplasty. Exploratory laparotomy was performed in 7 (39%) patients. At 2-3 months, 7 patients were voiding and 11 required assisted bladder emptying. Median length of long-term follow up was 12 months (range 5-25), and 8 patients were voiding and 10 required assisted bladder emptying. Postoperative need for assisted bladder emptying was significantly associated with assisted bladder emptying preoperatively, a shorter urethra and increasing common channel length, UGS and exploratory laparotomy. Spinal cord imaging findings were not associated., Discussion: Bladder emptying following cloaca repair is likely a result of congenital function and surgical effects. Indeed, increasingly cloaca complexity requiring UGS and laparotomy was associated with both pre- and post-operative assisted bladder emptying. The lack of association with spinal cord imaging may reflect a divergence between anatomy and function., Conclusion: Approximately half of patients required assisted bladder emptying in this study. Associated factors included urethral and common channel length, the need for assisted bladder emptying preoperatively, the type of surgical approach and additional laparotomy. Being diapered with seemingly normal voiding prior to surgery did not guarantee normal bladder function postoperatively., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Several teams have been publishing global estimates of excess deaths during the COVID-19 pandemic. Here, we examine potential flaws and underappreciated sources of uncertainty in global excess death calculations. Adjusting for changing population age structure is essential. Otherwise, excess deaths are markedly overestimated in countries with increasingly aging populations. Adjusting for changes in other high-risk indicators, such as residence in long-term facilities, may also make a difference. Death registration is highly incomplete in most countries; completeness corrections should allow for substantial uncertainty and consider that completeness may have changed during pandemic years. Excess death estimates have high sensitivity to modelling choice. Therefore different options should be considered and the full range of results should be shown for different choices of pre-pandemic reference periods and imposed models. Any post-modelling corrections in specific countries should be guided by pre-specified rules. Modelling of all-cause mortality (ACM) in countries that have ACM data and extrapolating these models to other countries is precarious; models may lack transportability. Existing global excess death estimates underestimate the overall uncertainty that is multiplicative across diverse sources of uncertainty. Informative excess death estimates require risk stratification, including age groups and ethnic/racial strata. Data to-date suggest a death deficit among children during the pandemic and marked socioeconomic differences in deaths, widening inequalities. Finally, causal explanations require great caution in disentangling SARS-CoV-2 deaths, indirect pandemic effects and effects from measures taken. We conclude that excess deaths have many uncertainties, but globally deaths from SARS-CoV-2 may be the minority of calculated excess deaths., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Approximately 4% to 35% of pediatric patients undergoing treatment for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy) develop drug-induced hyperglycemia. Though hyperglycemia is associated with poor outcomes, no guidelines for identifying drug-induced hyperglycemia currently exist, and the time course for developing hyperglycemia remains relatively uncharacterized after induction therapy. The present study evaluated a hyperglycemia screening protocol that was implemented to identify hyperglycemia more promptly, examined predictors of hyperglycemia during ALL and LLy therapy, and described the timeline for developing hyperglycemia. A retrospective review of 154 patients diagnosed with ALL or LLy at Cook Children's Medical Center between March 2018 and April 2022 was performed. Predictors of hyperglycemia were examined with Cox regression. The hyperglycemia screening protocol was ordered for 88 (57%) patients. Fifty-four (35%) patients developed hyperglycemia. In multivariate analyses, age 10 years or older (hazard ratio = 2.50, P = 0.007) and weight loss (vs gain) during induction (hazard ratio = 3.39, P < 0.05) were associated with hyperglycemia. The present study identified a population of patients at risk of developing hyperglycemia and identifies strategies for hyperglycemia screening. In addition, the present study showed that some patients developed hyperglycemia after induction therapy, which highlights the importance of continued blood glucose monitoring in at-risk patients. Implications and suggestions for further research are discussed., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism., Competing Interests: Declaration of interests N.W., J.C.F., and A.G. are co-inventors of a patent on the composition, method, and use for FFA screening, application no: 52199-550P01US. A.G. serves as a founding advisor to a new company launched by Atlas Ventures, an agreement reviewed and managed by Brigham and Women’s Hospital, Mass General Brigham, and the Broad Institute of MIT and Harvard in accordance with their conflict of interest policies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: China witnessed a surge of Omicron infections after abandoning 'zero COVID' strategies on 7 December 2022. The authorities report very sparse deaths based on very restricted criteria, but massive deaths are speculated., Methods: We aimed to estimate the COVID-19 fatalities in Mainland China until summer 2023 using the experiences of Hong Kong and of South Korea in 2022 as prototypes. Both these locations experienced massive Omicron waves after having had very few SARS-CoV-2 infections during 2020-2021. We estimated age-stratified infection fatality rates (IFRs) in Hong Kong and South Korea during 2022 and extrapolated to the population age structure of Mainland China. We also accounted separately for deaths of residents in long-term care facilities in both Hong Kong and South Korea., Results: Infection fatality rate estimates in non-elderly strata were modestly higher in Hong Kong than South Korea and projected 987,455 and 619,549 maximal COVID-19 deaths respectively, if the entire China population were infected. Expected COVID-19 deaths in Mainland China until summer 2023 ranged from 49,962 to 691,219 assuming 25-70% of the non-elderly population being infected and variable protection of elderly (from none to three-quarter reduction in fatalities). The main analysis (45% of non-elderly population infected and fatality impact among elderly reduced by half) estimated 152,886-249,094 COVID-19 deaths until summer 2023. Large uncertainties exist regarding potential changes in dominant variant, health system strain and impact on non-COVID-19 deaths., Conclusions: The most critical factor that can affect total COVID-19 fatalities in China is the extent to which the elderly can be protected., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Children with Hirschsprung disease have postoperative long-term sequelae in defecation that contribute to morbidity and mortality and significantly impact their quality of life. Pediatric patients experience ongoing long-term defecation concerns, which can include fecal incontinence (FI) and postoperative obstructive symptoms, such as constipation and Hirschsprung-associated enterocolitis. The American Pediatric Surgical Association has developed guidelines for management of these postoperative obstructive symptoms and FI. However, the evaluation and management of patients with postoperative defecation problems varies among different pediatric gastroenterology centers. This position paper from the Neurogastroenterology & Motility Committee of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition reviews the current evidence and provides suggestions for the evaluation and management of postoperative patients with Hirschsprung disease who present with persistent defecation problems., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

The application of artificial intelligence (AI) has been considered a revolutionary change in drug discovery and development. In 2020, the AlphaFold computer program predicted protein structures for the whole human genome, which has been considered a remarkable breakthrough in both AI applications and structural biology. Despite the varying confidence levels, these predicted structures could still significantly contribute to structure-based drug design of novel targets, especially the ones with no or limited structural information. In this work, we successfully applied AlphaFold to our end-to-end AI-powered drug discovery engines, including a biocomputational platform PandaOmics and a generative chemistry platform Chemistry42. A novel hit molecule against a novel target without an experimental structure was identified, starting from target selection towards hit identification, in a cost- and time-efficient manner. PandaOmics provided the protein of interest for the treatment of hepatocellular carcinoma (HCC) and Chemistry42 generated the molecules based on the structure predicted by AlphaFold, and the selected molecules were synthesized and tested in biological assays. Through this approach, we identified a small molecule hit compound for cyclin-dependent kinase 20 (CDK20) with a binding constant Kd value of 9.2 ± 0.5 μM ( n = 3) within 30 days from target selection and after only synthesizing 7 compounds. Based on the available data, a second round of AI-powered compound generation was conducted and through this, a more potent hit molecule, ISM042-2-048, was discovered with an average Kd value of 566.7 ± 256.2 nM ( n = 3). Compound ISM042-2-048 also showed good CDK20 inhibitory activity with an IC 50 value of 33.4 ± 22.6 nM ( n = 3). In addition, ISM042-2-048 demonstrated selective anti-proliferation activity in an HCC cell line with CDK20 overexpression, Huh7, with an IC 50 of 208.7 ± 3.3 nM, compared to a counter screen cell line HEK293 (IC 50 = 1706.7 ± 670.0 nM). This work is the first demonstration of applying AlphaFold to the hit identification process in drug discovery., Competing Interests: Insilico Medicine is a company developing an AI-based end-to-end integrated pipeline for drug discovery and development and engaged in aging and cancer research. Alán Aspuru-Guzik is co-founder and Chief Vision officer of Kebotix, an AI-powered materials and molecular discovery company and co-founder and Chief Scientific Officer of Zapata Computing, a quantum software computing company. Alán Aspuru-Guzik is a scientific advisor to Insilico Medicine. Michael Levitt is an advisor to Insilico Medicine., (This journal is © The Royal Society of Chemistry.)

Protein-ligand binding free-energy calculations using molecular dynamics (MD) simulations have emerged as a powerful tool for in silico drug design. Here, we present results obtained with the ARROW force field (FF)─a multipolar polarizable and physics-based model with all parameters fitted entirely to high-level ab initio quantum mechanical (QM) calculations. ARROW has already proven its ability to determine solvation free energy of arbitrary neutral compounds with unprecedented accuracy. The ARROW FF parameterization is now extended to include coverage of all amino acids including charged groups, allowing molecular simulations of a series of protein-ligand systems and prediction of their relative binding free energies. We ensure adequate sampling by applying a novel technique that is based on coupling the Hamiltonian Replica exchange (HREX) with a conformation reservoir generated via potential softening and nonequilibrium MD. ARROW provides predictions with near chemical accuracy (mean absolute error of ∼0.5 kcal/mol) for two of the three protein systems studied here (MCL1 and Thrombin). The third protein system (CDK2) reveals the difficulty in accurately describing dimer interaction energies involving polar and charged species. Overall, for all of the three protein systems studied here, ARROW FF predicts relative binding free energies of ligands with a similar accuracy level as leading nonpolarizable force fields.

The counts of confirmed cases and deaths in isolated SARS-CoV-2 outbreaks follow the Gompertz growth function for locations of very different sizes. This lack of dependence on region size leads us to hypothesize that virus spread depends on the universal properties of the network of social interactions. We test this hypothesis by simulating the propagation of a virus on networks of different topologies or connectivities. Our main finding is that we can reproduce the Gompertz growth observed for many early outbreaks with a simple virus spread model on a scale-free network, in which nodes with many more neighbors than average are common. Nodes that have very many neighbors are infected early in the outbreak and then spread the infection very rapidly. When these nodes are no longer infectious, the remaining nodes that have most neighbors take over and continue to spread the infection. In this way, the rate of spread is fastest at the very start and slows down immediately. Geometrically we see that the "surface" of the epidemic, the number of susceptible nodes in contact with the infected nodes, starts to rapidly decrease very early in the epidemic and as soon as the larger nodes have been infected. In our simulation, the speed and impact of an outbreak depend on three parameters: the average number of contacts each node makes, the probability of being infected by a neighbor, and the probability of recovery. Intelligent interventions to reduce the impact of future outbreaks need to focus on these critical parameters in order to minimize economic and social collateral damage., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Intraoperative evaluation of bowel perfusion is currently dependent upon subjective assessment. Thus, quantitative and objective methods of bowel viability in intestinal anastomosis are scarce. To address this clinical need, a conditional adversarial network is used to analyze the data from laser speckle contrast imaging (LSCI) paired with a visible-light camera to identify abnormal tissue perfusion regions., Approach: Our vision platform was based on a dual-modality bench-top imaging system with red-green-blue (RGB) and dye-free LSCI channels. Swine model studies were conducted to collect data on bowel mesenteric vascular structures with normal/abnormal microvascular perfusion to construct the control or experimental group. Subsequently, a deep-learning model based on a conditional generative adversarial network (cGAN) was utilized to perform dual-modality image alignment and learn the distribution of normal datasets for training. Thereafter, abnormal datasets were fed into the predictive model for testing. Ischemic bowel regions could be detected by monitoring the erroneous reconstruction from the latent space. The main advantage is that it is unsupervised and does not require subjective manual annotations. Compared with the conventional qualitative LSCI technique, it provides well-defined segmentation results for different levels of ischemia., Results: We demonstrated that our model could accurately segment the ischemic intestine images, with a Dice coefficient and accuracy of 90.77% and 93.06%, respectively, in 2560 RGB/LSCI image pairs. The ground truth was labeled by multiple and independent estimations, combining the surgeons' annotations with fastest gradient descent in suspicious areas of vascular images. The total processing time was 0.05 s for an image size of 256 × 256 ., Conclusions: The proposed cGAN can provide pixel-wise and dye-free quantitative analysis of intestinal perfusion, which is an ideal supplement to the traditional LSCI technique. It has potential to help surgeons increase the accuracy of intraoperative diagnosis and improve clinical outcomes of mesenteric ischemia and other gastrointestinal surgeries., (© 2022 The Authors.)

Different modeling approaches can be used to calculate excess deaths for the COVID-19 pandemic period. We compared 6 calculations of excess deaths (4 previously published [3 without age-adjustment] and two new ones that we performed with and without age-adjustment) for 2020-2021. With each approach, we calculated excess deaths metrics and the ratio R of excess deaths over recorded COVID-19 deaths. The main analysis focused on 33 high-income countries with weekly deaths in the Human Mortality Database (HMD at mortality.org) and reliable death registration. Secondary analyses compared calculations for other countries, whenever available. Across the 33 high-income countries, excess deaths were 2.0-2.8 million without age-adjustment, and 1.6-2.1 million with age-adjustment with large differences across countries. In our analyses after age-adjustment, 8 of 33 countries had no overall excess deaths; there was a death deficit in children; and 0.478 million (29.7%) of the excess deaths were in people <65 years old. In countries like France, Germany, Italy, and Spain excess death estimates differed 2 to 4-fold between highest and lowest figures. The R values' range exceeded 0.3 in all 33 countries. In 16 of 33 countries, the range of R exceeded 1. In 25 of 33 countries some calculations suggest R > 1 (excess deaths exceeding COVID-19 deaths) while others suggest R < 1 (excess deaths smaller than COVID-19 deaths). Inferred data from 4 evaluations for 42 countries and from 3 evaluations for another 98 countries are very tenuous. Estimates of excess deaths are analysis-dependent and age-adjustment is important to consider. Excess deaths may be lower than previously calculated., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage., Methods: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference., Results: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2-14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3-5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7-12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4-37.7; P , 0.026)., Conclusions: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

The ribosome stalling mechanism is a crucial biological process, yet its atomistic underpinning is still elusive. In this framework, the human XBP1u translational arrest peptide (AP) plays a central role in regulating the unfolded protein response (UPR) in eukaryotic cells. Here, we report multimicrosecond all-atom molecular dynamics simulations designed to probe the interactions between the XBP1u AP and the mammalian ribosome exit tunnel, both for the wild type AP and for four mutant variants of different arrest potencies. Enhanced sampling simulations allow investigating the AP release process of the different variants, shedding light on this complex mechanism. The present outcomes are in qualitative/quantitative agreement with available experimental data. In conclusion, we provide an unprecedented atomistic picture of this biological process and clear-cut insights into the key AP-ribosome interactions.

Introduction: Despite the proven benefit of adjuvant androgen deprivation therapy (ADT) for patients receiving primary radiation, there are few studies evaluating adjuvant ADT after prostatectomy. In the absence of evidence, opinions and practice patterns vary. We surveyed Canadian prostate cancer surgeons about their use of adjuvant ADT and their opinions on the design of a potential adjuvant ADT trial., Methods: An electronic survey was devised and distributed using a modified Dillman approach. The survey was sent to 38 Canadian urologists that perform radical prostatectomy and representing all 17 major academic institutions in Canada and all 10 Canadian provinces. Reminders were sent three and four weeks following the original request. In addition to demographic information, we asked surgeons about their current use of postoperative adjuvant ADT and their opinion about the need for a clinical trial. To inform trial design, we asked respondents their opinions about which patients should be eligible, what duration of ADT was most appropriate, and which outcomes are clinically meaningful. The survey was sent in February 2020 and all responses were received by March 2020., Results: All 38 (100%) invited urologists completed the survey. Only 3 (7%) respondents currently offer postoperative adjuvant ADT as an option for patients without metastases. 35 (92%) urologists believed that a trial is needed before short-term adjuvant treatment should be offered to prevent recurrence. 15 (45%) urologists believed an adjuvant ADT trial was most appropriate for patients with an estimated PSA recurrence risk of >25% and 16 (42%) believed a recurrence risk of >50% was most appropriate. 25 (66%) respondents believed 12-month was the optimal duration of treatment with adjuvant ADT for a randomized trial. 37 (97%) respondents felt that prolonging the time to PSA recurrence and/or pelvic radiation was a clinically important outcome. The majority (20; 53%) of respondents would recommend 12 months of adjuvant ADT in their practice if a randomized trial showed a 50% relative risk reduction in PSA recurrence at 5-year postoperative., Conclusion: The vast majority of Canadian prostate cancer surgeons do not offer adjuvant ADT following prostatectomy in patients without metastases. Based on the results from this survey, a randomized trial was considered warranted and feasible, and would influence patient care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: A significant proportion of transfemoral cerebral angiography complications are related to the access site, with no clear consensus concerning the optimal closure technique. In this study, we examined the usefulness of a shortened closure protocol for transfemoral diagnostic cerebral angiography., Methods: We performed a retrospective review of patients who underwent transfemoral (4Fr sheath) diagnostic cerebral angiography procedures at our institution. We included patients > 18 years old who underwent the shortened closure protocol to achieve hemostasis at the access site. The shortened protocol entailed the use of nonocclusive manual compression for 15 min followed by 2 h of bed rest, with additional 10-15 min of compression for new hematoma. We collected and analyzed the patients' demographics, use of antiplatelet and anticoagulation medications, sheath size, and others., Results: The study cohort comprised 119 patients with a mean age was 54 years with (88%) females. Forty-one patients (34%) were on antiplatelet medications, with 12 (10%) on dual antiplatelet therapy (DAPT). Four patients (3%) (two on DAPT, one on Aspirin alone, and one was not on any antiplatelet medication) had access site hematoma that required additional compression. Subgroup analysis showed that within the DAPT, Aspirin alone, and no antiplatelet medications groups, (17%), (3%), and (1%) of patients developed access site hematoma, respectively., Conclusion: This pilot study demonstrates that our closure protocol for transfemoral angiograms is safe and effective. There was a trend toward higher access-site complications in patients on DAPT. Further studies are required to expand on and validate our results., (© 2022. The Author(s).)

The main goal of molecular simulation is to accurately predict experimental observables of molecular systems. Another long-standing goal is to devise models for arbitrary neutral organic molecules with little or no reliance on experimental data. While separately these goals have been met to various degrees, for an arbitrary system of molecules they have not been achieved simultaneously. For biophysical ensembles that exist at room temperature and pressure, and where the entropic contributions are on par with interaction strengths, it is the free energies that are both most important and most difficult to predict. We compute the free energies of solvation for a diverse set of neutral organic compounds using a polarizable force field fitted entirely to ab initio calculations. The mean absolute errors (MAE) of hydration, cyclohexane solvation, and corresponding partition coefficients are 0.2 kcal/mol, 0.3 kcal/mol and 0.22 log units, i.e. within chemical accuracy. The model (ARROW FF) is multipolar, polarizable, and its accompanying simulation stack includes nuclear quantum effects (NQE). The simulation tools' computational efficiency is on a par with current state-of-the-art packages. The construction of a wide-coverage molecular modelling toolset from first principles, together with its excellent predictive ability in the liquid phase is a major advance in biomolecular simulation., (© 2022. The Author(s).)

Competing Interests: Competing interestsThe author Rui Chen is an Associate Editor for this journal Current Medicine. The paper was handled by the other Editor and has undergone rigorous peer review process. Author Rui Chen was not involved in the journal's review of, or decisions related to, this manuscript.

Introduction: Distal anterior cerebral artery aneurysms (DACAA) are a rare and difficult entity to manage. Endovascular treatment has evolved for safe and durable treatment of these lesions. The objective of this study is to report the safety, efficacy, and outcomes of endovascular treatment of DACAA., Methods: A retrospective review of DACAA endovascularly treated at 5 different institutions was performed. Data included demographics, rupture status, radiographic features, endovascular technique, complication rates, and long-term angiographic and clinical outcomes. A primary endpoint was a good clinical outcome (modified Rankin scale 0-2). Secondary endpoints included complications and radiographic occlusion at follow-up., Results: A total of 84 patients were reviewed. The mean age was 56, and 64 (71.4%) were female. Fifty-two (61.9%) aneurysms were ruptured. A good functional outcome was achieved in 59 patients (85.5%). Sixty (71.4%) aneurysms were treated with primary coiling, and the remaining 24 were treated with flow diversion. Adequate occlusion was achieved in 41 (95.3%) aneurysms treated with coiling, and 17 (89.5%) with flow diversion. There were total 11 (13%) complications. In the flow diversion category, there were 2, both related to femoral access. In the coiling category, there were 9: 5 thromboembolic, 3 ruptures, and 1 related to femoral access., Conclusion: Endovascular treatment, and in particular, flow diversion for DACAA, is safe, feasible, and associated with good long-term angiographic and clinical outcomes., (Published by Elsevier Inc.)

Objectives: The study objective was to assess whether moderate-to-vigorous intensity physical activity (MVPA) change in cancer survivors (n = 68, mean age = 64 years) was maintained 12-weeks following the Wearable Activity Technology and Action Planning (WATAAP) intervention. Secondary aims were to assess the effects of the intervention on blood pressure (BP) and body mass index (BMI), and to explore group differences between baseline and 24-weeks., Design: Randomized controlled trial., Methods: MVPA and sedentary behaviour were assessed using an accelerometer at baseline, the end of the intervention (12-weeks), and at 24-weeks. Generalised linear mixed models with random effects were used to examine between-group and within-group changes in MVPA, sedentary behaviour, BP and BMI., Results: MVPA was significantly higher in the intervention group compared with the control group at 24-weeks following adjustment for known confounders (141.4 min/wk. (95% CI = 9.1 to 273.8), p = 0.036). At 24-weeks participants in the intervention group had maintained their increased levels of MVPA (change from 12-weeks = 8.8 min/wk.; 95% CI = -43 to 61; p = 0.74). The reduction in MVPA in the control group over the first 12-weeks was also maintained at 24-weeks (5.4 min/wk.; 95% CI = -3.6 to 4.6; p = 0.80). Secondary outcomes did not differ between groups at 24-weeks., Conclusions: Our results suggest distance-based interventions using wearable technology produce increases in MVPA that endure at least 12-weeks after the intervention is completed., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the utility of high-resolution flat-detector computed tomography (HR-FDCT) compared with conventional flat-detector computed tomography (FDCT) for stent placement in symptomatic intracranial atherosclerotic stenosis (ICAS)., Methods: We retrospectively reviewed the clinical data of 116 patients with symptomatic ICAS who underwent stent implantation. Images were acquired using conventional FDCT [voxel size = 0.43 mm (isotropic)] and HR-FDCT [voxel size = 0.15 mm (isotropic)]. Immediately after stent deployment, dual-volume three-dimensional (3D) fusion images were obtained from 3D digital subtraction angiography (DSA) and HR-FDCT. The image quality for stent visualization was graded from 0 to 2 (0: not able to assess; 1: limited, but able to assess; 2: clear visualization), and the stent-expansion status ("full," "under-expanded" or "poor apposition") was recorded., Results: A total of 116 patients with symptomatic ICAS were treated successfully using 116 stents (58 Neuroform TM EZ, 42 Enterprise TM , and 16 Apollo TM ). The mean pre-stent stenosis was 80.5 ± 6.4%, which improved to 20.8 ± 6.9% after stenting. Compared with FDCT, HR-FDCT improved visualization of the fine structures of the stent to improve the image quality that significantly (mean score: 1.63 ± 0.60 vs . 0.41 ± 0.59, P < 0.001). In 19 patients, stent under-expansion ( n = 11) or poor apposition ( n = 8) was identified by HR-FDCT but not by conventional FDCT. After balloon dilatation, stent malapposition was shown to have improved on HR-FDCT. None of the 19 patients with stent malapposition experienced short-term complications during hospitalization or had in-stent stenosis at 6-month follow-up., Conclusion: High-resolution flat-detector computed tomography (HR-FDCT) improves visualization of the fine structures of intracranial stents deployed for symptomatic ICAS compared with that visualized using conventional FDCT. High-resolution flat-detector computed tomography improves assessment of stent deployment and could reduce the risk of complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wang, Ma, Levitt, Mossa-Basha, Shi, Ran, Ren, Han and Zhu.)

Objective: Chronic subdural hematomas (cSDHs) are an increasingly prevalent neurologic disease that often requires surgical intervention to alleviate compression of the brain. Management of cSDHs relies heavily on computed tomography (CT) imaging, and serial imaging is frequently obtained to help direct management. The volume of hematoma provides critical information in guiding therapy and evaluating new methods of management. We set out to develop an automated program to compute the volume of hematoma on CT scans for both pre- and postoperative images., Methods: A total of 21,710 images (128 CT scans) were manually segmented and used to train a convolutional neural network to automatically segment cSDHs. We included both pre- and postoperative coronal head CTs from patients undergoing surgical management of cSDHs., Results: Our best model achieved a DICE score of 0.8351 on the testing dataset, and an average DICE score of 0.806 ± 0.06 on the validation set. This model was trained on the full dataset with reduced volumes, a network depth of 4, and postactivation residual blocks within the context modules of the encoder pathway. Patch trained models did not perform as well and decreasing the network depth from 5 to 4 did not appear to significantly improve performance., Conclusions: We successfully trained a convolutional neural network on a dataset of pre- and postoperative head CTs containing cSDH. This tool could assist with automated, accurate measurements for evaluating treatment efficacy., (Copyright © 2020 Elsevier Inc. All rights reserved.)