What Are the Real Issues in Providing Extracorporeal Membrane Oxygenation (ECMO) Support: A Survey.

INTRODUCTION: By using a novel survey our study aimed to assess the challenges ECMO and Critical Care (CC) teams face when initiating and managing patient's ECMO support. METHODS: A qualitative survey-based observational study was performed of members of 2 Critical Care Medicine organizations involved in decision-making around the practice of Extracorporeal Membrane Oxygenation (ECMO). The range of exploratory questions covered ethical principles of informed consent, autonomy and goals of care discussions, beneficence, non-maleficence (offering life-sustaining treatments in end-of-life care), and justice (insurance-related limitations of treatment). Questions also covered pragmatic practice and quality improvement areas, such as exploring whether palliative care or ethics teams were involved in such decision-making. RESULTS: 305 members received the survey links, and a total of 61 completed surveys were received, for an overall response rate of 20% among all eligible members. Only 70% of the participants who manage ECMO patients are involved in the ECMO initiation decision process. The majority do not involve Ethics or Palliative care at the initial ECMO initiation decision step. Of the ethical and moral dilemmas reported, the majority revolved around 1. Prognostication of patients receiving VV and VA ECMO support, 2. Lack of knowledge of patient's wishes and goals, 3. Disconnect between expectations of families and outcomes and 4. Staff moral distress around when to stop ECMO in case of futility. CONCLUSION: Our survey highlights areas of distress and dilemma which have been stressed before in the initiation, management, and outcomes of ECMO patients, however with the increasing use of this modality of cardiopulmonary mechanical support being offered, the survey results can offer a guidance using sound ethical principles.

Hybrid programming-model strategies for GPU offloading of electronic structure calculation kernels.

To address the challenge of performance portability and facilitate the implementation of electronic structure solvers, we developed the basic matrix library (BML) and Parallel, Rapid O(N), and Graph-based Recursive Electronic Structure Solver (PROGRESS) library. The BML implements linear algebra operations necessary for electronic structure kernels using a unified user interface for various matrix formats (dense and sparse) and architectures (CPUs and GPUs). Focusing on density functional theory and tight-binding models, PROGRESS implements several solvers for computing the single-particle density matrix and relies on BML. In this paper, we describe the general strategies used for these implementations on various computer architectures, using OpenMP target functionalities on GPUs, in conjunction with third-party libraries to handle performance critical numerical kernels. We demonstrate the portability of this approach and its performance in benchmark problems.

Survival and Decision-Making in Patients Turned Down for Abdominal Aortic Aneurysm Repair: A Retrospective Study with Focus on COVID-19 Impact.

OBJECTIVES: To investigate and analyse various aspects related to patients who have been placed on a "turn-down list" for elective or emergency repair of abdominal aortic aneurysms (AAA). METHODS: This retrospective study analysed data from the Black Country Vascular Network (BCVN). Multidisciplinary team (MDT) meetings assessed AAA patients referred through National Abdominal Aortic Aneurysm Screening Programme (NAAASP)or directly to vascular surgery. Patients considered unfit for intervention were added to a prospectively kept turndown list. Survival and cause of death data were collected, along with cardiopulmonary exercise testing (CPET) results and British Aneurysm Repair (BAR) scores for some patients. The study covered a period from January 2015 to May 2023. RESULTS: After exclusions 247 (16%) patients were placed on the turndown list with a median age of 85 years (IQR 8 years). The mortality of turndown cases on medical grounds was 74.1%. Survival was significantly higher for patients who completed CPET before being turned down (p = 0.004). Gender analysis revealed a higher proportion of females being turned down compared to males (p = 0.044). COVID-19 led to a notable reduction in the number of discussed cases and interventions, while the turndown rates remained consistent. Survival at one year in turndown patients was 66%, at three it was 29%, at four years it was18% and at 7 years it was 5%. Most patients whose cause of death was known died of respiratory complications (30%) or malignancy (19%). BAR scores and aneurysm size were not significant predictors of mortality. CONCLUSION: Patients on the turndown list have a substantial mortality rate. A significant proportion of female patients were being turned down compared to men and the reasons for this are not clear. Patients who completed CPET before being turned down had a longer survival time. While COVID-19 impacted healthcare services reducing the number of interventions, it did not influence turndown decisions. The study showed that the cause of death for a significant number of patients was respiratory complications or malignancy.

The incidence of surgical site infection following major lower limb amputation: A systematic review.

Surgical site infections (SSIs) following major lower limb amputation (MLLA) in vascular patients are a major source of morbidity. The objective of this systematic review was to determine the incidence of SSI following MLLA in vascular patients. This review was prospectively registered with the International Prospective Register of Systematic Reviews (CRD42023460645). Databases were searched without date restriction using a pre-defined search strategy. The search identified 1427 articles. Four RCTs and 21 observational studies, reporting on 50 370 MLLAs, were included. Overall SSI incidence per MLLA incision was 7.2% (3628/50370). The incidence of SSI in patients undergoing through-knee amputation (12.9%) and below-knee amputation (7.5%) was higher than the incidence of SSI in patients undergoing above-knee amputation, (3.9%), p < 0.001. The incidence of SSI in studies focusing on patients with peripheral arterial disease (PAD), diabetes or including patients with both was 8.9%, 6.8% and 7.2%, respectively. SSI is a common complication following MLLA in vascular patients. There is a higher incidence of SSI associated with more distal amputation levels. The reported SSI incidence is similar between patients with underlying PAD and diabetes. Further studies are needed to understand the exact incidence of SSI in vascular patients and the factors which influence this.

Water Networks in Photosystem II Using Crystalline Molecular Dynamics Simulations and Room-Temperature XFEL Serial Crystallography.

Structural dynamics of water and its hydrogen-bonding networks play an important role in enzyme function via the transport of protons, ions, and substrates. To gain insights into these mechanisms in the water oxidation reaction in Photosystem II (PS II), we have performed crystalline molecular dynamics (MD) simulations of the dark-stable S1 state. Our MD model consists of a full unit cell with 8 PS II monomers in explicit solvent (861 894 atoms), enabling us to compute the simulated crystalline electron density and to compare it directly with the experimental density from serial femtosecond X-ray crystallography under physiological temperature collected at X-ray free electron lasers (XFELs). The MD density reproduced the experimental density and water positions with high fidelity. The detailed dynamics in the simulations provided insights into the mobility of water molecules in the channels beyond what can be interpreted from experimental B-factors and electron densities alone. In particular, the simulations revealed fast, coordinated exchange of waters at sites where the density is strong, and water transport across the bottleneck region of the channels where the density is weak. By computing MD hydrogen and oxygen maps separately, we developed a novel Map-based Acceptor-Donor Identification (MADI) technique that yields information which helps to infer hydrogen-bond directionality and strength. The MADI analysis revealed a series of hydrogen-bond wires emanating from the Mn cluster through the Cl1 and O4 channels; such wires might provide pathways for proton transfer during the reaction cycle of PS II. Our simulations provide an atomistic picture of the dynamics of water and hydrogen-bonding networks in PS II, with implications for the specific role of each channel in the water oxidation reaction.

Predicting Visual Field Worsening with Longitudinal OCT Data Using a Gated Transformer Network.

PURPOSE: To identify visual field (VF) worsening from longitudinal OCT data using a gated transformer network (GTN) and to examine how GTN performance varies for different definitions of VF worsening and different stages of glaucoma severity at baseline. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: A total of 4211 eyes (2666 patients) followed up at the Johns Hopkins Wilmer Eye Institute with at least 5 reliable VF results and 1 reliable OCT scan within 1 year of each reliable VF test. METHODS: For each eye, we used 3 trend-based methods (mean deviation [MD] slope, VF index slope, and pointwise linear regression) and 3 event-based methods (Guided Progression Analysis, Collaborative Initial Glaucoma Treatment Study scoring system, and Advanced Glaucoma Intervention Study [AGIS] scoring system) to define VF worsening. Additionally, we developed a "majority of 6" algorithm (M6) that classifies an eye as worsening if 4 or more of the 6 aforementioned methods classified the eye as worsening. Using these 7 reference standards for VF worsening, we trained 7 GTNs that accept a series of at least 5 as input OCT scans and provide as output a probability of VF worsening. Gated transformer network performance was compared with non-deep learning models with the same serial OCT input from previous studies-linear mixed-effects models (MEMs) and naive Bayes classifiers (NBCs)-using the same training sets and reference standards as for the GTN. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC). RESULTS: The M6 labeled 63 eyes (1.50%) as worsening. The GTN achieved an AUC of 0.97 (95% confidence interval, 0.88-1.00) when trained with M6. Gated transformer networks trained and optimized with the other 6 reference standards showed an AUC ranging from 0.78 (MD slope) to 0.89 (AGIS). The 7 GTNs outperformed all 7 MEMs and all 7 NBCs accordingly. Gated transformer network performance was worse for eyes with more severe glaucoma at baseline. CONCLUSIONS: Gated transformer network models trained with OCT data may be used to identify VF worsening. After further validation, implementing such models in clinical practice may allow us to track functional worsening of glaucoma with less onerous structural testing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Nationwide Clinical Practice Patterns of Anesthesiology Critical Care Physicians: A Survey to Members of the Society of Critical Care Anesthesiologists.

BACKGROUND: Despite the growing contributions of critical care anesthesiologists to clinical practice, research, and administrative leadership of intensive care units (ICUs), relatively little is known about the subspecialty-specific clinical practice environment. An understanding of contemporary clinical practice is essential to recognize the opportunities and challenges facing critical care anesthesia, optimize staffing patterns, assess sustainability and satisfaction, and strategically plan for future activity, scope, and training. This study surveyed intensivists who are members of the Society of Critical Care Anesthesiologists (SOCCA) to evaluate practice patterns of critical care anesthesiologists, including compensation, types of ICUs covered, models of overnight ICU coverage, and relationships between these factors. We hypothesized that variability in compensation and practice patterns would be observed between individuals. METHODS: Board-certified critical care anesthesiologists practicing in the United States were identified using the SOCCA membership distribution list and invited to take a voluntary online survey between May and June 2021. Multiple-choice questions with both single- and multiple-select options were used for answers with categorical data, and adaptive questioning was used to clarify stem-based responses. Respondents were asked to describe practice patterns at their respective institutions and provide information about their demographics, salaries, effort in ICUs, as well as other activities. RESULTS: A total of 490 participants were invited to take this survey, and 157 (response rate 32%) surveys were completed and analyzed. The majority of respondents were White (73%), male (69%), and younger than 50 years of age (82%). The cardiothoracic/cardiovascular ICU was the most common practice setting, with 69.5% of respondents reporting time working in this unit. Significant variability was observed in ICU practice patterns. Respondents reported spending an equal proportion of their time in clinical practice in the operating rooms and ICUs (median, 40%; interquartile range [IQR], 20%-50%), whereas a smaller proportion-primarily those who completed their training before 2009-reported administrative or research activities. Female respondents reported salaries that were $36,739 less than male respondents; however, this difference was not statistically different, and after adjusting for age and practice type, these differences were less pronounced (-$27,479.79; 95% confidence interval [CI], -$57,232.61 to $2273.03; P = .07). CONCLUSIONS: These survey data provide a current snapshot of anesthesiology critical care clinical practice patterns in the United States. Our findings may inform decision-making around the initiation and expansion of critical care services and optimal staffing patterns, as well as provide a basis for further work that focuses on intensivist satisfaction and burnout.

Graph-based quantum response theory and shadow Born-Oppenheimer molecular dynamics.

Graph-based linear scaling electronic structure theory for quantum-mechanical molecular dynamics simulations [A. M. N. Niklasson et al., J. Chem. Phys. 144, 234101 (2016)] is adapted to the most recent shadow potential formulations of extended Lagrangian Born-Oppenheimer molecular dynamics, including fractional molecular-orbital occupation numbers [A. M. N. Niklasson, J. Chem. Phys. 152, 104103 (2020) and A. M. N. Niklasson, Eur. Phys. J. B 94, 164 (2021)], which enables stable simulations of sensitive complex chemical systems with unsteady charge solutions. The proposed formulation includes a preconditioned Krylov subspace approximation for the integration of the extended electronic degrees of freedom, which requires quantum response calculations for electronic states with fractional occupation numbers. For the response calculations, we introduce a graph-based canonical quantum perturbation theory that can be performed with the same natural parallelism and linear scaling complexity as the graph-based electronic structure calculations for the unperturbed ground state. The proposed techniques are particularly well-suited for semi-empirical electronic structure theory, and the methods are demonstrated using self-consistent charge density-functional tight-binding theory both for the acceleration of self-consistent field calculations and for quantum-mechanical molecular dynamics simulations. Graph-based techniques combined with the semi-empirical theory enable stable simulations of large, complex chemical systems, including tens-of-thousands of atoms.

Report of the third conference on next-generation sequencing for adventitious virus detection in biologics for humans and animals.

Next-generation sequencing (NGS) has been proven to address some of the limitations of the current testing methods for adventitious virus detection in biologics. The International Alliance for Biological Standardization (IABS), the U.S. Food and Drug Administration (FDA), and the European Directorate for the Quality of Medicines and Healthcare (EDQM) co-organized the "3rd Conference on Next-generation Sequencing for Adventitious Virus Detection in Biologics for Humans and Animals", which was held on September 27-28, 2022, in Rockville, Maryland, U.S.A. The meeting gathered international representatives from regulatory and public health authorities and other government agencies, industry, contract research organizations, and academia to present the current status of NGS applications and the progress on NGS standardization and validation for detection of viral adventitious agents in biologics, including human and animal vaccines, gene therapies, and biotherapeutics. Current regulatory expectations were discussed for developing a scientific consensus regarding using NGS for detection of adventitious viruses. Although there are ongoing improvements in the NGS workflow, the development of reference materials for facilitating method qualification and validation support the current use of NGS for adventitious virus detection.

A vascular multi-arm multi-stage trial to prevent groin wound surgical site infection: A feasibility survey.

Surgical site infection (SSI) is common following arterial surgery involving a groin incision. There is a lack of evidence regarding interventions to prevent groin wound SSI, therefore, a survey of vascular clinicians was undertaken to assess current opinion and practice, equipoise and feasibility of a randomised controlled trial (RCT). Participants at the Vascular Society of Great Britain and Ireland 2021 Annual Scientific Meeting were surveyed regarding three separate interventions designed to prevent SSI in the groin; impregnated incise drapes, diakylcarbomoyl chloride dressings and antibiotic impregnated collagen sponges. Results were collated via an online survey using the Research Electronic Data Capture platform. Seventy-five participants completed the questionnaire, most were consultant vascular surgeons (50/75, 66.7%). The majority agree that groin wound SSI is a major problem (73/75, 97.3%), and would be content using either of the three interventions (51/61, 83.6%) and had clinical equipoise to randomise patients to any of the three interventions versus standard of care (70/75, 93.3%). There was some reluctance to not use impregnated incise drapes as may be considered "standard of care". Groin wound SSI is perceived as major problem in vascular surgery, and a multicentre RCT of three preventative interventions appears acceptable to vascular surgeons.

Systematic review of groin wound surgical site infection incidence after arterial intervention.

The objectives were to determine the surgical site infection incidence (including superficial/deep) fter arterial intervention through non-infected groin incisions and identify variables associated with incidence. MEDLINE, EMBASE and CENTRAL databases were searched for randomised controlled trials and observational studies of adults undergoing arterial intervention through a groin incision and reported surgical site infection. Infection incidence was examined in subgroups, variables were subjected to meta-regression. One hundred seventeen studies reporting 65 138 groin incisions in 42 347 patients were included. Overall surgical site infection incidence per incision was 8.1% (1730/21 431): 6.3% (804/12 786) were superficial and 1.9% (241/12 863) were deep. Superficial infection incidence was higher in randomised controlled trials (15.8% [278/1762]) compared with observational studies (4.8% [526/11 024]); deep infection incidence was similar (1.7% (30/1762) and 1.9% (211/11 101) respectively). Aneurysmal pathology (ß = -10.229, P < .001) and retrospective observational design (ß = -1.118, P = .002) were associated with lower infection incidence. Surgical site infection being a primary outcome was associated with a higher incidence of surgical site infections (ß = 3.429, P = .017). The three-fold higher incidence of superficial surgical site infection reported in randomised controlled trials may be because of a more robust clinical review of patients. These results should be considered when benchmarking practice and could inform future trial design.

Unsupervised Machine Learning Shows Change in Visual Field Loss in the Idiopathic Intracranial Hypertension Treatment Trial.

PURPOSE: We previously reported that archetypal analysis (AA), a type of unsupervised machine learning, identified and quantified patterns of visual field (VF) loss in idiopathic intracranial hypertension (IIH), referred to as archetypes (ATs). We assessed whether AT weight changes over time are consistent with changes in conventional global indices, whether visual outcome or treatment effects are associated with select AT, and whether AA reveals residual VF defects in eyes deemed normal after treatment. DESIGN: Analysis of data collected from a randomized controlled trial. PARTICIPANTS: Two thousand eight hundred sixty-two VFs obtained from 165 participants during the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: We applied a 14-AT model derived from IIHTT VFs. We examined changes in individual AT weights over time for all study eyes and evaluated differences between treatment groups. We created an AT change score to assess overall VF change from baseline. We tested threshold baseline AT weights for association with VF outcome and treatment effect at 6 months. We determined the abnormal ATs with meaningful weight at outcome for VFs with a mean deviation (MD) of -2.00 dB or more. MAIN OUTCOME MEASURES: Individual AT weighting coefficients and MD. RESULTS: Archetype 1 (a normal VF pattern) showed the greatest weight change for all study eyes, increasing from 11.9% (interquartile range [IQR], 0.44%-24.1%) at baseline to 31.2% (IQR, 16.0%-45.5%) at outcome (P < 0.001). Archetype 1 weight change (r = 0.795; P < 0.001) and a global score of AT change (r = 0.988; P < 0.001) correlated strongly with MD change. Study eyes with baseline AT2 (a mild diffuse VF loss pattern) weight of 44% or more (≥ 1 standard deviation more than the mean) showed higher AT2 weights at outcome than those with AT2 weight of < 44% at baseline (P < 0.001). Only the latter group showed a significant acetazolamide treatment effect. Archetypal analysis revealed residual VF loss patterns, most frequently representing mild diffuse loss and an enlarged blind spot in 64 of 66 study eyes with MD of -2.00 dB or more at outcome. CONCLUSIONS: Archetypal analysis provides a quantitative approach to monitoring VF changes in IIH. Baseline AT features may be associated with treatment response and VF outcome. Archetypal analysis uncovers residual VF defects not otherwise revealed by MD.

Mix-and-inject XFEL crystallography reveals gated conformational dynamics during enzyme catalysis.

How changes in enzyme structure and dynamics facilitate passage along the reaction coordinate is a fundamental unanswered question. Here, we use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL), ambient-temperature X-ray crystallography, computer simulations, and enzyme kinetics to characterize how covalent catalysis modulates isocyanide hydratase (ICH) conformational dynamics throughout its catalytic cycle. We visualize this previously hypothetical reaction mechanism, directly observing formation of a thioimidate covalent intermediate in ICH microcrystals during catalysis. ICH exhibits a concerted helical displacement upon active-site cysteine modification that is gated by changes in hydrogen bond strength between the cysteine thiolate and the backbone amide of the highly strained Ile152 residue. These catalysis-activated motions permit water entry into the ICH active site for intermediate hydrolysis. Mutations at a Gly residue (Gly150) that modulate helical mobility reduce ICH catalytic turnover and alter its pre-steady-state kinetic behavior, establishing that helical mobility is important for ICH catalytic efficiency. These results demonstrate that MISC can capture otherwise elusive aspects of enzyme mechanism and dynamics in microcrystalline samples, resolving long-standing questions about the connection between nonequilibrium protein motions and enzyme catalysis.

The Open Perimetry Initiative: A framework for cross-platform development for the new generation of portable perimeters.

The Open Perimetry Initiative was formed in 2010 with the aim of reducing barriers to clinical research with visual fields and perimetry. Our two principal tools are the Open Perimetry Interface (OPI) and the visualFields package with analytical tools. Both are fully open source. The OPI package contains a growing number of drivers for commercially available perimeters, head-mounted devices, and virtual reality headsets. The visualFields package contains tools for the analysis and visualization of visual field data, including methods to compute deviation values and probability maps. We introduce a new frontend, the opiApp, that provides tools for customization for visual field testing and can be used as a frontend to run the OPI. The app can be used on the Octopus 900 (Haag-Streit), the Compass (iCare), the AP 7000 (Kowa), and the IMO (CREWT) perimeters, with permission from the device manufacturers. The app can also be used on Android phones with virtual reality headsets via a new driver interface, the PhoneHMD, implemented on the OPI. The use of the tools provided by the OPI library is showcased with a custom static automated perimetry test for the full visual field (up to 50 degrees nasally and 80 degrees temporally) developed with the OPI driver for the Octopus 900 and using visualFields for statistical analysis. With more than 60 citations in clinical and translational science journals, this initiative has contributed significantly to expand research in perimetry. The continued support of researchers, clinicians, and industry are key in transforming perimetry research into an open science.

Cellular stress orchestrates the localization of hnRNP H to stress granules.

Heterogeneous nuclear ribonucleoprotein (hnRNP) H is a member of hnRNP H/F protein subfamily of hnRNPs that regulate the maturation and post-transcriptional processing of pre-mRNA. As a component of an mRNA export complex, hnRNP H shuttles mature mRNA from the nucleus to the cytoplasm. Although hnRNP H is primarily a nuclear protein, it can accumulate in the cytoplasm in certain tissues and cell types; however, the physiological relevance of hnRNP H cytoplasmic accumulation is unknown. Here we show that under cellular stress hnRNP H accumulates in the cytoplasm and is required for efficient recovery from cellular stress. Moreover, we find that cytoplasmic hnRNP H localizes to stress granules and that the RRM3 domain of hnRNP H is necessary for this localization. Together, our results demonstrate that hnRNP H accumulates in the cytoplasm under cellular stress and is recruited to stress granules.

Battle Buddies: Rapid Deployment of a Psychological Resilience Intervention for Health Care Workers During the COVID-19 Pandemic.

The outbreak of the coronavirus disease 2019 (COVID-19) and its rapid global spread have created unprecedented challenges to health care systems. Significant and sustained efforts have focused on mobilization of personal protective equipment, intensive care beds, and medical equipment, while substantially less attention has focused on preserving the psychological health of the medical workforce tasked with addressing the challenges of the pandemic. And yet, similar to battlefield conditions, health care workers are being confronted with ongoing uncertainty about resources, capacities, and risks; as well as exposure to suffering, death, and threats to their own safety. These conditions are engendering high levels of fear and anxiety in the short term, and place individuals at risk for persistent stress exposure syndromes, subclinical mental health symptoms, and professional burnout in the long term. Given the potentially wide-ranging mental health impact of COVID-19, protecting health care workers from adverse psychological effects of the pandemic is critical. Therefore, we present an overview of the potential psychological stress responses to the COVID-19 crisis in medical providers and describe preemptive resilience-promoting strategies at the organizational and personal level. We then describe a rapidly deployable Psychological Resilience Intervention founded on a peer support model (Battle Buddies) developed by the United States Army. This intervention-the product of a multidisciplinary collaboration between the Departments of Anesthesiology and Psychiatry & Behavioral Sciences at the University of Minnesota Medical Center-also incorporates evidence-informed "stress inoculation" methods developed for managing psychological stress exposure in providers deployed to disasters. Our multilevel, resource-efficient, and scalable approach places 2 key tools directly in the hands of providers: (1) a peer support Battle Buddy; and (2) a designated mental health consultant who can facilitate training in stress inoculation methods, provide additional support, or coordinate referral for external professional consultation. In parallel, we have instituted a voluntary research data-collection component that will enable us to evaluate the intervention's effectiveness while also identifying the most salient resilience factors for future iterations. It is our hope that these elements will provide guidance to other organizations seeking to protect the well-being of their medical workforce during the pandemic. Given the remarkable adaptability of human beings, we believe that, by promoting resilience, our diverse health care workforce can emerge from this monumental challenge with new skills, closer relationships, and greater confidence in the power of community.

Biomolecular Solvation Structure Revealed by Molecular Dynamics Simulations.

To compare ordered water positions from experiment with those from molecular dynamics (MD) simulations, a number of MD models of water structure in crystalline endoglucanase were calculated. The starting MD model was derived from a joint X-ray and neutron diffraction crystal structure, enabling the use of experimentally assigned protonation states. Simulations were performed in the crystalline state, using a periodic 2 × 2 × 2 supercell with explicit solvent. Water X-ray and neutron scattering density maps were computed from MD trajectories using standard macromolecular crystallography methods. In one set of simulations, harmonic restraints were applied to bias the protein structure toward the crystal structure. For these simulations, the recall of crystallographic waters using strong peaks in the MD water electron density was very good, and there also was substantial visual agreement between the boomerang-like wings of the neutron scattering density and the crystalline water hydrogen positions. An unrestrained simulation also was performed. For this simulation, the recall of crystallographic waters was much lower. For both restrained and unrestrained simulations, the strongest water density peaks were associated with crystallographic waters. The results demonstrate that it is now possible to recover crystallographic water structure using restrained MD simulations but that it is not yet reasonable to expect unrestrained MD simulations to do the same. Further development and generalization of MD water models for force-field development, macromolecular crystallography, and medicinal chemistry applications is now warranted. In particular, the combination of room-temperature crystallography, neutron diffraction, and crystalline MD simulations promises to substantially advance modeling of biomolecular solvation.

Scaling molecular dynamics beyond 100,000 processor cores for large-scale biophysical simulations.

The growing interest in the complexity of biological interactions is continuously driving the need to increase system size in biophysical simulations, requiring not only powerful and advanced hardware but adaptable software that can accommodate a large number of atoms interacting through complex forcefields. To address this, we developed and implemented strategies in the GENESIS molecular dynamics package designed for large numbers of processors. Long-range electrostatic interactions were parallelized by minimizing the number of processes involved in communication. A novel algorithm was implemented for nonbonded interactions to increase single instruction multiple data (SIMD) performance, reducing memory usage for ultra large systems. Memory usage for neighbor searches in real-space nonbonded interactions was reduced by approximately 80%, leading to significant speedup. Using experimental data describing physical 3D chromatin interactions, we constructed the first atomistic model of an entire gene locus (GATA4). Taken together, these developments enabled the first billion-atom simulation of an intact biomolecular complex, achieving scaling to 65,000 processes (130,000 processor cores) with 1 ns/day performance. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor.

We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.

Artery Ligation for Infected Femoral Pseudoaneurysms Does Carry a High Risk of Major Amputation.

BACKGROUND: Arterial ligation has been described in the literature as a safe and effective procedure with a relatively low number of patients requiring major amputations. METHODS: We performed a retrospective analysis of a prospectively held database of all patients who underwent arterial ligation for infected femoral pseudoaneurysms due to chronic intravenous drug abuse from January 2012 to March 2018. Information recorded for each patient included age, gender, blood investigations, microbiologic results, diagnostic modality, operative details, outcome of surgery, postoperative complications, and follow-up. RESULTS: There were 25 patients identified, with 2 of them undergoing bilateral ligations. It was more common in men (4:1), and the mean age at presentation was 39.7 years (standard deviation 8.2 y). Nine patients underwent major limb amputation for severe limb ischemia (7 transfemoral amputations and two 53 hip disarticulation). Average hospital stay was 24 days, and there was no mortality. We found a trend with a higher level of arterial ligation, leading to a higher rate of amputation. CONCLUSIONS: Our study is the first to show that there is a trend toward a higher risk of amputation with a higher level of ligation in this cohort of patients, and therefore, we suggest avoidance of external iliac artery ligation even at the most distal part just under the ligament, leaving the circumflex iliac vessel in circuit. Arterial ligation also carries a higher risk of major amputation than previously reported.