bluuebunny/crossref_metadata_2025_split huggingface dataset:
Encapsulation Dynamics of Neuromuscular Blocking Drugs by Sugammadex
Authors: Irani Amir Hossein , Voss Logan , Whittle Nicola , Sleigh Jamie W. 
Published: November 2022

Background
The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain “tentacles,” as previously suggested.

Methods
Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices.

Results
Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R
2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol–sugammadex interaction.

Conclusions
Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
Cardiac Surgery Unit Advanced Life Support Training
Authors: Whitlock John P. 
Published: November 2022

Background
Although the body of knowledge related to Cardiac Surgery Unit Advanced Life Support (CSU-ALS) guideline has grown over the last 10 years, there is no existing literature examining the impact of this training on patient mortality outcomes.

Objectives
This article describes one institution's experience related to patient mortality outcomes following a rigorous training program following the CSU-ALS guideline. Because of the small numbers associated with cardiac arrests after cardiac surgery (0.7%-8%), statistical significance was not a goal.

Methods
A quasi-experimental design was used to compare mortality outcomes before and after CSU-ALS training. One hundred percent of the staff were trained in the initial year, and 85% to 90% of the staff maintained competency in the following years. The author used 10 years of retrospective data to compare mortality rates 4 years before and 6 years after the intervention.

Results
The retrospective data showed a decrease in the percentage of failure-to-rescue rate in the intervention group (control 16% vs intervention 2%). Fisher exact testing implies that the observed frequencies were not significantly different from the expected frequencies (P = .072 and P = .135). Because of the small sample size, statistical significance could not be established.

Discussion
This institution experienced an extremely positive track record in outcomes despite its inability to prove a statistically significant correlation to the CSU-ALS training. The overall observed and self-reported confidence level of the staff during the study period was outside the project scope but deserves mention and further research.
The Circle of Life
Authors: Lindsay Julie , Pautler Mary , Papesca James Thomas 
Published: November 2022

Background
During the course of a baccalaureate education, nursing students may encounter patient situations that are unexpected and emergent, including death. The use of simulation can offer students the opportunity to practice their communication skills with family centered-care and their teamwork in a safe environment with these emotionally charged patient situations.

Objectives
The aim of this study was to provide students with a final summative simulation that could encompass as much of the curriculum as possible.

Methods
We developed a simulation experience involving a 32-week pregnant woman diagnosed with H1N1, who deteriorated and needed intubation and an emergency C-section. Students were required to care not only for the pregnant patient who was decompensating but also for the premature infant while working with two providers, a chaplain, and the “husband/father” in an intensive care environment.

Results
Around 94% of the students thought the simulation was beneficial and helped them improve clinical judgments, assessments, and interprofessional and patient/family communication. Students felt this simulation was challenging and recommended it to continue for other senior classes. Students found the debriefing and open discussion with all participants beneficial.

Discussion
The use of a summative simulation encompassing as much of the nursing curriculum as possible can be an effective tool to assess student learning and engagement.
Recent Trends in the Incidence of Gastric Cancer in the United States
Authors: Liu Kyle S. , Raza Syed Ahsan , El-Serag Hashem B. , Thrift Aaron P. 
Published: November 2022

Background:
Gastric cancer (GC) incidence rates overall in the United States have declined over recent decades and are predicted to continue declining. However, there have been mixed recent findings regarding the potential stabilization of rates and potential divergent trends by age group. We used the most recent cancer data for the United States and examined trends in GC between 1992 and 2019, overall and in important subgroups of the population.

Methods:
Age-adjusted GC incidence rates and trends in adults 20 years or older were calculated using data from the Surveillance, Epidemiology, and End Results (SEER) 12 program. Secular trends were examined overall and by age group, sex, race/ethnicity, SEER registry, and tumor location. We used joinpoint regression to compute annual percent changes, average annual percent changes, and associated 95% CI.

Results:
GC rates decreased by 1.23% annually from 1992 to 2019. Despite overall decreases, GC incidence rates increased for age groups below 50 years, predominately driven by noncardia GC (74.3% of all GCs). Cardia GC (26.7% of GC) rates decreased in all age groups except for 80 to 84 years. Overall GC rates decreased for both sexes, all races, and for all SEER registry regions, with the largest decreases occurring in males, Asians and Pacific Islanders, and in Hawaii. Age-period-cohort analysis revealed that birth cohorts before 1940 and after 1980 both had increased rates of GC compared with the reference birth cohort of 1955.

Conclusion:
GC rates overall have continued to decline through 2019, despite increases in the rate of noncardia GC for younger age groups.
Pharmacogenomic Profiling of Pediatric Patients on Psychotropic Medications in an Emergency Department
Authors: Ghosh Pallavi , Martinez Jesse , Shah Nipam , Kenan Will , Fowler Andrew , Limdi Nita , Burns Lindsey , Cogan Elizabeth S. , Gardiner Anna , Hain Daniel , Johnson Holly , Lewis David , Shelton Richard , Liebelt Erica 
Published: November 2022

Objective
The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population.

Methods
This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered “incongruent,” and medications without a GDI were considered “congruent.” Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement.

Results
Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications (P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01).

Conclusions
Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.
Efficacy, safety, and tolerability of isoniazid preventive therapy for tuberculosis in people living with HIV
Authors: Jagi Jaya Laxmi , Thomas Christy , Gudi Sai Krishna , Undela Krishna 
Published: November 2022

Objective:
The aim of this study was to systematically assess the efficacy, safety, and tolerability of isoniazid preventive therapy (IPT) for tuberculosis (TB) in people with HIV (PWH).

Design:
A systematic review and meta-analysis.

Methods:
A thorough literature search was performed using PubMed, Cochrane CENTRAL, and Google Scholar from their inception to June 30, 2021. All randomized controlled trials (RCTs) investigating the efficacy, safety, or tolerability of IPT on PWH compared with placebo or active comparators were included in the study. The heterogeneity among the studies was identified by using the I
2 statistic and Cochran's Q test.

Results:
Out of the 924 nonduplicate RCTs identified through database searching and other sources, 26 studies comprising 38 005 patients were included. The overall effect estimate identified the reduction of active TB incidence [odds ratio (OR) 0.69; 95% confidence interval (95% CI) 0.57–0.84; P < 0.001], but not all-cause mortality (OR 0.91; 95% CI 0.82, 1.02; P = 0.10) with IPT compared with the control. In addition, no significant association was identified between the use of IPT and the risk of peripheral neuropathy (OR 1.50; 95% CI 0.96–2.36; P = 0.08) and hepatotoxicity (OR 1.21; 95% CI 0.97–1.52; P = 0.09).

Conclusion:
This systematic review and meta-analysis identified a significant reduction in the incidence of active TB, but not all-cause mortality, among PWH who received IPT compared with the control. Lesser number of outcomes may be the reason for nonsignificant results in terms of safety outcomes of IPT. Therefore, there is a need for extensive and long-term studies to address these issues further, especially in TB/HIV endemic areas.
Costal Cartilage Harvest Through a Small Incision in Asian Rhinoplasty After Breast Augmentation
Authors: Song Zhen , Zhang Xulong , You Jianjun , Wang Huan , Zheng Ruobing , Xu Yihao , Guo Junsheng , Tian Le , Fan Fei 
Published: November 2022

Background:
The costal cartilage is widely used in rhinoplasty. Although different surgical methods of costal cartilage harvest have been developed, few studies have reported the method of costal cartilage harvest for patients after breast augmentation. This study aims to provide our experience of costal cartilage harvest through a small incision approach.

Methods:
A retrospective review was performed for patients undergoing esthetic rhinoplasty with costal cartilage after breast augmentation between May 2019 and May 2021. Postoperative pain was evaluated with the Visual Analog Scale, and the scars at the donor site were assessed 1 year postoperatively with the Modified Vancouver Scar Scale.

Results:
A total of 23 female patients were included. The average follow-up time was 21.4 months. No complications of massive bleeding, pleural injury, or breast implant injury during the surgery, wound dehiscence, or wound infection in the harvested site were observed. No patients complained of changes in breast morphology or breast asymmetry after costal cartilage harvest. Results of Visual Analog Scale for donor-site pain indicated pain in donor-site peaked at 12 hours after surgery and gradually decreased. All patients were satisfied with the scarring of the donor sites after surgery.

Conclusion:
The better scar performance, low complication rates, and high satisfaction among patients suggest that this is a safe technique to harvest costal cartilage with a small incision in rhinoplasty for patients after breast augmentation.
Plastid Genome Assembly Using Long-read Data (ptGAUL)
Authors: Zhou Wenbin , Armijos Carolina E. , Lee Chaehee , Lu Ruisen , Wang Jeremy , Ruhlman Tracey A. , Jansen Robert K. , Jones Alan M. , Jones Corbin D. 
Published: November 2022

AbstractAlthough plastid genome (plastome) structure is highly conserved across most seed plants, investigations during the past two decades revealed several disparately related lineages that experienced substantial rearrangements. Most plastomes contain a large, inverted repeat and two single-copy regions and few dispersed repeats, however the plastomes of some taxa harbor long repeat sequences (>300 bp). These long repeats make it difficult to assemble complete plastomes using short-read data leading to misassemblies and consensus sequences that have spurious rearrangements. Single-molecule, long-read sequencing has the potential to overcome these challenges, yet there is no consensus on the most effective method for accurately assembling plastomes using long-read data. We generated a pipeline,plastidGenomeAssemblyUsingLong-read data (ptGAUL), to address the problem of plastome assembly using long-read data from Oxford Nanopore Technologies (ONT) or Pacific Biosciences platforms. We demonstrated the efficacy of the ptGAUL pipeline using 16 published long-read datasets. We showed that ptGAUL produces accurate and unbiased assemblies. Additionally, we employed ptGAUL to assemble four newJuncus(Juncaceae) plastomes using ONT long reads. Our results revealed many long repeats and rearrangements inJuncusplastomes compared with basal lineages of Poales.
Updated benchmarking of variant effect predictors using deep mutational scanning
Authors: Livesey Benjamin J. , Marsh Joseph A. 
Published: November 2022

AbstractVariant effect predictors (VEPs) provide a potential solution to the influx of variants of uncertain clinical significance produced by genome sequencing studies. However, the assessment of VEP performance is fraught with biases introduced by benchmarking against clinical observations. In this study, building on our previous work, we use independently generated measurements of protein function from deep mutational scanning (DMS) experiments for 26 human proteins to benchmark 55 different VEPs, while introducing minimum data circularity. The top VEPs are dominated by unsupervised methods including EVE, DeepSequence and ESM-1v, a new protein language model that ranked first overall. However, the strong performance of recent supervised VEPs, in particular VARITY, shows that developers are taking data circularity and bias issues seriously. We also assess the performance of DMS and unsupervised VEPs for discriminating between known pathogenic and putatively benign missense variants. Our findings are mixed, demonstrating that some DMS datasets perform exceptionally at variant classification, while others are poor. Notably, we observe a striking correlation between VEP agreement with DMS data and performance in identifying clinically relevant variants, with EVE, DeepSequence and ESM-1v performing best, further supporting the utility of DMS as an independent benchmark.
OpenFold: Retraining AlphaFold2 yields new insights into its learning mechanisms and capacity for generalization
Authors: Ahdritz Gustaf , Bouatta Nazim , Floristean Christina , Kadyan Sachin , Xia Qinghui , Gerecke William , O’Donnell Timothy J , Berenberg Daniel , Fisk Ian , Zanichelli Niccolò , Zhang Bo , Nowaczynski Arkadiusz , Wang Bei , Stepniewska-Dziubinska Marta M , Zhang Shang , Ojewole Adegoke , Guney Murat Efe , Biderman Stella , Watkins Andrew M , Ra Stephen , Lorenzo Pablo Ribalta , Nivon Lucas , Weitzner Brian , Ban Yih-En Andrew , Sorger Peter K , Mostaque Emad , Zhang Zhao , Bonneau Richard , AlQuraishi Mohammed 
Published: November 2022

AbstractAlphaFold2 revolutionized structural biology with the ability to predict protein structures with exceptionally high accuracy. Its implementation, however, lacks the code and data required to train new models. These are necessary to (i) tackle new tasks, like protein-ligand complex structure prediction, (ii) investigate the process by which the model learns, which remains poorly understood, and (iii) assess the model’s generalization capacity to unseen regions of fold space. Here we report OpenFold, a fast, memory-efficient, and trainable implementation of AlphaFold2. We train OpenFold from scratch, fully matching the accuracy of AlphaFold2. Having established parity, we assess OpenFold’s capacity to generalize across fold space by retraining it using carefully designed datasets. We find that OpenFold is remarkably robust at generalizing despite extreme reductions in training set size and diversity, including near-complete elisions of classes of secondary structure elements. By analyzing intermediate structures produced by OpenFold during training, we also gain surprising insights into the manner in which the model learns to fold proteins, discovering that spatial dimensions are learned sequentially. Taken together, our studies demonstrate the power and utility of OpenFold, which we believe will prove to be a crucial new resource for the protein modeling community.
Genome editing of an African elite rice variety confers resistance against endemic and emergingXanthomonas oryzaepv.oryzaestrains
Authors: Schepler-Luu Van , Sciallano Coline , Stiebner Melissa , Ji Chonghui , Boulard Gabriel , Diallo Amadou , Auguy Florence , Char Si Nian , Arra Yugander , Schenstnyi Kyrylo , Buchholzer Marcel , Loo Eliza P.I. , Bilaro Atugonza L. , Lihepanyama David , Mkuya Mohammed , Murori Rosemary , Oliva Ricardo , Cunnac Sebastien , Yang Bing , Szurek Boris , Frommer Wolf B. 
Published: November 2022

AbstractBacterial leaf blight (BB) of rice, caused byXanthomonas oryzaepv.oryzae(Xoo), threatens global food security and the livelihood of small-scale rice producers. Analyses ofXoocollections from Asia, Africa and the Americas demonstrated surprising continental segregation, despite robust global rice trade. Here, we report unprecedented BB outbreaks in Tanzania. The causative strains, unlike endemicXoo, carry Asian-type TAL effectors targeting the sucrose transporterSWEET11aand suppressingXa1. Phylogenomics clustered these strains withXoostrains from China. African rice varieties do not carry suitable resistance genes. To protect African rice production against this emerging threat, we developed a hybrid CRISPR-Cas9/Cpf1 system to edit six TALe-binding elements in threeSWEETpromoters of the East African elite variety Komboka. The edited lines show broad-spectrum resistance against Asian and African strains ofXoo, including strains recently discovered in Tanzania. This strategy could help to protect global rice crops from BB pandemics.
Longitudinal dynamics of the human vaginal ecosystem across the reproductive cycle
Authors: Costello Elizabeth K. , DiGiulio Daniel B. , Robaczewska Anna , Symul Laura , Wong Ronald J. , Shaw Gary M. , Stevenson David K. , Holmes Susan P. , Kwon Douglas S. , Relman David A. 
Published: November 2022

AbstractThe vaginal ecosystem is closely tied to human health and reproductive outcomes. However, its dynamics in the wake of childbirth remain poorly characterized. Here, we profiled the vaginal microbiota and cytokine milieu of subjects sampled throughout pregnancy (two cohorts;n= 196 pregnancies) and, in a subset, for one year postpartum (one cohort;n= 72 pregnancies). Delivery was associated with a vaginal pro-inflammatory cytokine response and the depletion of dominant taxa – typically,Lactobacillusspecies. By contrast, neither the progression of gestation nor the approach of labor strongly altered the vaginal ecosystem. At ~9.5 months postpartum (the latest timepoint at which cytokines were analyzed), elevated inflammation was associated with vaginal bacterial communities that had remained perturbed (i.e., highly diverse) from the time of delivery. Using time-to-event analysis, we found that the one-year postpartum probability of transitioning toLactobacillusdominance was 49.4% (95% confidence interval (CI) [33.6%, 61.5%];n= 58 at-risk cases, 86.2% of whom experienced this state prior to delivery). As diversity and inflammation declined postpartum, dominance byL. crispatus, the quintessential health-associated state, failed to recover: its prevalence before, immediately after, and one year after delivery was 41%, 4%, and 9%, respectively. Over the same period, states quasi-dominated by non-Lactobacillusspecies grew more common. Prompted by these findings, we revisited our pre-delivery data, discovering that a history of prior live birth was associated with a lower odds ofL. crispatusdominance in pregnant subjects (odds ratio (OR) 0.14; 95% CI [0.06, 0.32];P< 0.001) – an outcome modestly tempered by a longer (>18-month) interpregnancy interval. Our results suggest that reproductive history and childbirth in particular remodel the vaginal ecosystem and that the timing and degree of recovery from delivery may help determine the subsequent health of the woman and of future pregnancies.