bluuebunny/crossref_metadata_2025 huggingface dataset:
The interconnection between galaxy mergers, AGN activity, and rapid quenching of star formation in simulated post-merger galaxies
Authors: Quai Salvatore , Byrne-Mamahit Shoshannah , Ellison Sara L , Patton David R , Hani Maan H
Published: December 2022

We investigate the role of galaxy mergers on supermassive black hole (SMBH) accretion and star formation quenching in three state-of-the-art cosmological simulations with contrasting physics models: EAGLE, Illustris, and IllustrisTNG (TNG). We find that recently coalesced ‘post-mergers’ in all three simulations have elevated SMBH accretion rates by factors of ∼2–5. However, rapid (within 500 Myr of coalescence) quenching of star formation is rare, with incidence rates of $0.4{{\ \rm per\ cent}}$ in Illustris, $4.5{{\ \rm per\ cent}}$ in EAGLE, and $10{{\ \rm per\ cent}}$ in TNG. The rarity of quenching in post-mergers results from substantial gas reservoirs that remain intact after the merger. The post-mergers that do successfully quench tend to be those that had both low pre-merger gas fractions as well as those that experience the largest gas losses. Although rare, the recently quenched fraction of post-mergers is still elevated compared to a control sample of non-mergers by factors of two in TNG and 11 in EAGLE. Conversely, quenching is rarer in Illustris post-mergers than in their control. Recent observational results by Ellison et al. have found rapid quenching to be at least 30 times more common in post-mergers, a significantly higher excess than found in any of the simulations. Our results therefore indicate that whilst merger-induced SMBH accretion is a widespread prediction of the simulation, its link to quenching depends sensitively on the physics models, and that none of the subgrid models of the simulations studied here can fully capture the connection between mergers and rapid quenching seen in observations.
Constraints on clumps in the representative wind of the WN8 Wolf–Rayet star HD 96548 = WR 40 with simultaneous broad-band light and linear-polarization variability
Authors: Ignace R , Moffat A F J , Robert C , Drissen L
Published: December 2022

We report precision ground-based broad-band optical intensity and linear-polarization light curves for the sky’s brightest WN8 star, WR 40. WN8 stars are notorious for their high level of variability, stemming from stochastic clumps in their strong winds that are slower and less hot than the winds of most other Wolf–Rayet (WR) stars. We confirm previous results that many WR stars display an amplitude of variability that is an order of magnitude higher in photometry than in polarimetry. For the first time, the unique nature of near simultaneity of our photometric and polarimetric observations of WR 40 allows us to check whether the two types of variability show correlated behaviour, of which we find none. Assuming simple temporal functions for the brightness and polarization of individual clumps, a model for simulated light curves is found to reproduce the properties of the observations, specifically the absence of correlation between photometric and polarimetric variations, the ratio of standard deviations for photometric and polarimetric variability, and the ratio of the average intrinsic polarization relative to its standard deviation. Mapping the solution for time variability to a spatial coordinate suggests that the wind clumps of WR 40 are free-free emitting in addition to light scattering.
CHD8suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing
Authors: Kerschbamer Emanuela , Arnoldi Michele , Tripathi Takshashila , Pellegrini Miguel , Maturi Samuele , Erdin Serkan , Salviato Elisa , Di Leva Francesca , Sebestyén Endre , Dassi Erik , Zarantonello Giulia , Benelli Matteo , Campos Eric , Basson M Albert , Gusella James F , Gustincich Stefano , Piazza Silvano , Demichelis Francesca , Talkowski Michael E , Ferrari Francesco , Biagioli Marta
Published: December 2022

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in ‘regulation of RNA splicing’ and ‘mRNA catabolic process’. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.
Transposase N-terminal phosphorylation and asymmetric transposon ends inhibit piggyBac transposition in mammalian cells
Authors: Luo Wentian , Hickman Alison B , Genzor Pavol , Ghirlando Rodolfo , Furman Christopher M , Menshikh Anna , Haase Astrid , Dyda Fred , Wilson Matthew H
Published: December 2022

DNA transposon systems are widely used in mammalian cells for genetic modification experiments, but their regulation remains poorly understood. We used biochemical and cell-based assays together with AlphaFold modeling and rational protein redesign to evaluate aspects of piggyBac transposition including the previously unexplained role of the transposase N-terminus and the need for asymmetric transposon ends for cellular activity. We found that phosphorylation at predicted casein kinase II sites in the transposase N-terminus inhibits transposition, most likely by preventing transposase–DNA interactions. Deletion of the region containing these sites releases inhibition thereby enhancing activity. We also found that the N-terminal domain promotes transposase dimerization in the absence of transposon DNA. When the N-terminus is deleted, the transposase gains the ability to carry out transposition using symmetric transposon left ends. This novel activity is also conferred by appending a second C-terminal domain. When combined, these modifications together result in a transposase that is highly active when symmetric transposon ends are used. Our results demonstrate that transposase N-terminal phosphorylation and the requirement for asymmetric transposon ends both negatively regulate piggyBac transposition in mammalian cells. These novel insights into the mechanism and structure of the piggyBac transposase expand its potential use for genomic applications.
Australian genome-wide association study confirms higher female risk for adult glioma associated with variants in the region of CCDC26
Authors: Alpen Karen , Vajdic Claire M , MacInnis Robert J , Milne Roger L , Koh Eng-Siew , Hovey Elizabeth , Harrup Rosemary , Bruinsma Fiona , Nguyen Tuong L , Li Shuai , Joseph David , Benke Geza , Dugué Pierre-Antoine , Southey Melissa C , Giles Graham G , Rosenthal Mark , Drummond Katharine J , Nowak Anna K , Hopper John L , Kapuscinski Miroslaw , Makalic Enes
Published: December 2022

Background

Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex.

Methods

We analyzed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7 573 692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma. Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex.

Results

We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL, and 20q13.33 GMEB2 (P < .05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P = .0024) with the association being nominally significant for both sexes (P < .05).

Conclusions

Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analyzing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.
Gradual transitions in genetics and songs between coastal and inland populations of Setophaga townsendi
Authors: Ore Madelyn J , Wang Silu , Irwin Darren E
Published: December 2022

Setophaga townsendi is a species of wood warbler (family Parulidae) in northwestern North America that has geographic structure in the mitochondrial and nuclear genomes: while interior populations have differentiated mitonuclear ancestry from the sister species S. occidentalis, coastal populations have a mix of inland and S. occidentalis mitonuclear ancestries. This coastal to inland transition in genomic ancestry raises the possibility of similar geographic structure in phenotypic traits, especially those involved in mate choice. Using qualitative and multivariate approaches, we investigated whether there is a sharp transition between coastal and inland populations in both song and in nuclear DNA. We find there is a shallow geographic cline in Type I song but not in Type II song. Nuclear DNA shows a gradient between coast and inland. There is little correlation between variation in song and the isolation-by-distance pattern in the nuclear DNA. Learned songbird song is shaped by both genetic and cultural processes. There has been a debate on whether song learning promotes or slows down population differentiation. By comparing the within-species variation in song and genetic structures, we can expand our understanding of the dynamic interplay between mating signals and population differentiation.
Reconstructing Extinct Hominin Diets
Authors: Grine Frederick E.
Published: December 2022

Knowledge of the dietary habits of extinct hominin species and ancient human populations is central to any understanding of their ecology. Owing to the importance of diet in both biological and cultural realms, multifarious approaches have been employed in its elucidation: archaeology, dental calculus, pathology, functional morphology, dental microwear, biogeochemistry, and genetics and genomics. Some of these paradigms have deep historical roots, while others are owing to more recent technical advances. Some produce data that are indirectly related to the object of discovery, resulting in hypothetical dietary inferences. A number provide more direct evidence about the foods that were consumed. Each method of discovery has strengths and limitations that should be recognized when the resultant data are employed in diet retrodiction. Not all approaches are equally relevant to the temporal scale of the hominin evolutionary record. Seven avenues of dietary investigation are reviewed, several of which have been employed in tandem. Reconstructions that combine data from different methods will inevitably provide more complete depictions of palaeodietary ecology.
The added value of predictive biomarkers in treat-to-target strategies for rheumatoid arthritis patients: a conceptual modelling study
Authors: Wientjes Maike H M , Ulijn Evy , Kievit Wietske , Landewé Robert B M , Meek Inger , den Broeder Nathan , van Herwaarden Noortje , van den Bemt Bart J F , Verhoef Lise M , den Broeder Alfons A
Published: December 2022

Objectives

To quantify the additional value of a hypothetical biomarker predicting response to treatment for RA regarding efficacy and costs by using a modelling design.

Methods

A Markov model was built comparing a usual care T2T strategy with a biomarker-steered strategy for RA patients starting biologic therapy. Outcome measures include time spent in remission or low disease activity (LDA) and costs. Four additional scenario analyses were performed by varying biomarker or clinical care characteristics: (i) costs of the biomarker; (ii) sensitivity and specificity of the biomarker; (iii) proportion of eligible patients tapering; and (iv) medication costs.

Results

In the base model, patients spent 2.9 months extra in LDA or remission in the biomarker strategy compared with usual care T2T over 48 months. Total costs were €43 301 and €42 568 for, respectively, the usual care and biomarker strategy, and treatment costs accounted for 91% of total costs in both scenarios. Cost savings were driven due to patients in the biomarker strategy experiencing remission or LDA earlier, and starting tapering sooner. Cost-effectiveness was not so much driven by costs or test characteristics of the biomarker (scenario 1/2), but rather by the level of early and proactive tapering and drug costs (scenarios 3/4).

Conclusions

The use of a biomarker for prediction of response to b/tsDMARD treatment in RA can be of added value to current treat-to-target clinical care. However, gains in efficacy are modest and cost gains are depending on a combination of early proactive tapering and high medication costs.
Envisioning translational hyperscanning: how applied neuroscience might improve family-centered care
Authors: Provenzi Livio , Roberti Elisa , Capelli Elena
Published: December 2022

From the very beginning of their life, human beings are immersed in a social and interactive environment that contributes to shaping their social and cognitive development under typical and at-risk conditions. In order to understand human development in its bidirectional relationship with the social environment, we need to develop a ‘complexity-sensitive’ approach in neuroscience. Recent advances have started to do so with the application of hyperscanning techniques which involve recording adult and child neural activity simultaneously and highlighting the presence of similar patterns of brain activity in the dyad. Numerous studies focused on typically developing children have been published in recent years with the application of this technique to different fields of developmental research. However, hyperscanning techniques could also be extremely beneficial and effective in studying development in atypical and clinical populations. Such application, namely translational hyperscanning, should foster the transition toward a two-brain translational neuroscience. In this paper, we envision how the application of hyperscanning to atypical and clinical child populations can inform family-centered care for children and their parents.
6K1, NIa-VPg, NIa-Pro, and CP of Wheat Streak Mosaic Virus Are Collective Determinants of Wheat Streak Mosaic Disease in Wheat
Authors: Tatineni Satyanarayana , Alexander Jeffrey , Nunna Haritha
Published: December 2022

Wheat streak mosaic virus (WSMV; genus  Tritimovirus, family  Potyviridae) is the causal agent of the most economically important wheat streak mosaic disease of wheat ( Triticum aestivum) in the Great Plains region of the United States. WSMV determinants responsible for wheat streak mosaic disease in wheat are unknown. Triticum mosaic virus (TriMV), a wheat-infecting virus, was used as an expression vector for the transient expression of each of the WSMV-encoded cistrons in wheat. WSMV-encoded 6K1, NIa-VPg, NIa-Pro, and CP cistrons in TriMV elicited symptoms specific to different stages of wheat streak mosaic disease without significantly affecting the genomic RNA accumulation. WSMV 6K1 produced early wheat streak mosaic disease-like symptoms of severe chlorotic streaks and patches. NIa-VPg and CP caused severe chlorotic streaks, followed by moderate stunting (only with NIa-VPg) of wheat, mimicking early- and mid-stage symptoms of wheat streak mosaic disease. WSMV NIa-Pro caused mild chlorotic streaks, followed by dark green leaves with severe stunting, representing the late symptoms of wheat streak mosaic disease. Collectively, these data suggest that cumulative effects of WSMV-encoded 6K1, NIa-VPg, NIa-Pro, and CP are responsible for different stages of wheat streak mosaic disease symptoms in wheat. Furthermore, deletion analysis of wheat streak mosaic disease determinants revealed that complete 6K1 and NIa-Pro, amino acids 3 to 60 and 121 to 197 of NIa-VPg, and amino acids 101 to 294 of CP are responsible for wheat streak mosaic disease-like symptoms in wheat. This study suggests that management strategies for wheat streak mosaic disease in wheat should target WSMV determinants of the disease phenotype.
Accelerated Healing from Severe Radiation Dermatitis Using Noncontact, Low-frequency Ultrasound-assisted Saline Wash Therapy
Authors: Luu Yen , Han Joseph , Owji Shayan , Kamat Samir , Luu Chuc , Ungar Jonathan , Gulati Nicholas
Published: December 2022

Radiotherapy (RT) is a modality for cancer management that frequently causes critical injury to tissues adjacent to the targeted cancer site. Acute radiation dermatitis (RD) is one of the most common adverse effects of RT and may lead to secondary infection, disfigurement, and discontinuation of therapy. The authors report the efficacy of a multidisciplinary collaboration between radiation oncology, dermatology, and wound care teams in the management of severe, acute RD. This case report describes the use of noncontact, low-frequency ultrasound (NCLFU)-assisted saline wash therapy leading to accelerated healing of severe RD in an older man treated with RT for scalp squamous cell carcinoma. Although NCLFU-assisted saline wash therapy provides gentle debridement of wound surfaces and has demonstrated efficacy in the management of chronic wounds, the potential role for NCLFU therapy in RD management has not yet been explored.
A Novel Classification for Diabetic Foot Ulcers of the First Ray
Authors: Tamir Eran , Rabau Oded , Beer Yiftah , Smorgick Yossi , Kaufman Hanna , Finestone Aharon S.
Published: December 2022

OBJECTIVE

Diabetic foot ulcers of the first ray result from several distinct biomechanical mechanisms related to anatomical deformities, which must be addressed if surgical offloading is contemplated. The objective of this study was to create a classification of the anatomical deformities of first-ray ulcers that could lead to better standardization of treatment and reporting.

METHODS

The authors performed a file review of patients with diabetic neuropathy diagnosed with first-ray ulcers over a period of 3 years in an outpatient setting. Anatomical deformities were diagnosed clinically and reported with ulcer location. The primary classification was the metatarsophalangeal joint, the interphalangeal joint, and the distal phalanx.

RESULTS

Records for 59 patients (mean age, 62 years) with University of Texas A1 and A2 ulcers were reviewed. Mean ulcer duration was 2 months. The more common deformities were hallux valgus (41%), hallux valgus interphalangeus (14%), and hallux malleus (20%), and these were primarily associated with metatarsophalangeal, interphalangeal joint, and tip-of-toe ulcers, respectively (P< .0001).

CONCLUSIONS

By classifying ulcer locations, the relevant corrective surgery may be chosen. Although some prophylactic procedures may be safe and effective, prophylactic hallux valgus correction in the diabetic foot requires further study.
Evolution of Educational Commission for Foreign Medical Graduates Certification in the Absence of the USMLE Step 2 Clinical Skills Examination
Authors: Mladenovic Jeanette , van Zanten Marta , Pinsky William W.
Published: December 2022

The United States Medical Licensing Examination Step 2 Clinical Skills (CS) was paused in 2020 because of the ongoing COVID-19 pandemic and discontinued in 2021. Step 2 CS was an important tool to assess readiness of international medical graduates (IMGs) to enter graduate medical education (GME) in the United States. This article describes the Educational Commission for Foreign Medical Graduates’ (ECFMG’s) response to the discontinuation of Step 2 CS. ECFMG certifies IMGs who seek eligibility for GME and licensure in the United States. Requirements for ECFMG certification include, among other factors, demonstration of adequate clinical skills and English proficiency, which were previously assessed as part of Step 2 CS. Beginning in June 2020 and during the next year, ECFMG modified the certification process with the introduction of 6 opportunities (pathways) for IMGs to demonstrate adequate clinical skills and a new test of English proficiency. In addition, permanent ECFMG certification is now granted only after the successful completion of the first year of residency, as determined by the program director. The COVID-19 pandemic and discontinuation of Step 2 CS caused a significant crisis for many IMGs who sought entrance into the United States, impacting the careers of those who had planned entry and those who would be eligible for U.S. training and the future workforce. Despite challenges due to the ongoing global pandemic, ECFMG certification continues to allow qualified physicians to enter U.S. GME and ensures that these individuals are ready to begin supervised training.
Implementing a Trauma-Informed Approach at a Student-Run Clinic for Individuals Seeking Asylum
Authors: Jaradeh Katrin , Sergi Francesco , Kivlahan Coleen , Nava Gonzales Cesar , Cury Mar , DeFries Triveni
Published: December 2022

Problem

Health care professionals complete forensic medical evaluations (FMEs) to corroborate evidence of persecution among individuals seeking asylum. Many FMEs are conducted at student-run clinics for individuals seeking asylum (or student-run asylum clinics; SRACs). Trauma-informed care (TIC) recognizes that trauma is pervasive and seeks to mitigate reexposure to trauma in health care interactions. Given that FMEs involve recalling trauma, TIC is an ideal model for supporting the individuals involved in an FME.

Approach

The authors operationalized TIC principles in an SRAC model (the Human Rights Cooperative) at the University of California, San Francisco. Between April 2019 and April 2022, the SRAC provided 3 to 10 pro bono FMEs per month, as well as community referrals for individuals seeking asylum, clinician and medical student training on FMEs and TIC, and research on FMEs. This report describes the SRAC operations, organized by the 10 implementation domains of the Substance Abuse and Mental Health Services Administration guidance to organizations for implementing a trauma-informed approach.

Outcomes

Between April 2019 and April 2022, the SRAC completed 160 FMEs. Sixty-nine clinicians performed FMEs, and 119 first-year medical students participated in the accompanying elective. Qualitative survey responses by clinicians, lawyers, students, and clients (individuals seeking asylum) highlighted the trauma-informed principles of safety; trustworthiness and transparency; empowerment, voice, and choice; peer support; collaboration and mutuality; and cultural, historical, and gender issues. All students who acted as leaders sustained their engagement with the SRAC over time.

Next Steps

Future research should use validated tools to assess secondary trauma and resilience within SRACs. The SRAC concept, which engages medical students and experienced clinicians in learning skills that can be used in the pursuit of health justice and equity, should be expanded and supported in U.S. medical schools across the country, which is facing unprecedented levels of migration.
Questions of Well-Being and Inclusion in Online Undergraduate Medical Education During COVID-19: A 2-Phased Focused Scoping Review
Authors: MacLeod Anna , Cameron Paula , Luong Victoria , Parker Robin , Li Vinson , Munroe-Lynds Cora-Lynn
Published: December 2022

Purpose

Undergraduate medical education (UGME) was transformed by the rapid move to online curriculum delivery during the COVID-19 pandemic. Most research on online UGME has focused on measuring its effectiveness. However, medical educators also require evidence regarding its implications with respect to well-being and inclusion.

Method

To explore online learning transition, particularly the effect on well-being and inclusion, this 2-phased focused scoping review employed a revised Joanna Briggs Institute approach: (1) developing review questions and objectives; (2) determining eligibility criteria; (3) developing the search strategy; (4) extracting, analyzing, and discussing findings; (5) drawing conclusions; and (6) discussing implications for practice and further research.

Results

The review ultimately included 217 articles, of which 107 (49%) explored student and staff well-being during online UGME, 64 (30%) focused on inclusion in this context, and 46 (21%) examined both well-being and inclusion. Additionally, 137 of included articles (63%) were research/evaluation, 48 (22%) were descriptive, and 32 (15%) were opinion. Of the 137 research/evaluation studies, 115 (84%) were quantitative, 10 (7%) were qualitative, 8 (6%) were mixed methods, and 4 (3%) were Reviews. Among these research/evaluation studies, the most commonly used data collection method was surveys (n = 120), followed by academic tests (n = 14). Other methods included interviews (n = 6), focus groups (n = 4), written reflections (n = 3), user data (n = 1), and blood tests (n = 1).

Conclusions

Important questions remain regarding the safety and inclusiveness of online learning spaces and approaches, particularly for members of historically excluded groups and learners in low-resource settings. More rigorous, theoretically informed research in online medical education is required to better understand the social implications of online medical education, including more in-depth, qualitative investigations about well-being and inclusion and more strategies for ensuring online spaces are safe, inclusive, and supportive.
ASCCP Committee Opinion: Adjuvant Human Papillomavirus Vaccine for Patients Undergoing Treatment for Cervical Intraepithelial Neoplasia
Authors: Sharpless Kathryn E. , Marcus Jenna Z. , Kuroki Lindsay M. , Wiser Amy L. , Flowers Lisa
Published: December 2022

Objectives

Individuals treated for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) are at long-term risk of persistent or recurrent disease despite treatment. This committee opinion aims to summarize and provide evidence-based recommendations for adjuvant human papillomavirus (HPV) vaccination based on available, published literature.

Methods

A task force from the ASCCP Practice Committee reviewed current Centers for Disease Control and Prevention (CDC) guidelines and previously published literature about the role of adjuvant HPV vaccination in previously unvaccinated individuals undergoing treatment for CIN2+ and other HPV-related diseases.

Results

Current CDC guidelines recommend routine or catch-up HPV vaccination for individuals aged 9 to 26 years, and shared decision making regarding vaccination for individuals aged 27 to 45 years. Multiple published studies suggest a possible benefit for adjuvant HPV vaccination in previously unvaccinated individuals undergoing treatment for CIN2+.

Conclusions

The American Society for Colposcopy and Cervical Pathology recommends adherence to current CDC recommendations for vaccination of individuals aged 9 to 26 years and consideration of the possible benefit of adjuvant HPV vaccination during shared decision making for previously unvaccinated individuals aged 27 to 45 years who are undergoing treatment for CIN2+.
Assessing the national representativeness of estimates of antimicrobial resistant urogenital Neisseria gonorrhoeae in US men, Gonococcal Isolate Surveillance Project, 2008–2018
Authors: Nielsen Karen E. , St. Cyr Sancta B. , Pham Cau D. , Kreisel Kristen M.
Published: December 2022

Background

The percentage of Neisseria gonorrhoeae (GC) isolates with resistance or elevated minimum inhibitory concentrations (MICs) to antimicrobials has steadily increased. Current estimates are based on the Gonococcal Isolate Surveillance Project (GISP), a sentinel surveillance study of male GC in the United States. This analysis seeks to assess for adjustment prior to treating aggregated GISP estimates as nationally representative of all reported male urogenital infections.

Methods

We used multilevel regression with poststratification (MRP) to compute national estimates of the proportion of antimicrobial resistance (AMR – defined as exceeding MIC thresholds) in male GC using data from 2008-2018 GISP and case reports. Sensitivity analyses investigated the impact of analysis assumptions and unmeasured variables. We additionally produced estimates of 2018 AMR GC cases among US males.

Results

National estimates were consistent with unweighted estimates. The estimated proportion of incident AMR GC infections in men with urogenital GC in 2018 was 51.5% (95% CI: 50.1% - 52.9%), equating to an estimated 366,300 incident AMR GC infections in US men aged 15-39 years. Estimates of AMR for tested antimicrobials in male GC infections in 2018 ranged from 0.16% (95% CI: 0.08% - 0.24%) for ceftriaxone to 29.9% (95% CI: 28.6% - 31.1%) for ciprofloxacin. Sensitivity analyses revealed that unmeasured data on sex of sex partners could substantially impact weighted estimates.

Conclusions

AMR among reported incident male urogenital GC infections remains rare for ceftriaxone, the current standard of care. Aggregated GISP data are generally representative of men in the US who are reported with urogenital gonorrhea.
Impact of Pulmonary Complications on Outcomes and Resource Use After Elective Cardiac Surgery
Authors: Hadaya Joseph , Verma Arjun , Marzban Mehrab , Sanaiha Yas , Shemin Richard J. , Benharash Peyman
Published: December 2022

Objective:

To characterize the impact of pulmonary complications (PCs) on mortality, costs, and readmissions after elective cardiac operations in a national cohort and to test for hospital-level variation in PC.

Background:

PC after cardiac surgery are targets for quality improvement efforts. Contemporary studies evaluating the impact of PC on outcomes are lacking, as is data regarding hospital-level variation in the incidence of PC.

Methods:

Adults undergoing elective coronary artery bypass grafting and/or valve operations were identified in the 2016-2019 Nationwide Readmissions Database. PC was defined as a composite of reintubation, prolonged (>24 hours) ventilation, tracheostomy, or pneumonia. Generalized linear models were fit to evaluate associations between PC and outcomes. Institutional variation in PC was studied using observed-to-expected ratios.

Results:

Of 588,480 patients meeting study criteria, 6.7% developed PC. After risk adjustment, PC was associated with increased odds of mortality (14.6, 95% CI, 12.6–14.8), as well as a 7.9-day (95% CI, 7.6–8.2) increase in length of stay and $41,300 (95% CI, 39,600–42,900) in attributable costs. PC was associated with 1.3-fold greater hazard of readmission and greater incident mortality at readmission (6.7% vs 1.9%, P<0.001). Significant hospital-level variation in PC was present, with observed-to-expected ratios ranging from 0.1 to 7.7.

Conclusions:

Pulmonary complications remain common after cardiac surgery and are associated with substantially increased mortality and expenditures. Significant hospital-level variation in PC exists in the United States, suggesting the need for systematic quality improvement efforts to reduce PC and their impact on outcomes.
Negative Prognostic Impact of Tumor Deposits in Rectal Cancer
Authors: Agger Erik , Jörgren Fredrik , Jöud Anna , Lydrup Marie-Louise , Buchwald Pamela
Published: December 2022

Objective:

To investigate whether tumor deposits (TDs) in rectal cancer are associated with increased recurrence risk and decreased survival.

Background:

Tumor deposits (TDs) are considered a risk factor for recurrence after colon cancer resection, and the presence of TDs prompts adjuvant chemotherapy. The prognostic relevance of TDs in rectal cancer requires further exploration.

Methods:

All patients treated with abdominal resection surgery for rectal cancer in Sweden between 2011 and 2014 were eligible for inclusion in this retrospective cohort study based on prospectively collected data from the Swedish Colorectal Cancer Registry. The primary endpoint was local recurrence or distant metastasis. Secondary outcomes were overall and relative survival.

Results:

Five thousand four hundred fifty-five patients were identified of which 3769 patients were analyzed after exclusion. TDs were found in 404 (10.7%) patients, including 140 (3.7%) patients with N1c-status. In TD-positive patients, local recurrence and distant metastasis rates at 5 years were 6.3% [95% CI 3.8–8.8%] and 38.9% [95% CI, 33.6–43.5%] compared with 2.7% [95% CI, 2.1–3.3%] and 14.3% [95% CI, 13.1–15.5%] in TD-negative patients. In multivariable regression analysis, the risk of local recurrence and distant metastasis were increased; HR 1.86 [95% CI, 1.09–3.19; P=0.024] and 1.87 [95% CI, 1.52–2.31; P=<0.001], respectively. Overall survival at 5 years was 68.8% [95% CI, 64.4–73.4%] in TD-positive patients and 80.7% [95% CI, 79.4–82.1%] in TD-negative patients. pN1c-patients had similar outcomes regarding local recurrence, distant metastasis, and survival as pN1a-b stage patients. TD-positive pN1a-b patients had significantly worse outcomes whereas TDs did not affect outcomes in pN2a-b patients.

Conclusion:

This study suggests that TDs have a negative impact on the prognosis in rectal cancer. Thus, efforts should be made to diagnose TD-positive rectal cancer patients preoperatively.
Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial
Authors: Mei Wei-Jian , Wang Xiao-Zhong , Li Yun-Feng , Sun Yue-Ming , Yang Chun-Kang , Lin Jun-Zhong , Wu Zu-Guang , Zhang Rui , Wang Wei , Li Yong , Zhuang Ye-Zhong , Lei Jian , Wan Xiang-Bin , Ren Ying-Kun , Cheng Yong , Li Wen-Liang , Wang Zi-Qiang , Xu Dong-Bo , Mo Xian-Wei , Ju Hai-Xing , Ye Sheng-Wei , Zhao Jing-Lin , Zhang Hong , Gao Yuan-Hong , Zeng Zhi-Fan , Xiao Wei-Wei , Zhang Xiao-Peng , Zhang Xuan , Xie E , Feng Yi-Fei , Tang Jing-Hua , Wu Xiao-Jun , Chen Gong , Li Li-Ren , Lu Zhen-Hai , Wan De-Sen , Bei Jin-Xin , Pan Zhi-Zhong , Ding Pei-Rong
Published: December 2022

Objective:

To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF).

Background Data:

nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF.

Methods:

Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity.

Results:

Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm (P=0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm (P=0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P=0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P=0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis.

Conclusions:

nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.
Associations between Traditional Chinese Medicine Body Constitution and Cardiovascular Disease Risk in a White population
Authors: Shu Lihua , Yin Xiaolin , Zhu Xiangzhu , Zhao Jing , Deng Xinqing , Shubin Yevheniy Eugene , Murff Harvey J. , Ness Reid M. , Yu Chang , Shrubsole Martha J. , Dai Qi
Published: December 2022

Introduction

Traditional Chinese medicine (TCM) has guided generations of practice on disease treatment and health maintenance. The TCM principles include the framework of body constitution (BC). In essence, it represents one of the first attempts at applying the principle of personalized, precision medicine. Major limitations to broad implementation of the body constitution (BC) framework, and perhaps TCM as a whole, include not only a lack of empirical study about its relation to other models of health maintenance but also a poor understanding of its applicability outside of Chinese population.

Methods

We conducted a study using baseline data from the Personalized Prevention of Colorectal Cancer Trial. 191 participants from an almost entirely White population were evaluated for BC type.

Results

Fifty-seven (29.8%) were identified as neutral BC, while Blood-stasis (17.3%), Qi-deficient (13.6%), and Special diathesis (10.5%) were the pre-eminent pathologic subtypes. We also found there are substantial differences in proportions of TCM BC types in our study of white Americans conducted in US from previous studies conducted in Chinese populations. Additional analyses investigated the relationship between cardiovascular disease (CVD) risk and BC subtypes. Among them, Yang-deficiency, Yin-deficiency, and Blood stasis carried a lower risk of CVD.

Conclusions

It is important to understand the underlying mechanisms contributing to these differences, which may not only help to understand the underlying mechanism for TCM, but also help to identify novel factors or mechanisms for CVD risk, prevention and treatment.
Disentangling the spread dynamics of insect invasions using spatial networks
Authors: Estay Sergio A. , Silva Carmen P. , López Daniela N. , Labra Fabio A.
Published: December 2022

Describing and understanding spatiotemporal spread patterns in invasive species remains a longstanding interdisciplinary research goal. Here we show how a network-based top-down approach allows the efficient description of the ongoing invasion byDrosophila suzukiiin Chile. To do so, we apply theoretical graph methods to calculate the minimum cost arborescence graph (MCA) to reconstruct and understand the invasion dynamics ofD. suzukiisince the first detection in 2017. This method estimates a directed rooted weighted graph by minimizing the total length of the resulting graph. To describe the temporal pattern of spread, we estimate three metrics of spread: the median dispersal rate, the median coefficient of diffusion, and the median dispersal acceleration. The estimated MCA shows that over four years,D. suzukiicolonized a ~1,000 km long strip in the central valley of Chile, with an initial phase with long paths and connections and no clear direction pattern, folowed by a clearer north-east propagation pattern. The median dispersal rate for the entire period was 8.8 [7.4 – 10.6,95% CI], while the median diffusion coefficient was 19.6 meters2/day [13.6 – 27.9, 95% CI]. The observed spread dynamics and the log-normal distribution of accelerations are consistent with longdistance dispersal events. The complexities of real landscapes cannot be summarized in any model, but this study shows how an alternative top-down approach based on graph theory can facilitate the ecological analysis of the spread of an invasive species in a new territory.
Injury and a program of fetal wound healing in the fetal and neonatal extrahepatic bile duct
Authors: de Jong Iris E.M. , Hunt Mallory L. , Chen Dongning , Du Yu , Llewellyn Jessica , Gupta Kapish , Erxleben Dorothea , Rivas Felipe , Hall Adam R. , Furth Emma E. , Naji Ali , Liu Chengyang , Dhand Abhishek , Burdick Jason , Davey Marcus G. , Flake Alan W. , Porte Robert J. , Russo Pierre A. , Gaynor J. William , Wells Rebecca G.
Published: December 2022

Introduction

Biliary atresia (BA) is an obstructive cholangiopathy that initially affects the extrahepatic bile ducts (EHBDs) of neonates. The etiology is uncertain, but evidence points to a prenatal cause; however, the response of the fetal EHBD to injury remains unknown. The objective of this study was to define the fetal response to EHBD injury and to determine whether it follows a fetal wound healing paradigm.

Methods

Mouse, rat, sheep, and human EHBD samples were studied at different developmental time points. Models included a fetal sheep model of prenatal hypoxia, human BA EHBD remnants and liver samples taken at the time of the Kasai procedure, EHBDs isolated from neonatal rats and mice, and spheroids and other models generated from primary neonatal mouse cholangiocytes.

Results

A wide layer of high molecular weight HA encircling the lumen was characteristic of the normal perinatal but not adult EHBD. This layer, which was surrounded by collagen, expanded in injured ducts in parallel with extensive peribiliary gland (PBG) hyperplasia, increased mucus production and elevated serum bilirubin levels. BA EHBD remnants similarly showed increased HA centered around ductular structures compared with age-appropriate controls. High molecular weight HA typical of the fetal/neonatal ducts caused increased cholangiocyte spheroid growth, whereas low molecular weight HA induced abnormal epithelial morphology; low molecular weight HA caused matrix swelling in a bile duct-on-a-chip device.

Conclusion

The fetal/neonatal EHBD, including in human EHBD remnants from Kasai surgeries, demonstrated an injury response with high levels of HA typical of the regenerative, scarless program termed fetal wound healing. Although generally beneficial, the expanded peri-luminal HA layer may swell and lead to elevated bilirubin levels and obstruction of the EHBD.
Open-3DSIM: an Open-source three-dimensional structured illumination microscopy reconstruction platform
Authors: Cao Ruijie , Li Yaning , Chen Xin , Ge Xichuan , Li Meiqi , Guan Meiling , Hou Yiwei , Fu Yunzhe , Jiang Shan , Gao Baoxiang , Xi Peng
Published: December 2022

With optical section and defocus removal effect, three-dimensional structured illumination microscopy (3DSIM) can get a whole sight of intracellular organelle. Here, Open-3DSIM is reported as an open-source reconstruction platform with double improvement on lateral and axial resolution. MATLAB code, ImageJ version and Exe application are provided for biologists and engineers to maximize its user-friendliness and prompt its further development. Through adaptive parameter estimation and spectrum filter optimization, we demonstrate its superior performance of artifact suppression and defocus elimination over other algorithms on various specimens, under gradient signal-to-noise levels. Moreover, with the capacity to extract the dipole orientation, Open-3DSIM paves a new avenue for interpreting the subcellular structures in six dimensions (xyzθλt).
A non-conserved histidine residue on KRAS drives paralog selectivity of the KRAS G12D inhibitor MRTX1133
Authors: Keats Miles A. , Han John J. W. , Lee Yeon-Hwa , Lee Chih-Shia , Luo Ji
Published: December 2022

The discovery of small molecule inhibitors against mutant KRAS protein was a recent breakthrough in targeted therapy. Understanding the mechanism of selectivity by KRAS inhibitors and the mechanism of resistance to them can guide the future development of KRAS inhibitors. MRTX1133 was the first non-covalent inhibitor against the KRAS G12D mutant that demonstrated specificity and potency in pre-clinical tumor models. We used isogenic cell lines expressing a single RAS allele to evaluate the selectivity of this compound. We found that in addition to KRAS G12D, MRTX1133 shows significant activity against several other KRAS mutants as well as wildtype KRAS protein. In contrast, MRTX1133 exhibits no activity against both G12D and wildtype forms of HRAS and NRAS proteins. Functional analysis revealed that the selectivity of MRTX1133 towards KRAS is associated with its binding to histidine 95 on KRAS, a residue that is not conserved in HRAS and NRAS. Reciprocal mutation of amino acid 95 among the three RAS paralogs resulted in reciprocal change in their sensitivity towards MRTX1133. Thus, histidine 95 is an essential selectivity handle for MRTX1133 towards KRAS. This knowledge could aid the development of future KRAS-selective inhibitors.
Research and Diagnostic Algorithmic Rules (RADAR) and RADAR plots for the first episode of major depressive disorder: effects of childhood and recent adverse experiences on suicidal behaviors, neurocognition and phenome features
Authors: Maes Michael , Almulla Abbas F
Published: December 2022

This study was performed to ascertain whether a) a valid precision model and valid Research and Diagnostic Algorithmic Rules (RADAR) scores can be computed in patients experiencing first-episode depression; and b) adverse childhood experiences (ACEs) and negative life events (NLEs) are associated with suicidal behavior (SBs), cognitive impairment, and phenome RADAR scores.

This study recruited 90 patients with major depressive disorder (MDD) in an acute phase, of whom 71 showed a first-episode MDD (FEM), and 40 controls. We constructed RADAR scores for ACEs, NLEs encountered the last year, SBs and severity of depression, anxiety, chronic fatigue and physiosomatic symptoms using the Hamilton Depression and Anxiety Rating scales and the Fibro-Fatigue scale.

Partial least squares analysis showed that in FEM, one latent vector (labelled the phenome of FEM) could be extracted from depressive, anxiety, fatigue, physiosomatic, melancholia, and insomnia symptoms, SBs, and cognitive impairments. The latter were conceptualized as a latent vector extracted from the Verbal Fluency Test, Mini Mental State Examination, and ratings of memory and judgment, indicating a generalized cognitive decline (G-CoDe). We found that 60.8% of the variance in the FEM phenome was explained by the cumulative effects of NLEs and ACEs, in particular emotional neglect and, to a lesser extent, physical abuse, and by the interaction between ACEs and physical abuse, whereby the latter attenuates the effects of NLEs.

In conclusion, not the binary diagnosis of MDD (DSM/ICD) should be used in research and clinical settings but the RADAR scores and plots constructed here.