bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic profiles guide improved CRISPR/Cas9-mediated gene knockout in human T cells
Authors: Ito Yusuke , Inoue Satoshi , Nakashima Takahiro , Zhang Haosong , Li Yang , Kasuya Hitomi , Matsukawa Tetsuya , Wu Zhiwen , Yoshikawa Toshiaki , Kataoka Mirei , Ishikawa Tetsuo , Kagoya Yuki
Published: November 2023

Genetic modification of specific genes is emerging as a useful tool to enhance the functions of antitumor T cells in adoptive immunotherapy. Current advances in CRISPR/Cas9 technology enable gene knockout during in vitro preparation of infused T-cell products through transient transfection of a Cas9-guide RNA (gRNA) ribonucleoprotein complex. However, selecting optimal gRNAs remains a major challenge for efficient gene ablation. Although multiple in silico tools to predict the targeting efficiency have been developed, their performance has not been validated in cultured human T cells. Here, we explored a strategy to select optimal gRNAs using our pooled data on CRISPR/Cas9-mediated gene knockout in human T cells. The currently available prediction tools alone were insufficient to accurately predict the indel percentage in T cells. We used data on the epigenetic profiles of cultured T cells obtained from transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Combining the epigenetic information with sequence-based prediction tools significantly improved the gene-editing efficiency. We further demonstrate that epigenetically closed regions can be targeted by designing two gRNAs in adjacent regions. Finally, we demonstrate that the gene-editing efficiency of unstimulated T cells can be enhanced through pretreatment with IL-7. These findings enable more efficient gene editing in human T cells.
Epigenetic regulation of asymmetric cell division by the LIBR-BRD4 axis
Authors: Chen Hsiao-Fan , Chang Chia-Ting , Hsu Kai-Wen , Peng Pei-Hua , Lai Joseph Chieh-Yu , Hung Mien-Chie , Wu Kou-Juey
Published: November 2023

Asymmetric cell division (ACD) is a mechanism used by stem cells to maintain the number of progeny. However, the epigenetic mechanisms regulating ACD remain elusive. Here we show that BRD4, a BET domain protein that binds to acetylated histone, is segregated in daughter cells together with H3K56Ac and regulates ACD. ITGB1 is regulated by BRD4 to regulate ACD. A long noncoding RNA (lncRNA), LIBR (LncRNA Inhibiting BRD4), decreases the percentage of stem cells going through ACD through interacting with the BRD4 mRNAs. LIBR inhibits the translation of BRD4 through recruiting a translation repressor, RCK, and inhibiting the binding of BRD4 mRNAs to polysomes. These results identify the epigenetic regulatory modules (BRD4, lncRNA LIBR) that regulate ACD. The regulation of ACD by BRD4 suggests the therapeutic limitation of using BRD4 inhibitors to treat cancer due to the ability of these inhibitors to promote symmetric cell division that may lead to tumor progression and treatment resistance.
Changes in energy and macronutrient intakes during Ramadan fasting: a systematic review, meta-analysis, and meta-regression
Authors: Abdelrahim Dana N , El Herrag Salah Eddine , Khaled Meghit Boumediene , Radwan Hadia , Naja Farah , Alkurd Refat , Khan Moien A B , Zeb Falak , AbuShihab Katia H , Mahrous Lana , Obaideen Khaled , Kalam Faiza , Granata Iv Frank , Madkour Mohamed , Faris MoezAlIslam E
Published: November 2023

Context

Ramadan fasting (RF) is associated with various physiological and metabolic changes among fasting Muslims. However, it remains unclear whether these effects are attributable to changes in meal timing or changes in dietary energy and macronutrient intakes. Furthermore, the literature on the associations between RF, meal timing, and energy and macronutrient intakes is inconclusive.

Objectives

This systematic review aimed to estimate the effect sizes of RF on energy and macronutrient intakes (carbohydrates, protein, fats, dietary fiber, and water) and determine the effect of different moderators on the examined outcomes.

Data Sources

The Cochrane, CINAHL, EMBASE, EBSCOhost, Google Scholar, PubMed/MEDLINE, ProQuest Medical, Scopus, ScienceDirect, and Web of Science databases were searched from inception to January 31, 2022.

Data Extraction

The studies that assessed energy, carbohydrate, protein, fat, fiber, and water intakes pre- and post-fasting were extracted.

Data Analysis

Of the 4776 identified studies, 85 relevant studies (n = 4594 participants aged 9–85 y) were selected. The effect sizes for the studied variables were as follows: energy (number of studies [K] = 80, n = 3343 participants; mean difference [MD]: −142.45; 95% confidence interval [CI]: −215.19, −69.71), carbohydrates (K = 75, n = 3111; MD: −23.90; 95% CI: −36.42, −11.38), protein (K = 74, n = 3108; MD: −4.21; 95% CI: −7.34, −1.07), fats (K = 73, n = 3058; MD: −2.03; 95% CI: −5.73, 1.67), fiber (K = 16, n = 1198; MD: 0.47; 95% CI: −1.44, 2.39), and water (K = 17, n = 772; MD: −350.80; 95% CI: −618.09, 83.50). Subgroup analyses showed age significantly moderated the 6 dietary outcomes, and physical activity significantly moderated water intake. There were significant reductions in energy, carbohydrate, and protein intakes during RF.

Conclusions

The change in meal timing rather than quantitative dietary intake may explain various physiological and health effects associated with RF.
Rifampin Mono-Resistant Tuberculosis in New York City, 2010–2021: A Retrospective Case Series
Authors: Lindsey Joseph A , Easton Alice V , Modestil Herns , Dworkin Felicia , Burzynski Joseph , Nilsen Diana
Published: November 2023

Background

Although relatively rare, rifampin mono-resistant tuberculosis (RMR TB) poses important challenges to effective TB treatment and control. Information on the burden of RMR TB and treatment outcomes is needed to inform diagnosis and management.

Methods

Standardized variables were collected from the New York City (NYC) tuberculosis surveillance system for patients treated for RMR TB in NYC during 2010–2021.

Results

Of 7097 TB cases reported in 2010–2021, 31 (<1%) were treated clinically as RMR TB. Five (16%) of these patients had HIV. Seventeen patients (55%) had TB that was rifampin-resistant by both molecular and phenotypic drug susceptibility testing; 2 (6%) had rifampin resistance by phenotypic tests, and molecular tests were not done; and 12 (39%) were identified based only on molecular tests. Among these 12, 7 were rifampin-sensitive by phenotypic tests, and phenotypic testing could not be done for the other 5. Ten of the 31 (32%) were diagnosed in 2010–2015; the other 21 (including 10/12 diagnosed by molecular tests alone) were diagnosed in 2016–2021. Of the 31 patients, 21 (68%) completed treatment (median treatment duration of 18 months). Although the interval between tuberculosis treatment initiation and change to a non-rifamycin-containing regimen decreased significantly during the study period, the overall duration of treatment did not decrease significantly between 2010 and 2021.

Conclusions

Molecular drug susceptibility tests identified cases of RMR TB that were not detected by phenotypic testing and helped enable timely adjustment of tuberculosis treatment regimens. Short-course regimens are needed to reduce duration of treatment for RMR TB.
Socio-demographic variation in adherence to the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations within the UK Biobank prospective cohort study
Authors: Malcomson Fiona C , Parra-Soto Solange , Lu Liya , Ho Frederick , Celis-Morales Carlos , Sharp Linda , Mathers John C
Published: November 2023

Background

The 2018 (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are evidence-based lifestyle recommendations which aim to reduce the risk of cancer worldwide. Sociodemographic factors modulate lifestyle behaviours, and both cancer incidence and survival are socio-economically patterned. We investigated adherence to these recommendations and examined patterns of adherence across sociodemographic subgroups in the UK Biobank cohort.

Methods

We included 158 415 UK Biobank participants (mean age 56 years, 53% female). Total adherence scores were derived from dietary, physical activity and anthropometric data using the 2018 WCRF/AICR standardized scoring system. One-Way analysis of variance (ANOVA) was used to test for differences in total scores and in values for individual score components according to sociodemographic factors and Pearson’s Χ2 test to investigate associations between sociodemographic factors according to tertiles of adherence score.

Results

Mean total adherence score was 3.85 points (SD 1.05, range 0–7 points). Higher total scores were observed in females, and older (>57 years), Chinese or South Asian, and more educated participants. We found significant variations in adherence to individual recommendations by sociodemographic factors including education, Townsend deprivation index and ethnicity.

Conclusions

Identifying and understanding lifestyle and dietary patterns according to sociodemographic factors could help to guide public health strategies for the prevention of cancers and other non-communicable diseases.
Deficits in brain default mode network connectivity mediate the relationship between poor sleep quality and anxiety severity
Authors: Shen Zhifu , Yang Xue , She Tianwei , Zhao Guangli , Dou Zeyang , Luo Yucai , Lin Wenting , Dang Wantai , Yu Siyi
Published: November 2023

Study Objectives

Chronic insomnia disorder (CID) is a prevalent sleep disorder that frequently cooccurs with anxiety. The association between insomnia and anxiety has been established; however, the neurobiological basis of this relationship remains unclear. This study aimed to investigate the neural markers of CID patients with and without anxiety and to determine whether specific neural connectivity mediates the relationship between insomnia and anxiety.

Methods

This study included 180 participants, comprising CID patients with anxiety (CID-A), CID patients without anxiety (CID-NA), and good sleep controls. All participants completed self-reported measures of sleep quality and anxiety severity and underwent functional magnetic resonance imaging. Brain functional integration was measured using functional connectivity density (FCD) and resting-state functional connectivity (rsFC). Correlation and mediation analyses were used to examine the relationships among brain connectivity, sleep quality, and anxiety severity.

Results

The CID-NA and CID-A groups showed decreased local FCD in the medial prefrontal cortex (mPFC) and disrupted rsFC between the precuneus and other brain regions. Only the CID-A group exhibited altered long-range FCD in the precuneus and the rsFC between the anterior default mode network (DMN, e.g. mPFC) and posterior DMN (e.g. precuneus). Mediation analysis revealed DMN dysconnectivity underlying the association between poor sleep quality and anxiety symptoms.

Conclusions

This study identified shared and distinct brain circuit disruptions in the CID-NA and CID-A groups, with deficits in DMN connectivity as a potential neural mechanism through which disrupted sleep augments anxiety. These findings may facilitate the development of personalized therapies for insomnia and associated anxiety problems.
Macrophage migration inhibitory factor (MIF) promotes intervertebral disc degeneration through theNF‐κBpathway, and theMIFinhibitorCPSI‐1306 alleviates intervertebral disc degeneration in a mouse model
Authors: Zhang Yejin , Zheng Lin , Fang Jiawei , Ni Kainan , Hu Xingyu , Ye Lin , Lai Hehuan , Yang Tao , Chen Zhenzhong , He Dengwei
Published: November 2023

Lumbar intervertebral disc degeneration(IDD) is a prevalent inflammatory disease caused by many proinflammatory factors, such as TNF and IL‐1β. Migration inhibitory factor (MIF) is an upstream inflammatory factor widely expressed in vivo that is associated with a variety of inflammatory diseases or malignant tumors and has potential therapeutic value in many diseases. We explored the role of MIF in intervertebral disc degeneration by regulating the content of exogenous MIF or the expression of MIF in cells. Upon inducing degeneration of nucleus pulposus (NP) cells with IL‐1β, we found that the increase in intracellular and exogenous MIF promoted the catabolism induced by proinflammatory factors in NP cells, while silencing of the MIF gene alleviated the degeneration to some extent. In a mouse model, the intervertebral disc degeneration of MIF‐KO mice was significantly less than that of wild‐type mice. To explore the treatment of intervertebral disc degeneration, we selected the small‐molecular MIF inhibitor CPSI‐1306. CPSI‐1306 had a therapeutic effect on intervertebral disc degeneration in the mouse model. In summary, we believe that MIF plays an important role in intervertebral disc degeneration and is a potential therapeutic target for the treatment of intervertebral disc degeneration.
Minoxidil-associated pericardial effusion and impending tamponade
Authors: Lew Michelle J. , Amato Jordan
Published: November 2023

A patient with a large pericardial effusion and impending tamponade exhibited clinical improvement with urgent pericardiocentesis. Further workup ruled minoxidil to be the likely cause of the effusion. After discontinuation of minoxidil, the effusion did not recur.
Six tips for successful grant writing
Authors: Mines Ashley
Published: November 2023

Physician associates/assistants (PAs) are poised to be excellent grant writers for local projects that can improve access to quality care and improve the finances of historically underserved, urban, and rural healthcare communities. Because grant writing focuses on the dream of what is possible with funding, it contrasts with other forms of medical writing, which focus on past findings. This article aims to introduce PAs to six steps that can help them with grant writing, with a goal of improving patient care or starting community outreach projects.
Recurrent Severe Maternal Morbidity in an Obstetric Population With a High Comorbidity Burden
Authors: McIlwraith Claire , Sanusi Ayodeji , McGwin Gerald , Battarbee Ashley , Subramaniam Akila
Published: November 2023

OBJECTIVE:

To evaluate the risk of severe maternal morbidity (SMM) in subsequent pregnancies in patients who experienced SMM in a previous pregnancy compared with those who did not.

METHODS:

We conducted a retrospective cohort study of patients with two or more deliveries at 23 or more weeks of gestation at a single Southeastern U.S. tertiary care center between 2015 and 2018. The primary exposure was SMM including transfusion (transfusion SMM) in a previous pregnancy, as defined by the Centers for Disease Control and Prevention, using International Classification of Diseases, Ninth or Tenth Revision codes. The primary outcome was transfusion SMM in any subsequent pregnancy in the study time frame. Generalized estimating equation models were used to estimate the relative risk (RR) and associated 95% CIs of transfusion SMM in patients with transfusion SMM in a prior pregnancy compared with patients without transfusion SMM in a previous pregnancy. Severe maternal morbidity without transfusion (nontransfusion SMM) and cross-analysis to determine risk of a different type of SMM after a history of SMM were analyzed similarly.

RESULTS:

Of 852 included patients, transfusion SMM and nontransfusion SMM occurred in 90 (10.6%) and 18 (2.1%), respectively, in the first captured pregnancy and in 79 (9.3%) and 9 (1.1%), respectively, in subsequent pregnancies. Anemia (34.6–40.0%), obesity (33.4–40.4%), substance use disorder (14.2–14.6%), and preeclampsia (12.0–11.4%) were the most prevalent morbidities at first captured and subsequent pregnancies, respectively. There was a 16-fold higher risk of transfusion SMM in a subsequent pregnancy after experiencing transfusion SMM in the first captured pregnancy (57.8% vs 3.5%, RR 16.3 95% CI, 10.8–24.6). Nontransfusion SMM was similarly higher in patients with nontransfusion SMM in their first captured pregnancy compared with those without (16.7% vs 0.7%, RR 23.2 95% CI, 6.3–85.4). Additionally, patients who experienced transfusion SMM in their first captured pregnancies were at sixfold higher risk of developing nontransfusion SMM in a subsequent pregnancy (RR 6.2, 95% CI, 1.7–22.6). However, in cross-analysis of patients who experienced nontransfusion SMM, the risk of transfusion SMM in a subsequent pregnancy was not statistically significant.

CONCLUSION:

The risks of SMM in subsequent pregnancies after previous SMM are extremely high and are higher than previous estimates. Future studies should estimate the contributions of comorbidities and other structural determinants including social vulnerability to help design interventions to reduce subsequent pregnancy risks.
Müllerian Anomalies
Authors: Bortoletto Pietro , Romanski Phillip A. , Pfeifer Samantha M.
Published: November 2023

Müllerian anomalies represent a complex collection of developmental defects occurring in up to 5% of the general population. They are increasingly more common in individuals with infertility (8.0%) and in those with a history of pregnancy loss (13.3%); they have the highest prevalence in individuals with a history of both (24.5%). A wide spectrum of anomalies can occur based on the stage at which müllerian development ceases in utero, ranging from mild (eg, a partial uterine septum) to severe, with complete absence of the cervix, uterus, and fallopian tubes (eg, müllerian agenesis). The components of the reproductive tract involved and, importantly, whether an obstruction of the tract is involved correlates with the timing of presentation, the constellation of associated symptoms, and the necessity for either medical or surgical management. Individuals, regardless of the severity of the defect, should be counseled on the gynecologic, reproductive, and obstetric risks associated with their specific müllerian anomaly to minimize adverse sequela and outcomes. We will review the clinical presentation, diagnostic evaluation, and clinical counseling of individuals with müllerian anomalies.
Critical and non-critical coronavirus disease 2019 patients: which is the most predictive biomarker for disease severity and outcome?
Authors: Montrucchio Giorgia , Balzani Eleonora , Sales Gabriele , Bolla Cesare , Sarda Cristina , Della Selva Andrea , Perotto Massimo , Pomero Fulvio , Ravera Enrico , Rumbolo Francesca , Callegari Tiziana , Fanelli Vito , Mengozzi Giulio , Brazzi Luca
Published: November 2023

BACKGROUND

Severe acute respiratory syndrome-coronavirus-2 in coronavirus disease 2019 (COVID-19) patients leads to a wide range of clinical manifestations. The evaluation of mid-regional pro-adrenomedullin (MR-proADM) as a prognostic biomarker in noncritical wards (NON-ICU) and intensive care units (ICU), may have a potential in predicting disease severity and outcomes.

OBJECTIVE

To assess the difference in the prognostic power of MR-proADM in NON-ICU wards and in ICUs in a prospective multicentre cohort study.

DESIGN

From January to July 2021, all adult COVID-19 patients requiring admission for more than 48 h.

SETTING

One primary centre and two secondary centre hospitals.

PATIENTS

One hundred and twenty-three ICU and 77 NON-ICU patients.

INTERVENTION

MR-proADM, lymphocyte subpopulations and immunoglobulins were measured within 48 h and on days 3 and 7. A Log-rank test was used to compare survival curves, using a MR-proADM cut-off value of 1.5 nmol l−1. The predictive ability for mortality was compared using the area under the curve and 95% confidence interval (CI) of different receiver-operating characteristic curves.

MAIN OUTCOME MEASURES

The first 48 h MR-proADM values were significantly higher in the ICU group (median value 1.10 [IQR, 0.80 to 1.73] pg ml−1 vs. 0.90 [0.70 to 1.20] pg ml−1, P = 0.020), and statistically significant changes were observed over time for MR-proADM, CD3+, CD4+ and CD56+. In univariate analysis, MR-proADM was the only biomarker that significantly predicted mortality (P = 0.006). The logistic regression model showed an odds ratio for mortality equal to 1.83 (95% CI, 1.08 to 3.37) P = 0.035 for MR-proADM, 1.37 (1.15 to 1.68) P = 0.001 for MuLBSTA and 1.11 (1.05 to 1.18) P less than 0.001 for SAPS II.

CONCLUSION

MR-proADM admission values and trends over time appear to be a suitable marker of illness severity and a patient's risk of mortality in both ICU and NON-ICU settings. Lymphocyte subpopulation dysfunction seems to play a role in defining the severity of COVID-19 but is limited to ICU setting.

TRIAL REGISTRATION

on clinicaltrials.gov, NCT04873388 registered on March 2020.
Bacterial and Candida Colonization of Neonates in a Regional Hospital in South Africa
Authors: Mabena Fikile C. , Olwagen Courtney P. , Phosa Matshie , Ngwenya Innocent K. , Van der Merwe Lara , Khan Aaliyah , Mwamba Tshiama M. , Mpembe Ruth , Magobo Rindidzani E. , Govender Nelesh P. , Velaphi Sithembiso C. , Madhi Shabir A.
Published: November 2023

Background:

Neonatal colonization with multidrug-resistant (MDR) Enterobacter spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterococcus faecium (ESKAPE) and Candida spp. often precedes invasive hospital-acquired infections. We investigated the prevalence and dynamics of neonatal ESKAPE and Candida spp. colonization from hospital admission until discharge (or death) and followed up for invasive disease.

Methods:

Prospective longitudinal surveillance for neonatal ESKAPE and Candida spp. colonization was conducted over 6 months at a South African regional hospital. Neonates enrolled at birth had swabs (nasal, 2× skin and rectal) collected within 24 hours and every 48–96 hours thereafter, until discharge or death. ESKAPE and Candida spp. were cultured for and antimicrobial susceptibility was performed on bacterial isolates. Whole-genome sequencing was undertaken on paired samples with the same bacterial species from colonizing and invasive disease episodes in the same child.

Results:

Of 102 enrolled neonates, 79% (n = 81) were colonized by ≥1 ESKAPE organism by time of discharge or death. Forty-four percent (36/81) were colonized within 24 hours of birth. Common colonizers were K. pneumoniae (70%; n = 57) and Enterobacter spp. (43%; n = 35). Almost all MDR organisms (93%) were Gram-negative. Forty-two (45%, 42/93) newborns acquired Candida spp. (skin only) colonization, commonly Candida parapsilosis (69%; n = 29). For 2 children with K. pneumoniae colonization and sepsis, the bloodstream and colonizing isolates were genetically different, whereas the single A. baumannii colonizing and blood isolate pair were genetically identical.

Conclusions:

We report a high prevalence of MDR ESKAPE and Candida spp. colonization in a regional neonatal unit. Interventions to reduce the high incidence of hospital-acquired neonatal infections should include reducing high colonization rates.
A novel laparoscopic pancreaticoduodenal training model: optimization of the learning curve and simplification of postoperative complications
Authors: Tang Yichen , Peng Xuehui , He Yonggang , Li Jing , Zheng Lu , Huang Xiaobing
Published: November 2023

Purpose:

Laparoscopic pancreaticoduodenectomy requires a long learning curve. A preoperative training system was established to optimize the surgeons’ learning curve and reduce the incidence rate of complications at the beginning of the curve.

Methods:

The laparoscopic pancreaticojejunostomy model, and choledochojejunostomy and gastrojejunostomy training systems were developed, and corresponding evaluation systems were also defined. Surgeons B and C performed laparoscopic pancreaticoduodenectomy after completing training session. Surgical outcomes, postoperative complications and their learning curves were analyzed.

Results:

Patients operated by surgeons B and C experienced shorter operative durations following training session than those in nontrained group (called A) (P<0.001). B and C began entering the inflection point at the 26th and 20th case in learning curve, respectively. The incidence of postoperative pancreatic fistula in group B was 3.3%, significantly lower than 13.1% in group A (P=0.047). Patients in group B showed significantly lower incidence of biliary-enteric anastomosis leakage (0% vs. 8.2%, P=0.029) and Clavien–Dindo classification greater than or equal to 3 (3.3% vs. 14.8%, P=0.027) compared with those in group A. The incidence of surgical site infection in groups B (3.3%, P=0.004) and C (4.9%, P=0.012) was significantly lower than that in group A (19.7%). Moreover, the length of postoperative hospital stay was significantly shorter in groups B (12.5±5.9 days, P=0.002) and C (13.7±6.5 days, P=0.002) compared with group A (16.7±8.5 days).

Conclusions:

The laparoscopic pancreaticojejunostomy training model and evaluation system can shorten the operative duration, lower the risk of postoperative complications, and shorten the length of hospital stay.
Orthopaedic Nurse Navigators and Total Joint Arthroplasty Preoperative Optimization
Authors: Kebeh Martha , Dlott Chloe C. , Kurek Donna , Morris Jensa C. , Wiznia Daniel H.
Published: November 2023

Substance use is one of the most common risk factors contributing to complications following total joint arthroplasty. Preoperative optimization programs can help patients modify or stop substance use. The purpose of this study was to provide recommendations and resources that will help nurse navigators standardize and improve preoperative optimization protocols regarding substance use. In a semistructured format, we asked nurse navigators how smoking, alcohol use, and opioid use were addressed. We conducted a literature review and combined findings with nurse navigator reports to create practice recommendations. We recommend consistently referring patients who smoke to smoking cessation programs; using validated screening tools to evaluate alcohol use and involving internists in caring for patients at risk for withdrawal; and involving pain specialists and local resources to assist patients who use opioids. There is a breadth of resources for managing substance use that nurse navigators can utilize to support stronger and more consistent preoperative optimization protocols.
Better Before—Better After
Authors: Halsen Katrine , Svinøy Odd Einar , Hilde Gunvor , Langhammer Birgitta
Published: November 2023

Total hip replacement is considered a successful intervention for pain relief and improved function. However, poor presurgery physical function may increase the likelihood of delayed postsurgery recovery. The purpose of this study was to describe community-dwelling older adults' experiences with a prehabilitation program (preoperative exercise) before total hip replacement. Four participants were interviewed 13 and 15 weeks postsurgery. The interviews were recorded, transcribed, and analyzed with systematic text condensation. Physical, mental, and social limitations were, to a higher or lesser degree, part of the participants' life presurgery. The results indicate that tailored close supervised training presurgery increased the participants' amount of and adherence to exercise, confidence, and sense of control. The participants had a positive experience of increased strength during the training period and gained motivation to perform progressive training. The exercise program helped the participants be physically and mentally prepared. The results indicate that close supervised prehabilitation in community-dwelling older adults undergoing total hip replacement can contribute to improved function and increase the level of activity and self-efficacy postsurgery.
Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States
Authors: Crane Heidi M. , Nance Robin M , Ruderman Stephanie A. , Haidar Lara , Tenforde Mark W. , Heckbert Susan R. , Budoff Matthew J. , Hahn Andrew W. , Drumright Lydia N. , Ma Jimmy , Mixson L. S. , Lober William B. , Barnes Gregory S. , McReynolds Justin , Attia Engi F. , Peter Inga , Moges Tesfaye , Bamford Laura , Cachay Edward , Mathews William C , Christopolous Katerina , Hunt Peter W. , Napravnik Sonia , Keruly Jeanne , Moore Richard D. , Burkholder Greer , Willig Amanda L. , Lindstrom Sara , Whitney Bridget M. , Saag Michael S. , Kitahata Mari M. , Crothers Kristina A. , Delaney Joseph A.C.
Published: November 2023

Background:

People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era.

Methods:

We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking.

Results:

We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common.

Conclusions:

We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common.
Transanal Total Mesorectal Excision With Delayed Coloanal Anastomosis (TaTME-DCAA) Versus Laparoscopic Total Mesorectal Excision (LTME) and Robotic Total Mesorectal Excision (RTME) for Low Rectal Cancer: A Propensity Score-Matched Analysis of Short-term Outcomes, Bowel Function, and Cost
Authors: Seow-En Isaac , Wu Jingting , Tan Ivan En-Howe , Zhao Yun , Seah Aaron Wei Ming , Wee Ian Jun Yan , Ying-Ru Ng Yvonne , Kwong-Wei Tan Emile
Published: November 2023

Introduction:

Total mesorectal excision (TME) with delayed coloanal anastomosis (DCAA) is surgical option for low rectal cancer, replacing conventional immediate coloanal anastomosis (ICAA) with bowel diversion. This study aimed to assess the outcomes of transanal TME (TaTME) with DCAA versus laparoscopic TME (LTME) with ICAA versus robotic TME (RTME) with ICAA.

Methods:

This was a retrospective propensity score-matched analysis of patients who underwent elective TaTME-DCAA between November 2021 and June 2022. Patients were propensity-score matched in a ratio of 1:3 to patients who underwent LTME-ICAA and RTME-ICAA from January 2019 to December 2020. Outcome measures were histopathologic results, postoperative morbidity, function, and inpatient costs.

Results:

Twelve patients in the TaTME-DCAA group were compared with 36 patients in the LTME-ICAA and RTME-ICAA groups each after propensity score matching. Histopathologic results and postoperative morbidity rates were statistically similar. Overall stoma-related complication rates in the ICAA groups were 11%. Median total length of hospital stays for TME plus stoma reversal surgery was similar across all techniques (10 vs. 10 vs. 9 days; P=0.532). Despite a significantly shorter duration of follow-up, bowel function after TaTME-DCAA was comparable to that of LTME-ICAA and RTME-ICAA. Overall median inpatient costs of TaTME-DCAA were comparable to LTME-ICAA and significantly cheaper than RTME-ICAA ($31,087 vs. $29,927 vs. $36,750; P=0.002).

Conclusions:

TaTME with DCAA is a feasible and safe technique compared with other minimally invasive methods of TME, while avoiding bowel diversion and stoma-related complications, as well as comparing favorably in terms of overall hospitalization costs.
Preclinical Characterization of the Omicron XBB.1.5-Adapted BNT162b2 COVID-19 Vaccine
Authors: Modjarrad Kayvon , Che Ye , Chen Wei , Wu Huixian , Cadima Carla I. , Muik Alexander , Maddur Mohan S. , Tompkins Kristin R. , Martinez Lyndsey T. , Cai Hui , Hong Minah , Mensah Sonia , Cumbia Brittney , Falcao Larissa , Chang Jeanne S. , Fennell Kimberly F. , Huynh Kevin , McLellan Thomas J. , Sahasrabudhe Parag V. , Chen Wei , Cerswell Michael , Garcia Miguel A. , Li Shilong , Sharma Rahul , Li Weiqiang , Dizon Kristianne P. , Duarte Stacy , Gillett Frank , Smith Rachel , Illenberger Deanne M. , Sweeney Kari E. , Vogel Annette B. , Anderson Annaliesa S. , Sahin Ugur , Swanson Kena A.
Published: November 2023

As SARS-CoV-2 continues to evolve, increasing in its potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains the same mRNA backbone as the original BNT162b2 vaccine, modified by the incorporation of XBB.1.5-specific sequence changes in the encoded prefusion-stabilized SARS-CoV-2 spike protein (S(P2)). Biophysical characterization of Omicron XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation that adopts a flexible and predominantly open one-RBD-up state, with high affinity binding to the human ACE-2 receptor. When administered as a 4thdose in BNT162b2-experienced mice, the monovalent Omicron XBB.1.5 vaccine elicited substantially higher serum neutralizing titers against pseudotyped viruses of Omicron XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 and HV.1 sublineages and the phylogenetically distant BA.2.86 lineage than the bivalent Wild Type + Omicron BA.4/5 vaccine. Similar trends were observed against Omicron XBB sublineage pseudoviruses when the vaccine was administered as a 2-dose primary series in naïve mice. Strong S-specific Th1 CD4+and IFNγ+CD8+T cell responses were also observed. These findings, together with prior experience with variant-adapted vaccine responses in preclinical and clinical studies, suggest that the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine is anticipated to confer protective immunity against dominant SARS-CoV-2 strains.

ONE-SENTENCE SUMMARY

The monovalent Omicron XBB.1.5-adapted BNT162b2 mRNA vaccine encodes a prefusion-stabilized spike immunogen that elicits more potent neutralizing antibody responses against homologous XBB.1.5 and other circulating sublineage pseudoviruses compared to the bivalent Wild Type + Omicron BA.4/5 BNT162b2 vaccine, thus demonstrating the importance of annual strain changes to the COVID-19 vaccine.
Allosteric modulation of the CXCR4:CXCL12 axis by targeting receptor nanoclustering via the TMV-TMVI domain
Authors: García-Cuesta Eva M , Martínez Pablo , Selvaraju Karthik , Ulltjärn Gabriel , Gómez Pozo Adrián Miguel , D'Agostino Gianluca , Gardeta Sofia , Quijada-Freire Adriana , Blanco Gabella Patricia , Roca Carlos , del Hoyo Daniel , Jiménez-Saiz Rodrigo , García-Rubia Alfonso , Soler Palacios Blanca , Lucas Pilar , Ayala-Bueno Rosa , Santander Acerete Noelia , carrasco yolanda , Oscar Sorzano Carlos , Martinez Ana , Campillo Nuria E , Jensen Lasse D , Rodriguez Frade Jose Miguel , Santiago César , Mellado Mario
Published: November 2023

CXCR4 is a ubiquitously expressed chemokine receptor that regulates leukocyte trafficking and arrest in both homeostatic and pathological states. It also participates in organogenesis, HIV-1 infection and tumor development. Despite the potential therapeutic benefit of CXCR4 antagonists, only one, plerixafor (AMD3100), which blocks the ligand-binding site, has reached the clinic. Recent advances in imaging and biophysical techniques have provided a richer understanding of the membrane organization and dynamics of this receptor. Activation of CXCR4 by CXCL12 reduces the number of CXCR4 monomers/dimers at the cell membrane and increases the formation of large nanoclusters, which are largely immobile and are required for correct cell orientation to chemoattractant gradients. Mechanistically, CXCR4 activation involves a structural motif defined by residues in TMV and TMVI. Using this structural motif as a template, we performed in silico molecular modeling followed by in vitro screening of a small compound library to identify negative allosteric modulators of CXCR4 that do not affect CXCL12 binding. We identified AGR1.137, a small molecule that abolishes CXCL12-mediated receptor nanoclustering and dynamics and blocks the ability of cells to sense CXCL12 gradients both in vitro and in vivo while preserving ligand binding and receptor internalization.
Extraction and quantification of lineage-tracing barcodes with NextClone and CloneDetective
Authors: Putri Givanna H. , Pires Nichelle , Davidson Nadia M. , Blyth Catherine , Al’Khafaji Aziz M. , Goel Shom , Phipson Belinda
Published: November 2023

The study of clonal dynamics has significantly advanced our understanding of cellular heterogeneity and lineage trajectories. With recent developments in lineage-tracing protocols such as ClonMapper or SPLINTR, which combine DNA barcoding with single-cell RNA sequencing (scRNA-seq), biologists can trace the lineage and evolutionary paths of individual clones while simultaneously observing their transcriptomic changes over time. Here, we present NextClone and CloneDetective, an integrated highly scalable Nextflow pipeline and R package for efficient extraction and quantification of clonal barcodes from scRNA-seq data and DNA sequencing data tagged with lineage-tracing barcodes. We applied both NextClone and CloneDetective to data from a barcoded MCF7 cell line and demonstrate their utility for advancing clonal analysis in the era of high-throughput sequencing.

Availability and implementation

NextClone and CloneDetective are freely available and open-source on github (https://github.com/phipsonlab/NextCloneandhttps://github.com/phipsonlab/CloneDetective). Documentations and tutorials for NextClone and CloneDetective can be found athttps://phipsonlab.github.io/NextClone/andhttps://phipsonlab.github.io/CloneDetective/respectively.
Correlated evolution of beak and braincase morphology is present only in select bird clades
Authors: Xu Xiaoni , Natale Rossy
Published: November 2023

1

Complex morphological structures, such as skulls or limbs, are often composed of multiple morphological components (e.g. bones, sets of bones) that may evolve in a covaried manner with one another. Previous research has reached differing conclusions on the number of semi-independent units, or modules, that exist in the evolution of structures and on the strength of the covariation, or integration, between these hypothesized modules. We focus on the avian skull as an example of a complex morphological structure for which highly variable conclusions have been reached in the numerous studies analyzing support for a range of simple to complex modularity hypotheses. We hypothesized that past discrepancies may stem from both the differing densities of data used to analyze support for modularity hypotheses and the differing taxonomic levels of study. To test these hypotheses, we applied a comparative method to 3D geometric morphometric data collected from the skulls of a diverse order of birds (the Charadriiformes) to test support for 11 distinct hypotheses of modular skull evolution. Across all Charadriiformes, our analyses suggested that charadriiform skull evolution has been characterized by the semi-independent, but still correlated, evolution of the beak from the rest of the skull. When we adjusted the density of our morphometric data, this result held, but the strength of the signal varied substantially. Additionally, when we analyzed subgroups within the order in isolation, we found support for distinct hypotheses between subgroups. Taken together, these results suggest that differences in the methodology of past work (i.e. statistical method and data density) as well as clade-specific dynamics may be the reasons past studies have reached varying conclusions.
Sleep alterations as a function of 88 health indicators
Authors: Ujma Péter Przemyslaw , Bódizs Róbert
Published: November 2023

Alterations in sleep have been described in multiple health conditions and as a function of several medication effects. However, evidence generally stems from small univariate studies. Here, we apply a large-sample, data-driven approach to investigate patterns between changes in sleep macrostructure, quantitative sleep EEG and health. We use data from the MrOS Sleep Study, containing polysomnography and health data from a large sample (N=3086) of elderly American men to establish associations between sleep macrostructure, the spectral composition of the electroencephalogram, 38 medical disorders, 2 health behaviors and the use of 48 medications. Of sleep macrostructure variables, increased REM latency and reduced REM duration was the most common finding across health indicators, along with increased sleep latency and reduced sleep efficiency. We found that the majority of health indicators were not associated with objective EEG PSD alterations. Associations with the rest were highly stereotypical, with two principal components accounting for 85-95% of the PSD-health association. PC1 consists of a decrease of slow and an increase of fast PSD components, mainly in NREM. This pattern was most strongly associated with depression/SSRI medication use and age-related disorders. PC2 consists of changes in mid-frequency activity. Increased mid-frequency activity was associated with benzodiazepine use, while decreases are associated with cardiovascular problems and associated medications, in line with immune-mediated circadian demodulation in these disorders. Specific increases in sleep spindle frequency activity were associated with taking benzodiazepines and zolpidem. Sensitivity analyses supported the presence of both disorder and medication effects.
Isolating Single Cycles of Neural Oscillations in Population Spiking
Authors: Sabri Ehsan , Batista-Brito Renata
Published: November 2023

Neural oscillations are prominent features of brain activity, observable through frequency-specific power changes in electroencephalograms (EEG) and local field potentials (LFP). They also manifest as rhythmic coherence across brain regions. Although the identification of oscillations has primarily relied on EEG and LFP, the intrinsic relation between neural oscillations and neuronalspikingis noteworthy. We investigate the potential to detect individual cycles of neural rhythms solely through the spiking activity of neurons, leveraging recent advances in densely recording large populations of neurons within a local network. The numerous spikes from many neurons within a local network estimate the network’s activity over time, enabling the identification of cyclic patterns. Here, we utilize a Long Short Term Memory (LSTM) network to effectively isolate and align individual cycles of neural oscillations from the spiking of a densely recorded population of neurons. We applied this network to robustly isolate specific cycles in different brain regions of mice across different time scales, from gamma to ultra-slow rhythms spanning durations of up to hundreds of seconds. These ultra-slow rhythms, which are usually cut off in the LFP, are also detected in behavioral measures of arousal, such as pupil size and mouse facial motion, and show delayed coherence with corresponding rhythms in the population spiking. We used the isolated neural cycles to investigate two questions: 1) With isolated gamma cycles driven by sensory input, we achieved a more precise alignment of the trials in sensory stimulation experiments in the primary visual cortex (V1) of mice. This alignment compensates for the biological variation in the transmission times of sensory signals from the retina to V1 across trials. As a result, we retrieve more accurate neural dynamics in response to sensory stimulation. 2) We used the distinct cycles in population spiking of simultaneously recorded regions to measure the correlated spiking across brain regions separately on different time scales. We observed that the delay in population spiking between brain regions varies according to brain regions and different time scales.
The Hippo kinase LATS1 controls CTCF chromatin occupancy and the hormonal response of three-dimensionally grown breast cancer cells
Authors: Ramirez Julieta , Ferrari Roberto , Sanz Rosario T. , Valverde-Santiago Marta , Nacht A. Silvina , Castillo David , Le Dily Francois , Neguembor Maria Victoria , Malatesta Marco , Marti-Renom Marc A. , Beato Miguel , Vicent Guillermo P.
Published: November 2023

The cancer epigenome has been studied in cells cultured in 2D monolayers on plastic surfaces, but recent studies highlight the impact of the extracellular matrix (ECM) and the 3D environment on multiple cellular functions. Here, we report the physical, biochemical and genomic differences between T47D breast cancer cells cultured in 2D monolayer and as 3D spheroids in Matrigel. Cells within 3D spheroids exhibit a rounder nucleus with less accessible, more compacted chromatin, and altered expression of over 2,000 genes, the majority of which become repressed. Hi-C analysis reveals that cells grown in 3D exhibit enrichment in regions belonging to the B compartment, decrease on chromatin bound CTCF and increased fusion of Topologically Associating Domains (TADs). Upregulation of the Hippo pathway in 3D spheroids results in the activation of the LATS1 kinase, which promotes phosphorylation and displacement of CTCF from DNA, likely responsible for the observed TAD fusions. Cells grown in 3D exhibit higher progesterone receptor (PR) binding to chromatin, leading to an increase in the number hormone-regulated genes. This effect is in part mediated by the LATS1 activation, which favors cytoplasmic retention of YAP and CTCF removal.
Sensory encoding of emotion conveyed by the face and visual context
Authors: Soderberg Katherine , Jang Grace , Kragel Philip
Published: November 2023

Humans rapidly detect and interpret sensory signals that have emotional meaning. The posterior temporal sulcus (pSTS) and amygdala are known to be critical for this ability, but their precise contributions—whether specialized for facial features or sensory information more generally—remain contentious. Here we investigate how these structures process visual emotional cues using artificial neural networks (ANNs) to model fMRI signal acquired as participants view complex, naturalistic stimuli. Characterizing data from two archival studies (Ns = 20, 45), we evaluated whether representations from ANNs optimized to recognize emotion from either facial expressions alone or the broader visual context differ in their ability to predict responses in human pSTS and amygdala. Across studies, we found that representations of facial expressions were more robustly encoded in pSTS compared to the amygdala, whereas representations related to visual context were encoded in both regions. These findings demonstrate how the pSTS operates on abstract representations of facial expressions such as ‘fear’ and ‘joy’ to a greater extent than the amygdala, which more strongly encodes the emotional significance of visual information more broadly, depending on the context.