bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Combined Tumor Budding-Poorly Differentiated Clusters Grading System Predicts Recurrence and Survival in Stage I-III Colorectal Cancer
Authors: Shivji Sameer , Cyr David P. , Pun Cherry , Duan Kai , Sari Aysegul , Tomin Rossi , Ng Deanna , Brar Amanpreet , Zerhouni Siham , Kennedy Erin , Brar Mantaj , Swallow Carol J. , Conner James , Kirsch Richard
Published: May 2022

Tumor budding (TB) and poorly differentiated clusters (PDCs) are powerful prognostic factors in colorectal cancer (CRC). Despite their morphologic and biological overlap, TB and PDC are assessed separately and are distinguished by an arbitrary cutoff for cell cluster size. This cutoff can be challenging to apply in practice and its biological significance remains unclear. We developed a novel scoring system that incorporates TB and PDC into a single parameter (“Combined Score”; CS), eliminating the need for such cutoffs and allowing the prognostic value of PDC to be captured alongside TB. In a cohort of 481 stage I-III CRC resections, CS was significantly associated with American Joint Committee on Cancer (AJCC) stage, T-stage, N-stage, histologic grade, tumor deposits, lymphovascular invasion, and perineural invasion (P<0.0001). In addition, CS was significantly associated with decreased 5-year recurrence-free survival, overall survival, and disease-specific survival (P<0.0001). TB and PDC showed similar associations with oncologic outcomes, with hazard ratios consistently lower than for CS. The association between CS and oncologic outcomes remained significant in subgroup analyses stratified by AJCC stage, anatomic location (rectum/colon) and neoadjuvant therapy status. On multivariable analysis, CS retained its significant association with oncologic outcomes (P=0.0002, 0.005, and 0.009) for recurrence-free survival, disease-specific survival, and overall survival, respectively. In conclusion, CS provides powerful risk stratification in CRC which is at least equivalent to that of TB and PDC assessed individually. If validated elsewhere, CS has practical advantages and a biological rationale that may make it an attractive alternative to assessing these features separately.
Satisfaction With a Virtual Learning Collaborative Aimed at Implementing Treat-to-Target in Rheumatoid Arthritis
Authors: Ellrodt Jack , Pincus Theodore , Shadick Nancy A. , Stratton Jacklyn , Santacroce Leah , Katz Jeffrey N. , Smolen Josef , Solomon Daniel H. ,   For the TRACTION Virtual Learning Collaborative
Published: May 2022

Objective

Limited information is available concerning experiences of participants in a virtual learning collaborative (LC), and little qualitative data or participant feedback on how this format can be improved. One prior in-person LC in rheumatology successfully improved adherence with treat-to-target (TTT) for RA. We conducted a virtual LC on TTT and herein report on participant satisfaction.

Methods

We conducted a virtual LC with 18 rheumatology practices from across the United States during 2020 to 2021. The LC included a virtual kickoff meeting and monthly videoconferences, accompanied by data submission and feedback. At the conclusion of the LC, we surveyed the 45 LC participants concerning individual experience and satisfaction.

Results

All sites and 78% of participants responded to the surveys. The LC included small and large practices, 14 academic and 4 nonacademic, and respondents ranged in their roles: 24 physicians, 5 nurses or nurse practitioners, 3 administrators, and 3 other roles. Overall, 94% of respondents indicated they were either somewhat or very satisfied with the LC, and 94% said they would recommend a similar LC to a colleague. Aspects of the LC described as “very useful” included a kickoff meeting, intersite discussion, and monthly speakers; however, digital tools such as the Web site and meeting recordings were not found useful.

Conclusions

Virtual LCs are feasible, and participants reported strong satisfaction. Virtual LCs were highly valued by rheumatologists, trainees, and their practice staffs. Potential topics were identified for future LCs that could improve the quality of care delivered to rheumatology patients.
How Do Mexican Patients With Rheumatoid Arthritis Define Sexual and Reproductive Health? A Content Analysis Study
Authors: Ledón-LLanes Loraine Aitana , Contreras-Yáñez Irazú , Guaracha-Basáñez Guillermo Arturo , Valverde-Hernández Salvador Saúl , González-Marín Anayanci , Ballinas-Sánchez Ángel de Jesús , Durand Marta , Pascual-Ramos Virginia
Published: May 2022

Background

A patient-centered approach is essential for promoting sexual health (SH) and reproductive health (RH) in rheumatoid arthritis patients. The study aimed to describe and interpret Mexican rheumatoid arthritis outpatients' testimonies of their SH and RH definitions.

Methods

Qualitative and quantitative content analysis was conducted on free-text comments from 219 and 223 descriptions of patients' SH and RH definitions, respectively. A comprehensive system of major themes, categories, and subcategories was structured for each definition. The representational foundations of these categories and the context of their production were analyzed. Integration of quantitative and qualitative content analysis was used to comprehend patients' definitions of SH and RH. Internal review board approved the study.

Results

Ten major themes emerged for each definition, and their assigned frequencies differed between SH and RH definitions, and between groups of patients integrated according to age, education level, and sex. Both definitions had similar contents, expressed in the shared major themes and categories, and in managing at the same time SH- and RH-related contents within each definition. The “overall prevention-patient oriented care” major theme defined a common core for both definitions' contents. Meanwhile, a diversity of meanings was also evident particularly at the subcategory level.

Conclusions

In our population, SH content was distinguished by related diseases and their consequences, individual actions directed to prevention, and couple mentions. Meanwhile, RH was distinguished by a primarily biological perspective of the reproductive function, which was required at a particular life stage to concrete a family project.
Polysaccharide metabolism regulates structural colour in bacterial colonies
Authors: van de Kerkhof Gea T. , Schertel Lukas , Catòn Laura , Parton Thomas G. , Müller Karin H. , Greer Heather F. , Ingham Colin J. , Vignolini Silvia
Published: May 2022

The brightest colours in nature often originate from the interaction of light with materials structured at the nanoscale. Different organisms produce such coloration with a wide variety of materials and architectures. In the case of bacterial colonies, structural colours stem for the periodic organization of the cells within the colony, and while considerable efforts have been spent on elucidating the mechanisms responsible for such coloration, the biochemical processes determining the development of this effect have not been explored. Here, we study the influence of nutrients on the organization of cells from the structurally coloured bacteria
Flavobacterium
strain IR1. By analysing the optical properties of the colonies grown with and without specific polysaccharides, we found that the highly ordered organization of the cells can be altered by the presence of fucoidans. Additionally, by comparing the organization of the wild-type strain with mutants grown in different nutrient conditions, we deduced that this regulation of cell ordering is linked to a specific region of the IR1 chromosome. This region encodes a mechanism for the uptake and metabolism of polysaccharides, including a polysaccharide utilization locus (PUL operon) that appears specific to fucoidan, providing new insight into the biochemical pathways regulating structural colour in bacteria.
Phosphoproteomic mapping reveals distinct signaling actions and activation of protein synthesis and muscle hypertrophy by Isthmin-1
Authors: Zhao Meng , Danneskiold-Samsøe Niels Banhos , Ulicna Livia , Nguyen Quennie , Voilquin Laetitia , Lee David E. , White James P. , Jiang Zewen , Cuthbert Nickeisha , Paramasivam Shrika , Bielczyk-Maczynska Ewa , Van Rechem Capucine , Svensson Katrin J.
Published: May 2022

The secreted protein Isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53 % overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ∼ 450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this anti-diabetic circulating protein controls muscle biology.
Sustained pigmentation causes DNA damage and invokes translesion polymerase Pol κ for repair in melanocytes
Authors: Khanna Shivangi , Ghazi Madeeha , Subramanian Yogaspoorthi , Sultan Farina , Gupta Iti , Sharma Kanupriya , Chandna Sudhir , Gokhale Rajesh S , Natarajan Vivek T
Published: May 2022

The pigment melanin protects skin cells from ultraviolet (UV) radiation induced DNA damage. However, intermediates of eumelanin are highly reactive quinones that are potentially genotoxic. In this study, we systematically investigate the effect of sustained elevation of melanogenesis and map the consequent cellular repair response of melanocytes. Pigmentation increases DNA damage, causes cell cycle arrest, and invokes translesion polymerase Pol κ for DNA repair in primary human melanocytes, as well as mouse melanoma cells. Confirming the causal link, CRISPR-based genetic ablation of tyrosinase, the key melanin synthesizing enzyme results in depigmented cells with low Pol κ levels. However, silencing of Pol κ in pigmenting cells results in unchecked proliferation despite the presence of damaged DNA, that could potentially lead to genome instability. Thereby, our results indicate Pol κ to be a necessary evil to resolve melanin induced damage. Error-prone repair by Pol κ in part explains the mutational landscape observed in human melanoma. Thus, our study illuminates a hitherto unknown dark side of melanin and identifies (eu)melanogenesis as a key missing link between tanning response and mutagenesis mediatedviathe Pol κ-based low fidelity DNA repair response of melanocytes.

Key Highlights

Sustained melanogenesis causes DNA damage in melanocytes

Melanogenesis elicits replication stress and translesion repair by Pol κ

Pol κ resolves melanin-induced DNA damage and suppresses genome instability

Expression of Pol κ correlates with mutational load in human melanoma
Aspergillus fumigatus FhdA transcription factor is important for mitochondrial activity and codon usage regulation during the caspofungin paradoxical effect
Authors: Colabardini Ana Cristina , Van Rhijn Norman , LaBella Abigail L. , Valero Clara , Wang Fang , Dineen Lauren , Bromley Michael J. , Rokas Antonis , Goldman Gustavo H.
Published: May 2022

Aspergillus fumigatus is the main etiological agent of aspergillosis. The antifungal drug caspofungin (CSP) can be used against A. fumigatus and CSP tolerance is observed. Here, we show that the transcription factor FhdA is important for mitochondrial activity and regulates genes transcribed by RNA polymerase II and III. FhdA influences the expression of tRNAs that are important for mitochondrial function upon CSP. Our results show a completely novel mechanism that is impacted by CSP.
Reduced Neutralization of SARS-CoV-2 Omicron Variant in Sera from SARS-CoV-1 Survivors after 3-dose of Vaccination
Authors: Zhao Xuesen , Chen Danying , Hao Xiaohua , Qiu Yaruo , Du Juan , Zhang Yuanyuan , Xiao Fan , Li Xinglin , Song Yanjun , Song Rui , Wang Xi , Jin Ronghua
Published: May 2022

Recent studies found that Omicron variant escapes vaccine-elicited immunity. Interestingly, potent cross-clade pan-sarbecovirus neutralizing antibodies were found in survivors of the infection by SARS-CoV-1 after BNT162b2 mRNA vaccination (N Engl J Med. 2021 Oct 7;385(15):1401-1406). These pan-sarbecovirus neutralizing antibodies were observed to efficiently neutralize the infection driven by the S protein from both SARS-CoV and multiple SARS-CoV-2 variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta). However, whether these cross-reactive antibodies could neutralize the Omicron variant is still unknown. Based on the data collected from a cohort of SARS-CoV-1 survivors received 3-dose of immunization, our studies reported herein showed that a high level of neutralizing antibodies against both SARS-CoV-1 and SARS-CoV-2 were elicited by a 3rd-dose of booster vaccination of protein subunit vaccine ZF2001. However, a dramatically reduced neutralization of SARS-CoV-2 Omicron Variant (B.1.1.529) is observed in sera from these SARS-CoV-1 survivors received 3-dose of Vaccination. Our results indicates that the rapid development of pan-variant adapted vaccines is warranted.
SARS-CoV-2 Booster Effect and Waning Immunity in Hemodialysis Patients
Authors: Goggins Eibhlin , Sharma Binu , Ma Jennie Z. , Gautam Jitendra , Bowman Brendan
Published: May 2022

Background

Dialysis patients are extremely vulnerable to SARS-CoV-2 infection. We recently reported the results of a prospective cohort study measuring serial monthly semi quantitative IgG antibody levels to the SARS-CoV-2 spike protein receptor binding domain in fully vaccinated in-center hemodialysis patients after receiving the BNT162b2 (Pfizer-BioNTech) mRNA vaccination.

Methods

Prospective cohort study measuring the serologic response of hemodialysis patients to a booster dose of BNT162b2 vaccine at an average of 2, 6 and 11 weeks post vaccination.

Results

Of 35 hemodialysis patients in the original cohort, 27 (77.1%) received a third dose of BNT162b2. Antibody level significantly increased from pre-booster to 2 weeks post-booster (median (25th, 75th percentile) from 59.94 (29.69, 177.8) to 6216 (3806, 11730)), an average increase of 112 fold. Antibody levels dropped to a median of 2654 BAU/mL (1650, 8340) 6 weeks post-booster and to a median of 1444 BAU/mL (1102, 2020) between weeks 6 and 11 post-booster. Antibody levels at 11 weeks remained an average of 40 fold higher than pre-booster levels. Overall, antibody levels declined 47% month to month post-booster. Nine (33%) patients had negative or borderline detectable antibody levels pre-booster and 8 of 9 developed positive (>35.2 BAU/mL) antibody levels post-booster. Those with prior infection had a lower proportional increase in antibody level (51 fold) compared with the median change in COVID naïve patients (144 fold) from pre-booster to 2 weeks post-booster.

Conclusions

Our data demonstrates that hemodialysis patients obtain a robust humoral response from a third dose of the BNT162b2 vaccine although antibody levels wane over time.
Initial protection against Omicron in children and adolescents by BNT162b2
Authors: Amir Ofra , Goldberg Yair , Mandel Micha , Bar-On Yinon M. , Bodenheimer Omri , Freedman Laurence , Ash Nachman , Alroy-Preis Sharon , Huppert Amit , Milo Ron
Published: May 2022

BACKGROUND

The BNT162b2 (Pfizer-BioNTech) 2-dose vaccine for children and the BNT162b2 3rd dose for adolescents were approved shortly before the Omicron outbreak in Israel. The effects of these vaccines on the rates of Omicron confirmed infection are not yet clear.

METHODS

We extracted data for the Omicron-dominated (sub-lineage BA.1) period December 26, 2021 through January 8, 2022. We compared rates of confirmed Covid-19 infection between children 5-10 years old 14-35 days after receiving the 2nd dose to an internal control group of children 3-7 days after receiving the 1st dose (when the vaccine is not yet effective). Similarly, we compared confirmed infection rates in adolescents 12-15 years old 14-60 days after receiving a booster dose to an internal control group of adolescents 3-7 days after receiving the booster dose. We used Poisson regression, adjusting for age, sex, socioeconomic status, calendar week, and exposure.

RESULTS

In the 5-10 age group, the estimated rate of confirmed infection was 2.3 fold (95% CI, 2.0 to 2.5) lower in the 2nd dose group than in the internal control group. In adolescents, the third dose decreased confirmed infection rates by 3.3-fold (95% CI, 2.8 to 4.0).

CONCLUSIONS

A recent 2-dose BNT162b2 vaccination in children and a recent booster dose in adolescents reduced the rate of confirmed infection compared to the respective internal control groups. Future studies are needed to assess the duration of this protection and protection against other outcomes such as PIMS and long-COVID.
Endline Assessment of a Community-Based Program on Hypertension and Diabetes Management in Brazil
Authors: Flor Luisa Sorio , Wilson Shelley , Amorim Welma Wildes , Barone Mark TU , Bezerra Vanessa Moraes , Bhatt Paurvi , Bouskela Maria A Loguercio , Camarda Joseph N , Cimini Christiane CR , Cortes Matheus L , Daly Jessica , Endlich Patrick W , Fullman Nancy , Harris Katie Panhorst , Kochergin Clavdia N , Lima Marcia Maria Oliveira , Louzado José A , Maia Junia X , Marcolino Milena S , McNellan Claire R , de Medeiros Danielle Souto , Mistro Sostenes , Ng Marie , Oliveira Joao AQ , Oliveira Marcio Galvão , Phillips Bryan K , de O e Almeida Pinto Vânia S , Ribeiro Antonio Luiz P , Rumel Davi , Silva Kelle Oliveira , Soares Daniela Arruda , Thomson Blake , Gakidou Emmanuela
Published: May 2022

Background

Brazil HealthRise community-based program focused on improving technologies for care coordination, developing the local workforce, and identifying and educating individuals with hypertension and diabetes.

Objectives

To assess the impact of HealthRise on hypertension and diabetes management among patients in the region of Teófilo Otoni (TO) and in the city of Vitória da Conquista (VC).

Methods

Grantees routinely collected patient-level clinical in intervention areas from March 2017 to December 2018; endline qualitative interviews were conducted with patients, providers, administrators, and policymakers in both intervention and comparison sites. Paired t-tests were employed to measure the potential impact of the program on reducing systolic blood pressure (SBP) and hemoglobin A1c (HbA1c) between baseline and endline, and on increasing the percentage of enrollees meeting clinical targets (SBP < 140 mmHg for hypertension; < 8% HbA1c for diabetes). We analyzed qualitative data using thematic coding.

Results

Across sites, 2,764 hypertension patients and 244 diabetes patients were followed through endline. Participants experienced reductions in SBP in TO (−1.9 mmHg [−3.1;−0.7]) and VC (−4,2 mmHg [−5.2;−3.1]); more hypertension patients met treatment targets in these locations (TO: +3.9 percentage-points [0.4;7.2]; VC: +10.5 percentage-points [7.81;13.2]) by endline. HbA1c decreased in TO (−0.6 [−0.9;−0.4]) and VC (−0.9 [−1.4;−0.5]), and more individuals presented HbA1c < 8% by endline (TO: +10.2 percentage-points [3.8, 16.6]; VC: +25 percentage-points [12.2, 37.8]). Qualitative data pointed to overall enthusiasm for new technologies and care routine implemented by HealthRise, but challenges regarding program implementation, integration with other levels of care, and social determinants of health persisted.

Conclusions

Program showed positive effects on hypertension and diabetes outcomes. Community-based health interventions can help bridge healthcare gaps, but their full impact will remain limited until multisectoral policies and actions address underlying structural and social determinants of health more effectively.
Sox6 expression and aneurysms of the thoracic and abdominal aorta
Authors: Carmona-Berrio David , Adarve-Rengifo Isabel , Marshall Andrea G. , Vue Zer , Hall Duane D. , Miller-Fleming Tyne W. , Actkins Ky’Era V. , Beasley Heather K. , Almonacid Paula M. , Barturen-Larrea Pierina , Wells Quinn S. , Lopez Marcos G. , Garza-Lopez Edgar , Dai Dao-Fu , Shao Jianqiang , Neikirk Kit , Billings Federic T. , Curci John A. , Cox Nancy J. , Gama Vivian , Hinton Antentor , Gomez Jose A.
Published: May 2022

Background

Abdominal and thoracic aortic aneurysms (AAA; TAA) remain a large cause of deaths worldwide. This is in part a result of the lack of prognostic markers or early warning signs, leading to undiagnosed aortic aneurysms. Sox6 has been found to function as a regulator of renin expression controlling the rate limiting step in the renin angiotensin aldosterone system. We hypothesized that the transcription factor Sox6 may serve as an important regulator of mechanisms contributing to hypertension induced aortic aneurysms.

Methods

Our approach includes mRNA analysis, immunohistology staining, and protein expression studies in human samples from patients affected with AAA and TAA. In vivo, we use Angiotensin (II) to induce AAA in mice with a tamoxifen inducible Cre to specifically knock out Sox6 in smooth muscle cells. Additionally, we utilize large-scale biobank data linking de-identified medical records with genotype information to perform phenotype and laboratory-wide association scans to assess the effects of SOX6 expression in a clinical cohort.

Results

In a large biobank population, SOX6 gene expression is associated with aortic aneurysm in humans of European ancestry. Protein expression of Sox6 and TNFα was upregulated in tissue from patients affected by AAA and TAA. Moreover, we found that knocking out Sox6 in smooth muscle cells protected mice from hypertension-induced AAA, suggesting that Sox6 may be a molecular target in aortic aneurysms.

Conclusions

The data presented here suggest that the transcription factor Sox6 functions in the development of abdominal aortic aneurysms, and hypertension-induced rupture.

Clinical Perspective

Using electronic health records and biobank samples, we found that the transcription factor SOX6 is associated with abdominal and thoracic aortic aneurysm and its expression is upregulated in tissue from patients affected by those diseases.

Laboratory-wide association study (LabWAS) provides several clinical laboratory measurements associated with aortic aneurysm diagnosis that may be potential biomarkers for the disease.

Mice with smooth muscle-specific Sox6 knock out attenuated hypertension-induced abdominal aortic aneurysm. These novel mice may be useful tools to elucidate the mechanisms associated with abdominal aortic aneurysm.
Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease
Authors: ’t Hart LM , de Klerk JA , Bouland GA , Peerlings JHD , Blom M.T. , Cramer SJ , Bijkerk R , Beulens JWJ , Slieker RC
Published: May 2022

Introduction

Micro- and macrovascular complications are common among persons with type 2 diabetes. Recently there has been growing interest to investigate the potential of circulating small non-coding RNAs (sncRNAs) as contributors to the development of diabetic complications. In this study we investigate to what extent circulating sncRNAs levels associate with prevalent diabetic kidney disease (DKD) in persons with type 2 diabetes.

Methods

Plasma sncRNAs levels were determined using small RNA-seq, allowing detection of miRNAs, snoRNAs, piRNAs, tRNA-fragments and various other sncRNA classes. We tested for differentially expressed sncRNAs in persons with type 2 diabetes, with DKD (n=69) or without DKD (n=405). In secondary analyses, we also tested the association with eGFR, albuminuria (UACR) and the plasma proteome.

Results

In total seven sncRNAs were negatively associated with prevalent DKD (all PFDR≤0.05). Including one microRNA (miR-143-5p), five snoRNAs (U8, SNORD118, SNORD24, SNORD107, SNORD87) and a piRNA (piR-019825|DQ597218). Proteomic analyses showed that the seven sncRNAs, and especially the piRNA piR-019825, were associated with plasma levels of 24 proteins of which several have known associations with kidney function including TNF sR-I (TNFRFS1A), DAN (NBL1) and cystatin C (CST3).

Conclusion

We have identified novel small non-coding RNAs, primarily from classes other than microRNAs, that are associated with diabetic kidney disease. Our results shows that the involvement of small non-coding RNAs in DKD goes beyond the already known microRNAs and also involves other classes of sncRNA, in particular snoRNAs and the piRNA piR-019825, that have never been studied before in relation to kidney function.
Evaluation of triage checklist for mild COVID-19 outpatients in predicting subsequent emergency department visits and hospitalization during isolation period
Authors: Tanaka Yasuhiro , Yamamoto Kazuko , Morimoto Shimpei , Nabeshima Takeshi , Matsushima Kayoko , Ishimoto Hiroshi , Ashizawa Nobuyuki , Hirayama Tatsuro , Takeda Kazuaki , Gyotoku Hiroshi , Iwanaga Naoki , Takemoto Shinnosuke , Fukahori Susumu , Takazono Takahiro , Yamaguchi Hiroyuki , Kido Takashi , Sakamoto Noriho , Hosogaya Naoki , Akabame Shogo , Sugimoto Takashi , Yamanashi Hirotomo , Matsui Kosuke , Izumida Mai , Fujita Ayumi , Tashiro Masato , Tanaka Takeshi , Ariyoshi Koya , Furumoto Akitsugu , Morita Kouichi , Izumikawa Koichi , Yanagihara Katsunori , Mukae Hiroshi
Published: May 2022

Background and objective

Limited evidence exists regarding the outcomes of patients with coronavirus disease 2019 (COVID-19) who are not hospitalized. This study aimed to assess the outcomes for mild COVID-19 patients in terms of emergency department (ED) visits and hospital admission given initial outpatient triage evaluation and to identify the triage factors affecting these outcomes.

Methods

This retrospective cohort study investigated adult COVID-19 Japanese patients who were triaged at Nagasaki University Hospital between April 1, 2021, and May 31, 2021. A triage checklist with 30 factors was used to identify patients requiring hospitalization. Patients recommended for isolation were followed up for later ED visit or hospital admission.

Results

Overall, 338 COVID-19 patients (mean age, 44.7; 45% women) visited the clinic at an average of 5.4 days after symptom onset. Thirty-six patients (10.6%) were hospitalized from triage, and the rest were recommended for isolation. Seventy-two non-hospitalized patients (23.8%) visited ED during their isolation period, and 30 (9.9%) were hospitalized after ED evaluation. The mean duration to ED visit and hospitalization after symptom onset were 8.8 and 9.7 days, respectively. Checklist factors associated with hospitalization during the isolation period were age > 50 years, obesity with BMI > 25, underlying hypertension, tachycardia with HR > 100/min or blood pressure >135 mmHg at triage, and >□3-day delay in hospital visit after symptom onset.

Conclusion

Clinicians should be wary of COVID-19 patients with above risk factors and prompt them to seek follow-up assessment by a medical professional.

SUMMARY AT A GLANCE

Overall, 338 patients with mild COVID-19 were retrospectively followed up. Factors such as age >□50 years, BMI□> □25, underlying hypertension, high blood pressure and tachycardia at triage, and delayed visit after symptom onset were associated with emergency department visit and hospitalization during the isolation period.
Expected endpoints from future chikungunya vaccine trial sites informed by serological data and modeling
Authors: Tran Quan Minh , Soda James , Siraj Amir , Moore Sean , Clapham Hannah , Perkins T. Alex
Published: May 2022

In recent decades, there has been an increased interest in developing a vaccine for chikungunya. However, due to its unpredictable transmission, planning for a chikungunya vaccine trial is challenging. To inform decision making on the selection of sites for a vaccine efficacy trial, we developed a new framework for projecting the expected number of endpoint events at a given site. In this framework, we first accounted for population immunity using serological data collated from a systematic review and used it to estimate parameters related to the timing and size of past outbreaks, as predicted by an SIR transmission model. Then, we used that model to project the infection attack rate of a hypothetical future outbreak, in the event that one were to occur at the time of a future trial. This informed projections of how many endpoint events could be expected if a trial were to take place at that site. Our results suggest that some sites may have sufficient transmission potential and susceptibility to support future vaccine trials, in the event that an outbreak were to occur at those sites. In general, we conclude that sites that have experienced outbreaks within the past 10 years may be poorer targets for chikungunya vaccine efficacy trials in the near future. Our framework also generates projections of the numbers of endpoint events by age, which could inform study participant recruitment efforts.
Cardiac-Gated Spectroscopic Photoacoustic Imaging for Ablation-Induced Necrotic Lesion Visualization: In Vivo Demonstration in a Beating Heart
Authors: Gao Shang , Ashikaga Hiroshi , Suzuki Masahito , Mansi Tommaso , Kim Young-Ho , Ghesu Florin-Cristian , Kang Jeeun , Boctor Emad M. , Halperin Henry R. , Zhang Haichong K.
Published: May 2022

Radiofrequency (RF) ablation is a minimally invasive therapy for heart arrhythmia, including atrial fibrillation (A-fib), which creates lesions using an electric current to isolate the heart from abnormal electrical signals. However, conventional RF procedures do not involve intraoperative monitoring of the area and extent of ablation-induced necrosis, making the assessment of the procedure completeness challenging. Previous studies have suggested that spectroscopic photoacoustic (sPA) imaging is capable of differentiating ablated tissue from its non-ablated counterpart based on PA spectrum variation. Here, we aim to demonstrate the applicability of sPA imaging in an in vivo environment, where the cardiac motion presents, and introduce a framework for mapping the necrotic lesion using cardiac-gated sPA imaging. We computed the degree of necrosis, or necrotic extent (NE), by dividing the quantified ablated tissue contrast by the total contrast from both ablated and non-ablated tissues, visualizing it as continuous colormap to highlight the necrotic area and extent. To compensate for tissue motion during the cardiac cycle, we applied the cardiac-gating on sPA data, based on the image similarity. The in vivo validation of the concept was conducted in a swine model. As a result, the ablation-induced necrotic lesion at the surface of the beating heart was successfully depicted throughout the cardiac cycle through cardiac-gated sPA (CG-sPA) imaging. The results suggest that the introduced CG-sPA imaging system has great potential to be incorporated into clinical workflow to guide ablation procedures intraoperatively.
SCAMPP+FastTree: Improving Scalability for Likelihood-based Phylogenetic Placement
Authors: Chu Gillian , Warnow Tandy
Published: May 2022

Phylogenetic placement is the problem of placing “query” sequences into an existing tree (called a “backbone tree”), and is useful in both microbiome analysis and to update large evolutionary trees. The most accurate phylogenetic placement method to date is the maximum likelihood-based method pplacer, which uses RAxML to estimate numeric parameters on the backbone tree and then adds the given query sequence to the edge that maximizes the probability that the resulting tree generates the query sequence. Unfortunately, pplacer fails to return valid outputs on many moderately large datasets, and so is limited to backbone trees with at most ∼10,000 leaves. In TCBB 2022, Wedell et al. introduced SCAMPP, a technique to enable pplacer to run on larger backbone trees. SCAMPP operates by finding a small “placement subtree” specific to each query sequence, within which the query sequence are placed using pplacer. That approach matched the scalability and accuracy of APPLES-2, the previous most scalable method. In this study, we explore a different aspect of pplacer’s strategy: the technique used to estimate numeric parameters on the backbone tree. We confirm anecdotal evidence that using FastTree instead of RAxML to estimate numeric parameters on the backbone tree enables pplacer to scale to much larger backbone trees, almost (but not quite) matching the scalability of APPLES-2 and pplacer-SCAMPP. We then evaluate the combination of these two techniques – SCAMPP and the use of FastTree. We show that this combined approach, pplacer-SCAMPP-FastTree, has the same scalability as APPLES-2, improves on the scalability of pplacer-FastTree, and achieves better accuracy than the comparably scalable methods. Availability:https://github.com/gillichu/PLUSplacer-taxtastic.
A selective LIS1 requirement for mitotic spindle assembly discriminates distinct T-cell division mechanisms within the T-cell lineage
Authors: Argenty Jérémy , Rouquié Nelly , Bories Cyrielle , Mélique Suzanne , Duplan Valérie , Saoudi Abdelhadi , Fazilleau Nicolas , Lesourne Renaud
Published: May 2022

The ability to proliferate is a common feature of most T-cell populations. However, proliferation follows different cell-cycle dynamics and is coupled to different functional outcomes according to T-cell subsets. Whether the mitotic machineries supporting these qualitatively distinct proliferative responses are identical remains unknown. Here, we show that disruption of the microtubule-associated protein LIS1 leads to proliferative defects associated with a blockade of T-cell development after β-selection and of peripheral CD4+ T cell expansion after antigen priming. In contrast, cell divisions in CD8+ T cells occurred independently of LIS1 following T-cell antigen receptor stimulation, although LIS1 was required for proliferation elicited by pharmacological activation. In thymocytes and CD4+ T cells, LIS1-deficiency did not affect signaling events leading to activation but led to an interruption of proliferation after the initial round of division and to p53-induced cell death. Proliferative defects resulted from a mitotic failure, characterized by the presence of extra-centrosomes and the formation of multipolar spindles, causing abnormal chromosomes congression during metaphase and separation during telophase. LIS1 was required to stabilize dynein/dynactin complexes, which promote chromosome attachment to mitotic spindles and ensure centrosome integrity. Together, these results suggest that proliferative responses are supported by distinct mitotic machineries across T-cell subsets.
A generalizable framework to comprehensively predict epigenome, chromatin organization, and transcriptome
Authors: Zhang Zhenhao , Feng Fan , Qiu Yiyang , Liu Jie
Published: May 2022

Many deep learning approaches have been proposed to predict epigenetic profiles, chromatin organization, and transcription activity. While these approaches achieve satisfactory performance in predicting one modality from another, the learned representations are not generalizable across predictive tasks or across cell types. In this paper, we propose a deep learning approach named EPCOT which employs a pre-training and fine-tuning framework, and comprehensively predicts epigenome, chromatin organization, transcriptome, and enhancer activity in one framework. EPCOT is the first framework proposed to predict all of these genomic modalities and performs well in individual modality prediction, which is also generalizable to new cell and tissue types. EPCOT also maps from DNA sequence and chromatin accessibility profiles to generic representations which are generalizable across different modalities. Interpreting EPCOT model also provides biological insights including mapping between different genomic modalities, identifying TF sequence binding patterns, and analyzing cell-type specific TF impacts on enhancer activity.
Accurate inference of genome-wide spatial expression with iSpatial
Authors: Zhang Chao , Chen Renchao , Zhang Yi
Published: May 2022

Spatially resolved transcriptomic analyses can reveal molecular insights underlying tissue structure and context-dependent cell-cell or cell-environment interaction. Due to the current technical limitation, obtaining genome-wide spatial transcriptome at single-cell resolution is challenging. Here we developed a new algorithm named iSpatial to derive spatial pattern of the entire transcriptome by integrating spatial transcriptomic and single-cell RNA-seq datasets. Compared to other existing methods, iSpatial has higher accuracy in predicting gene expression and their spatial distribution. Furthermore, it reduces false-positive and false-negative signals in the original datasets. By testing iSpatial with multiple spatial transcriptomic datasets, we demonstrate its wide applicability to datasets from different tissues and by different techniques. Thus, we innovated a computational approach to reveal spatial organization of the entire transcriptome at single cell resolution without the need of new technology development. With numerous high quality datasets available in the public domain, iSpatial provides a unique way for understanding the structure, function of complex tissues and disease processes.

HIGHLIGHTS

iSpatial infers genome-wide spatial gene expression pattern by integrating spatial transcriptomic and scRNA-seq data

iSpatial outperforms existing approaches in inferring spatial gene expression patterns

iSpatial reduces false-positive/negative signals of the original spatial transcriptome

iSpatial is applicable to spatial transcriptomic datasets from different tissues and techniques
The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase
Authors: Khelashvili George , Kots Ekaterina , Cheng Xiaolu , Levine Michael V , Weinstein Harel
Published: May 2022

TMEM16F is a Ca2+-activated phospholipid scramblase in the TMEM16 family of membrane proteins. Unlike other TMEM16s exhibiting a membrane-exposed hydrophilic groove that serves as a translocation pathway for lipids, the experimentally determined structures of TMEM16F shows the groove in a closed conformation even under conditions of maximal scramblase activity. Here we describe the analysis of ∼400 µs all-atom ensemble molecular dynamics (MD) simulations of the TMEM16F dimer that revealed an allosteric mechanism leading to an open-groove state of the protein that is competent for lipid scrambling. The grove opens into a continuous hydrophilic conduit that is highly similar in structure to that seen in other activated scramblases. The allosteric pathway connects this opening to an observed destabilization of the Ca2+ ion bound at the distal site near the dimer interface, to the dynamics of specific protein regions that produces the open-groove state seen in our MD simulations to scramble phospholipids.
Role of Paravertebral muscle myostatin upregulation in the development of idiopathic scoliosis
Authors: Li Jiong , Xiang Gang , He Sihan , Yang Guanteng , Guo Chaofeng , Tang Mingxing , Zhang Hongqi
Published: May 2022

Paravertebral muscle (PVM) abnormalities play important roles in the pathogenesis of idiopathic scoliosis (IS), and elevated oxidative stress could result in PVM injury in IS patients, but the underlying mechanism of oxidative stress generation is still unclear. Increased apoptosis, impaired myogenesis and elevated oxidative stress were found in primary skeletal muscle mesenchymal progenitor cells (hSM-MPCs), which are essential for the myogenesis process of vertebrate skeletal muscles, of IS patients. Through RNA-sequencing and further analysis, we identified significantly upregulated myostatin (MSTN) in IS hSM-MPCs. Overexpression of MSTN in hSM-MPCs from control patients increased the expression of NADPH oxidase 4, promoted reactive oxygen species production and apoptosis, and suppressed myogenesis. However, MSTN knockdown decreased the expression of NADPH oxidase 4, inhibited reactive oxygen species production and apoptosis, and enhanced myogenesis in IS hSM-MPCs. In addition, overexpression of MSTN in the PVMs of mice induced elevated oxidative stress and scoliosis without abnormal vertebral structure. Altogether, our study suggested that abnormal PVM changes and accumulated oxidative stress in IS patients may result from upregulation of MSTN, which could contribute to the development of IS.
Machine learning models aimed at identifying risk factors for reducing morbidity and mortality still need to consider confounding related to calendar time variations
Authors: Rieckmann Andreas , Nguyen Tri-Long , Dworzynski Piotr , Fisker Ane Bærent , Rod Naja Hulvej , Ekstrøm Claus Thorn
Published: May 2022

Machine learning models applied to health data may help health professionals to prioritize resources by identifying risk factors that may reduce morbidity and mortality. However, many novel machine learning papers on this topic neither account for nor discuss biases due to calendar time variations. Often, efforts to account for calendar time (among other confounders) are necessary since patterns in health data – especially in low- and middle-income countries – may be influenced by calendar time variations such as temporal changes in risk factors and changes in the disease and mortality distributions over time (epidemiological transitions), seasonal changes in risk factors and disease and mortality distributions, as well as co-occurring artefacts in data due to changes in surveillance and diagnostics. Based on simulations, real-life data from Guinea-Bissau, and examples drawn from recent studies, we discuss how including calendar time variations in machine learning models is beneficial for generating more relevant and actionable results. In this brief report, we stress that explicitly handling temporal structures in machine learning models still remains to be considered (like in general epidemiological studies) to prevent resources from being misdirected to ineffective interventions.
Depressive and anxiety symptoms during the COVID-19 pandemic: A two-year follow-up
Authors: Bu Feifei , Steptoe Andrew , Fancourt Daisy
Published: May 2022

Background

There has been much research into the mental health impact of the COVID-19 pandemic and how it is related to time-invariant individual characteristics (e.g. age and gender). However, there is still a lack of research showing long-term trajectories of mental health across different stages of the pandemic. And little is known regarding the longitudinal association of time-varying contextual and individual factors (e.g. COVID-19 policy response and pandemic intensity) with mental health outcomes. This study aimed to provide a longitudinal profile of how depressive and anxiety symptoms changed by month between March 2020 and April 2022, and to examine their longitudinal associations with time-varying contextual and individual level factors.

Methods and findings

Drawing data from a large panel study of over 58,000 adults living in England, we showed that mental health changes were largely in line with changes in COVID-19 policy response and pandemic intensity. Further, data were analysed using fixed-effects, with models fitted separately across three stages of the COVID-19 pandemic. We found that more stringent policy response was associated with increased mental health symptoms, in particular during lockdown periods. Higher COVID-19 deaths were also associated with poorer mental health, but this association weakened over time. Finally, there was also evidence for the longitudinal association of mental health with individual level factors, including confidence in government/healthcare/essentials, COVID-19 knowledge, COVID-19 stress, COVID-19 infection and social support.

Conclusions

Our results provided empirical evidence on how changes in contextual and individual level factors were related to depressive and anxiety symptoms. While some factors clearly acted as consistent predictors of mental health during a pandemic, other factors were dependent on the specific situations occurring within society. This could provide important implications for policy making and for a better understanding of mental health of the general public during a national or global health crisis.
Bimodal electroencephalography-functional magnetic resonance imaging dataset for inner-speech recognition
Authors: Liwicki Foteini Simistira , Gupta Vibha , Saini Rajkumar , De Kanjar , Abid Nosheen , Rakesh Sumit , Wellington Scott , Wilson Holly , Liwicki Marcus , Eriksson Johan
Published: May 2022

The recognition of inner speech, which could give a ‘voice’ to patients that have no ability to speak or move, is a challenge for brain-computer interfaces (BCIs). A shortcoming of the available datasets is that they do not combine modalities to increase the performance of inner speech recognition. Multimodal datasets of brain data enable the fusion of neuroimaging modalities with complimentary properties, such as the high spatial resolution of functional magnetic resonance imaging (fMRI) and the temporal resolution of electroencephalography (EEG), and therefore are promising for decoding inner speech. This paper presents the first publicly available bimodal dataset containing EEG and fMRI data acquired nonsimultaneously during inner-speech production. Data were obtained from four healthy, right-handed participants during an inner-speech task with words in either a social or numerical category. Each of the 8-word stimuli were assessed with 40 trials, resulting in 320 trials in each modality for each participant. The aim of this work is to provide a publicly available bimodal dataset on inner speech, contributing towards speech prostheses.
Sperm collection and computer-assisted sperm analysis in the teleost model Japanese medaka (Oryzias latipes)
Authors: Closs Lauren , Sayyari Amin , Fontaine Romain
Published: May 2022

Japanese medaka (Oryzias latipes) are a teleost fish and an emerging vertebrate model for ecotoxicology, developmental, genetics, and physiology research. Medaka are also used extensively to investigate vertebrate reproduction, which is an essential biological function as it allows a species to perpetuate. Sperm quality is an important indicator of male fertility and thus reproduction success. Techniques for extracting sperm and sperm analysis are well documented for many species, including for teleost fish. Collecting semen is relatively simple in larger fish but can be more complicated in small model fish as they produce less sperm and are more delicate. This article therefore describes two methods of sperm collection in the small model fish Japanese medaka: testes dissection and abdominal massage. We demonstrate that both approaches are viable for medaka and show that abdominal massage can be performed a repeated number of times as the fish quickly recover from the procedure. We also describe a protocol for computer-assisted sperm analysis in medaka to objectively assess several important indicators of medaka sperm quality (motility, progressivity, duration of motility, relative concentration). The use of these procedures combined with the other advantages of using this small teleost model will greatly improve the understanding of the environmental, physiological, and genetic factors influencing fertility in vertebrate males.

This article describes two quick and efficient methods to collect semen from the small model fish medaka (Oryzias latipes), as well as a protocol to reliably assess sperm quality using computer-assisted sperm analysis (CASA).