bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgical Treatment of Peripheral Vascular Malformations: A Systematic Review and Meta-Analysis
Authors: Lokhorst Max M. , Jolink Folkert , Horbach Sophie E. R. , Spuls Phyllis I. , van der Horst Chantal M. A. M.
Published: April 2021

Background:

Surgical treatment of peripheral vascular malformations is widely performed as primary and secondary treatments. Excellent results have been reported; however, it is thought that complications are likely to occur because of damage to adjacent structures. This systematic review aimed to elucidate the indications and outcomes of surgical treatment of vascular malformations.

Methods:

PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for studies reporting outcomes of surgery in at least 15 patients with a single type of peripheral soft-tissue vascular malformation. The authors extracted data on patient and lesion characteristics, treatment characteristics, and outcomes (including complications). Meta-analysis was conducted on recurrence and complication rates.

Results:

A total of 3042 articles were found, of which 24 were included: nine studies on arteriovenous malformations, seven on venous malformations, and eight on lymphatic malformations, totaling 980 patients. Meta-analyses showed pooled proportions for recurrences of 11 percent in arteriovenous malformations, 5 percent in venous malformations, and 9 percent in lymphatic malformations. Pooled proportions of major complications were 9 percent for arteriovenous malformations, 3 percent for venous malformations, and 1 percent for lymphatic malformations. The authors found a 5 percent pooled recurrence proportion in total resections, compared with 28 percent in subtotal resections. The pooled odds ratio for recurrence in total and subtotal resections showed a significant lower recurrence rate after total resection (odds ratio, 0.14, p = 0.02).

Conclusions:

Surgical treatment of vascular malformations appears to be effective and safe in many cases. However, it seems that surgery is performed predominantly in small lesions, and subtotal resection has a higher risk of recurrence than total resection.
An Evidence-Based Guide for Managing Phalangeal Fractures
Authors: Ganesh Kumar Nishant , Chung Kevin C.
Published: April 2021

Learning Objectives:

After studying this article, the participant should be able to: 1. Describe treatment options for phalangeal fractures. 2. Choose an appropriate fracture management plan that optimizes patient goals and range of motion. 3. Describe closed and open reduction techniques of commonly encountered phalangeal fracture patterns.

Phalangeal fractures are the second most common upper extremity fracture. Although many can be treated with splinting, operative intervention may be required for unstable fracture patterns and those involving the articular surface. Failure to appropriately treat these fractures can result in finger stiffness, loss in range of motion, and functional deficits. The type of fixation method can range from percutaneous pinning to open reduction and internal fixation. This article presents a series of cases to illustrate the appropriate management of phalangeal fractures using an evidence-based approach.
Teleconferencing for Virtual Visiting Professors and Virtual Grand Rounds
Authors: Knaus William J. , Cheng Angela
Published: April 2021

The 2020 global pandemic related to the coronavirus has led to unprecedented interruptions in typical patient care and resident education. Teleconferencing software was deployed by many institutions to comply with quarantine and social-distancing regulations. To supplement the loss of clinical experience for trainees, the authors implemented a novel virtual-educational programming using virtual visiting professors and virtual grand rounds. The authors describe the two different formats and advantages such as access to multiple speakers on diverse, innovative topics and decreased financial burdens to the host program. However, the authors do acknowledge some disadvantages from lack of face-to-face social interaction/networking and the need to consider time-zone differences. Both new programs were embraced by trainees at the authors’ own institution and residents/medical students across the United States and Canada and around the world. The authors believe teleconferencing should be permanently incorporated into future educational opportunities for plastic surgeons, as it provides easy access to high-quality information.
Preshaping DIEP Flaps: Simplifying and Optimizing Breast Reconstruction Aesthetics
Authors: Odobescu Andrei , Keith Jerrod N.
Published: April 2021

One key component of a successful autologous breast reconstruction is insetting the flap to accurately resemble an aesthetic breast. The authors describe a novel technique used to shape a deep inferior epigastric artery perforator flap into a coned breast mound before introducing it into the breast pocket. With the flap perfusing on the chest wall, an area of skin estimating the size and location of the skin paddle is marked. The skin to be buried is then deepithelialized. Once hemostasis is ensured, the shaping is performed. Two 2-0 polydioxanone sutures are anchored in the Scarpa fascia at the 10- and 2-o’clock positions and then run at the level of the Scarpa fascia to the 6-o’clock position. The two sutures are then cinched together to achieve the desired shape and then tied. The flap is then placed in the breast pocket and secured into place at the inferomedial and inferolateral corners, and at its cranial aspect. The size of the skin paddle can then be finalized. In the authors’ series of 21 breast reconstructions in 11 patients using flap preshaping, they have not seen any compromise in flap perfusion, with one patient showing a small area of secondary fat necrosis. In addition, the flaps maintained their aesthetic breast shape throughout follow-up. The authors believe this technique for shaping inferior epigastric artery perforator flaps before inset into the breast pocket to be both safe and predictable, simplifying one of the more tedious aspects of autologous breast reconstruction.
Face Transplant: Current Update and First Canadian Experience
Authors: Govshievich Alexander , Saleh Eli , Boghossian Elie , Collette Suzon , Desy Delphine , Dufresne Simon , St-Jacques Helen , Chollet Andre , Tremblay Dominique , Guertin Charles , Tardif Michele , Poirier Jean , Ayad Tareck , Rahal Akram , Borsuk Daniel E.
Published: April 2021

Facial vascularized composite allotransplantation has emerged as a groundbreaking reconstructive solution for patients with severely disfiguring facial injuries. The authors report on the first Canadian face transplant. A 64-year-old man sustained a gunshot wound, which resulted in extensive midface bony and soft-tissue damage involving the lower two-thirds of the face. In May of 2018, he underwent a face transplant consisting of Le Fort III and bilateral sagittal split osteotomies in addition to skin from the lower two-thirds of the face and neck. Virtual surgical planning was used to fabricate osteotomy guides and stereolithographic models. Microsurgical anastomoses of the facial (three branches) and infraorbital nerves were performed bilaterally. At 18-month follow-up, the aesthetic outcome was excellent. Partial restoration of light touch sensation had been observed over the majority of the allograft. Although significantly affected, animation, speech, mastication, and deglutition were continuously improving with intensive therapy. Nevertheless, the patient was now tracheostomy and gastrostomy free. Despite these limitations, he reported a high degree of satisfaction with the procedure and had reintegrated into the community. Four grade I episodes of acute rejection with evidence of endotheliitis were successfully treated. Postoperative complications were mainly infectious, including mucormycosis of the left thigh, treated with surgical resection and antifungal therapy. Undoubtedly, immunosuppression represents the greatest obstacle in the field and limits the indications for facial vascularized composite allotransplantation. Continuous long-term follow-up is mandatory for surveillance of immunosuppression-related complications and functional assessment of the graft.
Outcomes of Furlow Double-Opposing Z-Plasty Palatoplasty for the Treatment of Symptomatic Overt and Occult Submucous Cleft Palate: A Comparison Study
Authors: Brooker Jack E. , Bykowski Michael , Cray James J. , Beiriger Justin , Roy Eva , Ford Matthew D. , Grunwaldt Lorelei , Davit Alexander , Goldstein Jesse A. , Jabbour Noel , Losee Joseph E.
Published: April 2021

Background:

The submucous cleft palate can be overt or occult and may require surgical repair. The double-opposing Z-plasty (Furlow repair) is the authors’ center’s preferred approach. This study evaluated complication rates, differences in outcome between overt and occult types, and patient factors associated with surgical failure.

Methods:

This retrospective study reviewed documentation on all patients who underwent Furlow Z-plasty for submucous cleft palate at a single center between 2004 and 2018. Speech pathology was quantified using the Pittsburgh Weighted Speech Score.

Results:

A total of 351 patients were included (125 overt and 226 occult cases). Furlow Z-plasty was successful (postoperative Pittsburgh Weighted Speech Score <7 without recommendation for secondary speech surgery) in 291 patients (82.1 percent). Apart from those requiring secondary surgery, there were no documented complications. Occult-type patients were 7.5 years old at palatoplasty with a speech score of 14.1; overt-type patients were 6.5 years old with a score of 15.7. Postoperative speech scores were similar for both groups. Secondary speech surgery patients had a higher preoperative score (16.9 versus 14.2). Age at time of palatoplasty and submucous cleft palate type were not predictive of the need for secondary surgery. Syndromic patients had higher preoperative and postoperative speech scores (15.6 and 7.5, respectively) than nonsyndromic patients (14.3 and 4.3) and needed secondary surgery more often (24.4 percent versus 9.2 percent). V-shaped velar vaulting on preoperative assessment was present in 92 percent of occult-type patients.

Conclusions:

Furlow palatoplasty is a safe and effective means of repairing submucous cleft palate. Patients with the occult type presented later with a lower Pittsburgh Weighted Speech Score. High preoperative speech score and syndromic status were associated with the need for secondary speech surgery. V-shaped velar vaulting is a reliable sign of occult submucous cleft palate.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, II.
Complications During the Inpatient Rehabilitation Period in Neurological Subjects
Authors: Klaphajone Jakkrit , Wattanapan Pattra , Tunwattanapong Punjama , Wangno Wuttiganok , Kuptniratsaikul Vilai ,   the KPI Team for Rehabilitation Service Indicator
Published: April 2021

Objective

To explore common complications in people with neurological conditions during rehabilitation admission.

Methods:

All neurological subjects, including those with stroke, spinal cord injury (SCI), and traumatic brain injury, who were admitted for intensive and less-intensive rehabilitation programs during January to December 2012 were recruited. Both avoidable and unavoidable complications and related factors were assessed.

Results:

Among 1146 subjects, 65% was male with a mean age of 54.5 years. Almost 90% were admitted for intensive rehabilitation. The common avoidable complications that occurred were urinary tract infection (UTI) (12.8%), musculoskeletal pain (7.0%), neuropathic pain (2.3%), pneumonia (1.5%), and pressure injury (1.2%). Spasticity, which is an unavoidable complication, occurred in 2.1% of subjects. Older age, male gender, diagnosis of SCI, and longer stay were important factors related to complications.

Conclusions:

Most of the common complications during rehabilitation were avoidable complications, especially UTI and pain. A heightened level of awareness and vigilance should be exercised in older male subjects, those with prolonged hospital stay, and those with a diagnosis of SCI.
Functional Status and Instrumental Activities of Daily Living After Transcatheter Aortic Valve Replacement
Authors: Fukui Shogo , Kawakami Michiyuki , Hayashida Kentaro , Ishikawa Aiko , Mori Naoki , Oguma Yuko , Fukuda Keiichi , Tsuji Tetsuya
Published: April 2021

The purpose of this study was to investigate changes over time in instrumental activities of daily living (IADL), physical function, physical frailty, cognitive function, and nutritional status after transcatheter aortic valve implantation (TAVI). Fifty consecutive older patients with aortic stenosis as possible candidates for TAVI were prospectively enrolled. Their average age was 84.6 ± 3.1 years, and 39 (78%) were female. The results of the linear mixed-effects model for the isometric knee extension muscular strength showed a significant change. IADL and nutritional status were significantly different preoperatively compared with 6 months postoperatively after transfemoral TAVI.
Incidence and Risk Factors of Postoperative Dysphagia in Severe Aortic Stenosis
Authors: Nakamura Takuya , Kawakami Michiyuki , Fukui Shogo , Takeuchi Sho , Liu Fumio , Kawaguchi Shinji , Hayashida Kentaro , Shimizu Hideyuki , Fukuda Keiichi , Tsuji Tetsuya , Liu Meigen
Published: April 2021

The aim of this study was to examine the incidence and risk factors of postoperative dysphagia in cases of severe aortic stenosis. The subjects were 192 severe aortic stenosis patients who underwent either surgical aortic valve replacement or transcatheter aortic valve implantation. We evaluated the frequency of postoperative dysphagia using the Food Intake Level Scale. Stepwise multivariate logistic regression analysis was performed to identify independent predictors of postoperative dysphagia. The only independent predictor of postoperative dysphagia was procedure type. The operative procedure type is a risk factor for postoperative dysphagia in cases of severe aortic stenosis.
Investigative study into whether an insect repellent has virucidal activity against SARS-CoV-2
Authors: Smither Sophie J. , Eastaugh Lin S. , Findlay James S. , Laws Thomas R. , Marriott Stephen N. , Notman Stuart , O’Brien Lyn M. , Phelps Amanda L. , Richards Mark , Ulaeto David , Watts Pat , Lever Mark S. , Govan Norman
Published: April 2021

A small-scale study with Mosi-guard Natural spray, an insect repellent containing Citriodiol, was performed to determine if it has virucidal activity against SARS-CoV-2. A liquid test examined the activity of the insect repellent and the individual components for virucidal activity. A surface contact test looked at the activity of the insect repellent when impregnated on a latex surface as a synthetic skin for potential topical prophylactic application. Both Mosi-guard Natural spray and Citriodiol, as well as other components of the repellent, had virucidal activity in the liquid contact test. On a latex surface used to simulate treated skin, the titre of SARS-CoV-2 was less over time on the Mosi-guard Natural-treated surface but virus was still recovered.
Single dose of BNT162b2 mRNA vaccine against SARS-CoV2 induces neutralizing antibody and polyfunctional T-cell responses in patients with CML
Authors: Harrington Patrick , Doores Katie J. , Radia Deepti , O’Reilly Amy , Jeff Lam Ho Pui , Seow Jeffrey , Graham Carl , Lechmere Thomas , McLornan Donal , Dillon Richard , Shanmugharaj Yogita , Espehana Andreas , Woodley Claire , Saunders Jamie , Curto-Garcia Natalia , O’Sullivan Jennifer , Kordasti Shahram , Malim Michael H. , Harrison Claire , de Lavallade Hugues
Published: April 2021

Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including patients with Chronic Myeloid Leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS-CoV-2 BNT162b2 (Pfizer-BioNTech) vaccine have been raised.

We evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 CML patients. Seroconversion and cellular immune response prior and after vaccination were assessed.

By day 21 post-vaccination, anti-Spike IgG were detected in 14/16 (87.5%) of CML patients and all developed a neutralizing antibody response (ID50>50), including medium (ID50 of 200-500) or high (501-2000) neutralising antibodies titres in 9/16 (56.25%) patients. T cell response was seen in 14/15 (93.3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response 9/15, polyfunctional CD8+ T cell response 9/15).

These data demonstrate the immunogenicity of a single dose of SARS-CoV-2 BNT162b2 vaccine in most CML patients with both neutralizing antibodies and polyfunctional T-cell responses seen, in contrast to patients with solid tumour or lymphoid haematological malignancies.

Funding

King’s Together Rapid COVID-19 Call awards to MHM, KJD; A Huo Family Foundation Award to MHM, KJD; Chronic Disease Research Foundation award CDRF-22/2020 to KJD, MHM; Wellcome Trust Investigator Award 106223/Z/14/Z to MHM; CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1); Fondation Dormeur, Vaduz for funding equipment to KJD
Preexisting diabetes and COVID-associated hyperglycaemia in patients with COVID-19 pneumonia
Authors: Laurenzi Andrea , Caretto Amelia , Molinari Chiara , Bazzigaluppi Elena , Brigatti Cristina , Marzinotto Ilaria , Mercalli Alessia , Melzi Raffaella , Nano Rita , Tresoldi Cristina , Landoni Giovanni , Ciceri Fabio , Lampasona Vito , Scavini Marina , Piemonti Lorenzo
Published: April 2021

Abstract

Aim

The aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or preexisting diabetes.

Methods

A cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n=112) or COVID-associated hyperglycaemia (n=55) was studied. Clinical outcomes and laboratory findings were analysed according to the presence of the two conditions. The time to viral clearance was assessed during the follow-up after hospital discharge.

Result

Patients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between COVID-associated hyperglycaemia and the time to swab negativization.

Conclusions

The recognition of hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.
Genetic Determinants of Blood Cell Traits Influence Susceptibility to Childhood Acute Lymphoblastic Leukemia
Authors: Kachuri Linda , Jeon Soyoung , DeWan Andrew T. , Metayer Catherine , Ma Xiaomei , Witte John S. , Chiang Charleston W. K. , Wiemels Joseph L. , de Smith Adam J.
Published: April 2021

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of ALL (2666 cases, 60,272 controls) and multi-trait GWAS of 9 blood cell indices in the UK Biobank. We identified 3000 blood cell trait-associated (P<5.0×10−8) variants, explaining 4.0% to 23.9% of trait variation, and including 115 loci associated with blood cell ratios (LMR: lymphocyte/monocyte, NLR: neutrophil/lymphocyte, PLR: platelet/lymphocyte). ALL susceptibility was genetically correlated with lymphocyte counts (rg=0.088, p=4.0×10−4) and PLR (rg= −0.072, p=0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (Odds ratio (OR)=1.16, p=0.031) and strengthened after accounting for other cell types (OR=1.48, p=8.8×10−4). We observed positive associations with increasing LMR (OR=1.22, p=0.0017) and inverse effects for NLR (OR=0.67, p=3.1×10−4) and PLR (OR=0.80, p=0.002). Our study shows that a genetically induced shift towards higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.
Model-based evaluation of alternative reactive class closure strategies against COVID-19
Authors: Liu Quan-Hui , Zhang Juanjuan , Peng Cheng , Litvinova Maria , Huang Shudong , Poletti Piero , Trentini Filippo , Guzzetta Giorgio , Marziano Valentina , Zhou Tao , Viboud Cecile , Bento Ana I. , Lv Jiancheng , Vespignani Alessandro , Merler Stefano , Yu Hongjie , Ajelli Marco
Published: April 2021

There are contrasting results concerning the effect of reactive school closure on SARS-CoV-2 transmission. To shed light on this controversy, here we develop a data-driven computational model of SARS-CoV-2 transmission to investigate mechanistically the effect on COVID-19 outbreaks of school closure strategies based on syndromic surveillance and antigen screening of students. We found that by reactively closing classes based on syndromic surveillance, SARS-CoV-2 infections are reduced by no more than 13.1% (95%CI: 8.6%-20.2 %), due to the low probability of timely symptomatic case identification among the young population. We thus investigated an alternative triggering mechanism based on repeated screening of students using antigen tests. Should population-level social distancing measures unrelated to schools enable maintaining the reproduction number (R) at 1.3 or lower, an antigen-based screening strategy is estimated to fully prevent COVID-19 outbreaks in the general population. Depending on the contribution of schools to transmission, this strategy can either prevent COVID-19 outbreaks for R up to 1.9 or to at least greatly reduce outbreak size in very conservative scenarios about school contribution to transmission. Moving forward, the adoption of antigen-based screenings in schools could be instrumental to limit COVID-19 burden while vaccines continue to roll out through 2021, especially in light of possible continued emergence of SARS-CoV-2 variants.
Resolutive results with oral corticosteroids for patients with COVID-19 in pulmonary inflammatory phase. Successful outpatient experience during the collapse of Belém do Pará Health System - Brazil
Authors: Zeballos Roberto S. , Cruz Luciana N.L. , Brilhante Vânia C.R. , Adriana V. Lima , Martins Carlliane L.L.P. , Lima Karla N.A. , Leão Michele C.G.L. , Cruz Belinete L. , Dysarz Alessandra B. , Lobato Paulo C.B. , Almeida Erika S. , Costa Rute A.P. , Araújo Klevison C. , Almeida Augusto C.C. , Junior Leônidas B.D. , Harada Kathia O. , Araújo Rita H.V.S. , Prestes Elaine X. , Souza Ivete M.S. , Pereira Avany M.P. , Rocha Antônio B.M.A. , Estevão Iracema A. , Carvalho Fagnei I.C. , Melo Paulo M.P.
Published: April 2021

In the face of new diseases, medicine needs to reinvent itself in order to contain and control epidemics, such as the one we have recently faced, COVID-19, a disease with a wide spectrum of clinical severity. A new moment has been established, since the application of well known, effective and safe medications for other diseases, has shown high success rates in the treatment of COVID-19. Thereunto, studies with early intervention are needed, which can change the unfavorable outcome of patients. In this article, we report the successful experience using an oral strategy during the collapse of Belém do Pará Health System, Brazil. Two hundred and ten patients were diagnosed with respiratory failure due to COVID-19, with no option of hospital treatment due to lack of beds and resources. These patients were then started on therapeutic regimen consisting of prednisolone, enoxaparin and macrolides associated and followed in outpatient facilities. Two hundred and eight patients had excellent therapeutic response and there were only two fatalities. These results push research boundaries, valuing outpatient treatment with early use of prednisolone in the initial pulmonary phase, preventing severe COVID-19 pneumonitis. Adoption of the proposed treatment intends to reduce the need for hospitalization, as well as lethality, with social robust benefits and incalculable economic savings since involves the use of accessible, safe and not expensive medications.
Multidimensional Sleep Health: Concepts, Advances, and Implications for Research and Intervention
Authors: Chung Joon , Goodman Matthew , Huang Tianyi , Bertisch Suzanne , Redline Susan
Published: April 2021

The new paradigm of multidimensional sleep health (‘sleep health’) offers both challenges and opportunities for sleep science. Buysse (2014) has described sleep health to be multidimensional, framed as positive attributes, operationalizable into composite measures of global sleep health, sensitive to upstream exposures, and consequential for downstream health. We highlight two paradigm-shifting effects of a multidimensional sleep health perspective. The first is the use of composite sleep metrics which i) enable quantification of population shifts in sleep health, ii) with possibly reduced measurement error, iii) greater statistical stability, and iv) reduced multiple-testing burdens. The second is that sleep dimensions do not occur in isolation, that is, they are commonly biologically or statistically dependent. These dependencies complicate hypothesis tests yet can be leveraged to inform scale construction, model interpretation, and inform targeted interventions. To illustrate these points, we i) extended Buysse’s Ru SATED model; ii) constructed a conceptual model of sleep health; and iii) showed exemplar analyses from the Multi-Ethnic Study of Atherosclerosis (n=735). Our findings support that sleep health is a distinctively useful paradigm to facilitate interpretation of a multitude of sleep dimensions. Nonetheless, the field of sleep health is still undergoing rapid development and is currently limited by: i) a lack of evidence-based cut-offs for defining optimal sleep health; ii) longitudinal data to define utility for predicting health outcomes; and iii) methodological research to inform how to best combine multiple dimensions for robust and reproducible composites.
B cells adapt their nuclear morphology to organize the immune synapse and help antigen extraction
Authors: Ulloa Romina , Corrales Oreste , Cabrera Fernanda , Jara-Wilde Jorge , José Saez Juan , Rivas Christopher , Lagos Jonathan , Härtel Steffen , Quiroga Clara , Gomes Edgar R , Yuseff María-Isabel , Muñoz Jheimmy Diaz
Published: April 2021

Upon interaction with immobilized antigens B cells form an immune synapse, where actin remodeling and re-positioning of the microtubule-organizing center (MTOC) together with lysosomes can facilitate antigen extraction. B cells have restricted cytoplasmic space, mainly occupied by a large nucleus, yet the role of nuclear morphology in the formation of the immune synapse has not been addressed. Here we show that, upon activation, B cells re-orientate and adapt the size of their nuclear groove facing the immune synapse, where the MTOC sits and lysosomes accumulate. Silencing nuclear envelope proteins, Nesprin-1 and Sun-1, impairs nuclear reorientation towards the synapse and leads to defects in actin organization at this level. Consequently, B cells are unable to internalize the BCR after antigen activation. Nesprin-1 and Sun-1-silenced B cells also fail to accumulate the tethering factor Exo70 at the center of the synaptic membrane and display defective lysosome positioning, impairing efficient antigen extraction at the immune synapse. Thus, changes in nuclear morphology and positioning emerge as critical regulatory steps to coordinate B cell activation.
Clinical Trends Among U.S. Adults Hospitalized with COVID-19, March-December 2020
Authors: Garg Shikha , Patel Kadam , Pham Huong , Kirley Pam D. , Kawasaki Breanna , Yousey-Hindes Kimberly , Anderson Evan J. , Weigel Andrew , Ryan Patricia A. , Reeg Libby , Como-Sabetti Kathryn , Davis Sarah Shrum , Muse Alison , Bennett Nancy M. , Billing Laurie , Sutton Melissa , Talbot H. Keipp , Hill Mary , Wortham Jonathan , Kim Lindsay , Havers Fiona ,   COVID-NET Surveillance Team
Published: April 2021

Background

The COVID-19 pandemic has caused substantial morbidity and mortality.

Objectives

To describe monthly demographic and clinical trends among adults hospitalized with COVID-19.

Design

Pooled cross-sectional.

Setting

99 counties within 14 states participating in the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network (COVID-NET).

Patients

U.S. adults (aged ≥18 years) hospitalized with laboratory-confirmed COVID-19 during March 1-December 31, 2020.

Measurements

Monthly trends in weighted percentages of interventions and outcomes including length of stay (LOS), intensive care unit admissions (ICU), invasive mechanical ventilation (IMV), vasopressor use and in-hospital death (death). Monthly hospitalization, ICU and death rates per 100,000 population.

Results

Among 116,743 hospitalized adults, median age was 62 years. Among 18,508 sampled adults, median LOS decreased from 6.4 (March) to 4.6 days (December). Remdesivir and systemic corticosteroid use increased from 1.7% and 18.9% (March) to 53.8% and 74.2% (December), respectively. Frequency of ICU decreased from 37.8% (March) to 20.5% (December). IMV (27.8% to 8.7%), vasopressors (22.7% to 8.8%) and deaths (13.9% to 8.7%) decreased from March to October; however, percentages of these interventions and outcomes remained stable or increased in November and December. Percentage of deaths significantly decreased over time for non-Hispanic White patients (p-value <0.01) but not non-Hispanic Black or Hispanic patients. Rates of hospitalization (105.3 per 100,000), ICU (20.2) and death (11.7) were highest during December.

Limitations

COVID-NET covers approximately 10% of the U.S. population; findings may not be generalizable to the entire country.

Conclusions

After initial improvement during April-October 2020, trends in interventions and outcomes worsened during November-December, corresponding with the 3rd peak of the U.S. pandemic. These data provide a longitudinal assessment of trends in COVID-19-associated outcomes prior to widespread COVID-19 vaccine implementation.
Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome
Authors: Marié Isabelle J. , Brambilla Lara , Azzouz Doua , Chen Ze , Baracho Gisele , Arnett Azlann , Li Haiyan S. , Liu Weiguo , Cimmino Luisa , Chattopadhyay Pratip , Silverman Gregg , Watowich Stephanie S. , Khor Bernard , Levy David E.
Published: April 2021

Maintenance of immune homeostasis involves a synergistic relationship between the host and the microbiome. Canonical interferon (IFN) signaling controls responses to acute microbial infection, through engagement of the STAT1 transcription factor. However, the contribution of tonic levels of IFN to immune homeostasis in absence of acute infection remains largely unexplored. We report that STAT1 KO mice spontaneously developed an inflammatory disease marked by myeloid hyperplasia and splenic accumulation of hematopoietic stem cells. Moreover, these animals developed inflammatory bowel disease. Profiling gut bacteria revealed a profound dysbiosis in absence of tonic IFN signaling, which triggered expansion of TH17 cells and loss of splenic Tregcells. Resolution of dysbiosis by antibiotic treatment averted the TH17 bias, and blocking IL17 signaling prevented myeloid expansion and splenic stem cell accumulation. Thus, tonic IFNs regulate gut microbial ecology, which is crucial for maintaining physiologic immune homeostasis and preventing inflammation.
Rapid induction of antigen-specific CD4+T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination
Authors: Painter Mark M. , Mathew Divij , Goel Rishi R. , Apostolidis Sokratis A. , Pattekar Ajinkya , Kuthuru Oliva , Baxter Amy E. , Herati Ramin S. , Oldridge Derek A. , Gouma Sigrid , Hicks Philip , Dysinger Sarah , Lundgreen Kendall A. , Kuri-Cervantes Leticia , Adamski Sharon , Hicks Amanda , Korte Scott , Giles Josephine R. , Weirick Madison E. , McAllister Christopher M. , Dougherty Jeanette , Long Sherea , D’Andrea Kurt , Hamilton Jacob T. , Betts Michael R. , Bates Paul , Hensley Scott E. , Grifoni Alba , Weiskopf Daniela , Sette Alessandro , Greenplate Allison R. , Wherry E. John
Published: April 2021

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+T cell responses in all subjects after the first vaccine dose. CD8+T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+and CD8+T cell responses in SARS-CoV-2 naïve subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+T cells.

Graphical Abstract
Glycowork: A Python package for glycan data science and machine learning
Authors: Thomès Luc , Burkholz Rebekka , Bojar Daniel
Published: April 2021

As a biological sequence, glycans occur in every domain of life and comprise monosaccharides that are chained together to form oligo- or polysaccharides. While glycans are crucial for most biological processes, existing analysis modalities make it difficult for researchers with limited computational background to include information from these diverse and nonlinear sequences into standard workflows. Here, we present glycowork, an open-source Python package that was designed for the processing and analysis of glycan data by end users, with a strong focus on glycan-related data science and machine learning. Glycowork includes numerous functions to, for instance, automatically annotate glycan motifs and analyze their distributions via heatmaps and statistical enrichment. We also provide visualization methods, routines to interact with stored databases, trained machine learning models, and learned glycan representations. We envision that glycowork can extract further insights from any glycan dataset and demonstrate this with several workflows that analyze glycan motifs in various biological contexts. Glycowork can be freely accessed athttps://github.com/BojarLab/glycowork/.
Co-option of the Limb Patterning Program in Cephalopod Lens Development
Authors: Neal Stephanie , McCulloch Kyle J. , Napoli Francesca , Daly Christina M. , Coleman James H. , Koenig Kristen M.
Published: April 2021

Across the Metazoa, similar genetic programs are found in the development of analogous, independently evolved, morphological features. The functional significance of this reuse and the underlying mechanisms of co-option remain unclear. Here we identify the co-option of the canonical bilaterian limb pattering program redeployed during cephalopod lens development, a functionally unrelated structure. We show radial expression of transcription factorsSP6-9/sp1, Dlx/dll, Pbx/exd, Meis/hth, and aPrdlhomolog in the squidDoryteuthis pealeii, similar to expression required inDrosophilalimb development. We assess the role of Wnt signaling in the cephalopod lens, a positive regulator in the developing limb, and find the regulatory relationship reversed, with ectopic Wnt signaling leading to lens loss. This regulatory divergence suggests that duplication of SP6-9 in cephalopods may mediate this co-option. These results suggest that the limb network does not exclusively pattern appendage outgrowth but is performing a more universal developmental function: radial patterning.
A comprehensive analysis of gene expression changes in a high replicate and open-source dataset of differentiating hiPSC-derived cardiomyocytes
Authors: Grancharova Tanya , Gerbin Kaytlyn A. , Rosenberg Alexander B. , Roco Charles M. , Arakaki Joy , DeLizzo Colette , Dinh Stephanie Q. , Donovan-Maiye Rory , Hirano Matthew , Nelson Angelique , Tang Joyce , Theriot Julie A. , Yan Calysta , Menon Vilas , Palecek Sean P. , Seelig Georg , Gunawardane Ruwanthi N.
Published: April 2021

We performed a comprehensive analysis of the transcriptional changes within and across cell populations during human induced pluripotent stem cell (hiPSC) differentiation to cardiomyocytes. Using the single cell RNA-seq combinatorial barcoding method SPLiT-seq, we sequenced >20,000 single cells from 55 independent samples representing two differentiation protocols and multiple hiPSC lines. Samples included experimental replicates ranging from undifferentiated hiPSCs to mixed populations of cells at D90 post-differentiation. As expected, differentiated cell populations clustered by time point, with differential expression analysis revealing markers of cardiomyocyte differentiation and maturation changing from D12 to D90. We next performed a complementary cluster-independent sparse regression analysis to identify and rank genes that best assigned cells to differentiation time points. The two highest ranked genes between D12 and D24 (MYH7andMYH6) resulted in an accuracy of 0.84, and the three highest ranked genes between D24 and D90 (A2M, H19, IGF2) resulted in an accuracy of 0.94, revealing that low dimensional gene features can identify differentiation or maturation stages in differentiating cardiomyocytes. Expression levels of select genes were validated using RNA FISH. Finally, we interrogated differences in differentiation population composition and cardiac gene expression resulting from two differentiation protocols, experimental replicates, and three hiPSC lines in the WTC-11 background to identify sources of variation across these experimental variables.
Exploring the genomic diversity and antimicrobial susceptibility ofBifidobacterium pseudocatenulatumin the Vietnamese population to aid probiotic design
Authors: The Hao Chung , Ngoc Minh Chau Nguyen , Thi Hong Chau Tran , Thi Nguyen To Nguyen , Pike Lindsay J. , Zellmer Caroline , Duc Trung Pham , Tran Tuan-Anh , Thanh Tuyen Ha , Van Minh Pham , Thwaites Guy E. , Rabaa Maia A. , Hall Lindsay J. , Baker Stephen
Published: April 2021

Bifidobacterium pseudocatenulatumis a member of the human gut microbiota, and has previously been used as a probiotic to improve gut integrity and reduce inflammatory responses. We showed previously thatB. pseudocatenulatumwas significantly depleted during dysenteric diarrhea, suggesting the organism may aid in recovery from diarrhea. Here, in order to investigate its probiotic potential, we aimed to assess the genomic diversity and predicted metabolic profiles ofB. pseudocatenulatumfound colonizing the gut of healthy Vietnamese adults and children. We found that the population ofB. pseudocatenulatumfrom each individual was distinct and highly diverse, with intra-clonal variation attributed to gain or loss of carbohydrate utilizing enzymes. TheB. pseudocatenulatumgenomes were enriched with glycosyl hydrolases that target plant-based non-digestible carbohydrates (GH13, GH43), but not host-derived glycans. Notably, the exopolysaccharide biosynthesis region from organisms isolated from healthy children showed greater genetic diversity, and was subject to a high degree of genetic modification. Antimicrobial susceptibility testing revealed that the VietnameseB. pseudocatenulatumwere uniformly susceptible to beta-lactams, but exhibited variable resistance to azithromycin, tetracycline, ciprofloxacin and metronidazole. The genomic presence ofermXandtetvariants conferred resistance against azithromycin and tetracycline, respectively; ciprofloxacin resistance was associated with mutation(s) in the quinolone resistance determining region (GyrA, S115 and/or D119). Our work provides the first detailed genomic and antimicrobial resistance characterization ofB. pseudocatenulatumfound in the Vietnamese population, which could inform the next phase of rational probiotic design.

Importance

Bifidobacterium pseudocatenulatumis a probiotic candidate with potential applications in several health conditions, but its efficacy is largely strain-dependent and associated with distinct genomic and biochemical features. However, most commercial probiotics have been developed by Western institutions, which may not have ideal efficacy when administered in developing countries. This study taps into the underexplored diversity of the organism in Vietnam, and provides more understanding to its lifestyles and antimicrobial susceptibility. These data are key for selecting an optimal probiotic candidate, from our established collection, for downstream investigations and validation. Thus, our work represents a model in identifying and characterizing bespoke probiotics from an indigenous population in a developing setting.
Structuring time: The hippocampus constructs sequence memories that generalize temporal relations across experiences
Authors: Bellmund Jacob L. S. , Deuker Lorena , Montijn Nicole D. , Doeller Christian F.
Published: April 2021

The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.
Molecular reconstruction of recurrent evolutionary switching in olfactory receptor specificity
Authors: Prieto-Godino Lucia L. , Schmidt Hayden R. , Benton Richard
Published: April 2021

Olfactory receptor repertoires exhibit remarkable functional diversity, but how these proteins have evolved is poorly understood. Through analysis of extant and ancestrally-reconstructed drosophilid olfactory receptors from the Ionotropic Receptor (IR) family, we investigated evolution of two organic acid-sensing receptors, IR75a and IR75b. Despite their low amino acid identity, we identify a common “hotspot” in their ligand-binding pocket that has a major effect on changing the specificity of both IRs, as well as at least two distinct functional transitions in IR75a during evolution. Ligand-docking into IR models predicts that the hotspot does not contact odor molecules, suggesting that this residue indirectly influences ligand/receptor interactions. Moreover, we show that odor specificity is refined by changes in additional, receptor-specific sites, including those outside the ligand-binding pocket. Our work reveals how a core, common determinant of ligand-tuning acts within epistatic and allosteric networks of substitutions to lead to functional evolution of olfactory receptors.
Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations
Authors: Tomar Anupratap , Polygalov Denis , McHugh Thomas
Published: April 2021

Chronic and acute stress differentially affect behaviour, as well as the structural integrity of the hippocampus, a key brain region involved in cognition and memory. However, it remains unclear if and how the facilitatory effects of acute stress on hippocampal information coding are disrupted as the stress becomes chronic. To examine this, we compared the impact of acute and chronic stress on neural activity in the CA1 subregion of male mice subjected to a chronic immobilization stress paradigm. We observed that following first exposure to stress (acute stress), the spatial information encoded in the hippocampus sharpened and the neurons became increasingly tuned to the underlying theta oscillation in the local field potential (LFP). However, following repeated exposure to same stress (chronic stress), spatial tuning was poorer and the power of both the slow-gamma (30-50 Hz) and fast-gamma (55-90 Hz) oscillations, which correlate with excitatory inputs into the region, decreased. These results support the idea that acute and chronic stress differentially affect neural computations carried out by hippocampal circuits and suggest that acute stress may improve cognitive processing.
The uniqueBrucellaeffectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins
Authors: Louche Artur , Blanco Amandine , Lacerda Thais Lourdes Santos , Lionnet Claire , Bergé Célia , Rolando Monica , Lembo Frédérique , Borg Jean-Paul , Buchrieser Carmen , Nagahama Masami , Gorvel Jean-Pierre , Gueguen-Chaignon Virginie , Terradot Laurent , Salcedo Suzana P.
Published: April 2021

The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. The mechanisms controlling nuclear protein localisation in the context of stress responses induced upon bacterial infection are still poorly understood. Here we show that theBrucella abortuseffectors NyxA and NyxB interfere with the host sentrin specific protease 3 (SENP3), which is essential for intracellular replication. Translocated Nyx effectors directly interact with SENP3viaa defined acidic patch identified from the crystal structure of NyxB, preventing its nucleolar localisation at the late stages of the infection. By sequestering SENP3, the Nyx effectors induce the cytoplasmic accumulation of the nucleolar AAA-ATPase NVL, the large subunit ribosomal protein L5 (RPL5) and the ribophagy receptor NUFIP1 in Nyx-enriched structures in the vicinity of replicating bacteria. This shuttling of ribosomal biogenesis-associated nucleolar proteins is negatively regulated by SENP3 and dependent on the autophagy-initiation protein Beclin1, indicative of a ribophagy-derived process induced duringBrucellainfection. Our results highlight a new nucleomodulatory function by two uniqueBrucellaeffectors, and reveal that SENP3 is a critical regulator of the subcellular localisation of multiple nucleolar proteins duringBrucellainfection, promoting intracellular replication.