bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in Pediatric Hospitalizations and Mortality during the COVID-19 Pandemic in an Urban Setting in Cameroon
Authors: Chiabi Andreas , Forgwei Mfie Nji , Bissong Marie , Niba Loveline , Abah Jevis Ning , Nsame Denis
Published: March 2022

Background

The first case of coronavirus disease 2019 (COVID-19) in Cameroon was recorded in March 2020. In response to the pandemic, most countries like Cameroon instituted a number of control measures to curb its spread accross the country. These COVID-19 control measures added to the fear of this disease within the population may have led to other detrimental health effects like: the pattern of hospitalizations and hospital outcomes.

Methods

We did a cross-sectional study with data from in-patient admission records of children admitted to the pediatric ward of the Regional Hospital Bamenda over a 24 months period (1st of March 2019 to the 28th of February 2021). The pre-pandemic period in Cameroon (that is, the first 12 months, from March 2019 to February 2020) and the pandemic period (that is, the last 12 months, from March 2020 to February 2021) were compared.

Results

A total of 2282 hospitalization records were included in the study. Most of the hospitalized children were males (57.23%). There was a 19.03% decline in pediatric hospitalizations during the first 12 months of the pandemic, which was statistically significant (p = 0.00024). The causes of hospitalizations and mortality remained similar over both periods, with severe malaria, the leading cause of admissions. Hospital deaths before and during the pandemic were 1.6% and 1.9%, respectively.

Conclusion

There was a statistically significant decline in pediatric hospitalizations during the first 12 months of the pandemic as compared to the same period before the pandemic. Hospital mortality and causes of hospitalizations remained similar over both the periods.
Salt- and Osmo-Responsive Sensor Histidine Kinases Activate the Bradyrhizobium diazoefficiens General Stress Response to Initiate Functional Symbiosis
Authors: Wülser Janine , Ernst Chantal , Vetsch Dominik , Emmenegger Barbara , Michel Anja , Lutz Stefanie , Ahrens Christian H. , Vorholt Julia A. , Ledermann Raphael , Fischer Hans-Martin
Published: March 2022

The general stress response (GSR) enables bacteria to sense and overcome a variety of environmental stresses. In alphaproteobacteria, stress-perceiving histidine kinases of the HWE and HisKA_2 families trigger a signaling cascade that leads to phosphorylation of the response regulator PhyR and, consequently, to activation of the GSR σ factor σEcfG. In the nitrogen-fixing bacterium Bradyrhizobium diazoefficiens, PhyR and σEcfG are crucial for tolerance against a variety of stresses under free-living conditions and also for efficient infection of its symbiotic host soybean. However, the molecular players involved in stress perception and activation of the GSR remained largely unknown. In this work, we first showed that a mutant variant of PhyR where the conserved phosphorylatable aspartate residue D194 was replaced by alanine (PhyRD194A) failed to complement the ΔphyR mutant in symbiosis, confirming that PhyR acts as a response regulator. To identify the PhyR-activating kinases in the nitrogen-fixing symbiont, we constructed in-frame deletion mutants lacking single, distinct combinations, or all of the 11 predicted HWE and HisKA_2 kinases, which we named HRXXN histidine kinases HhkA through HhkK. Phenotypic analysis of the mutants and complemented derivatives identified two functionally redundant kinases, HhkA and HhkE, that are required for nodulation competitiveness and during initiation of symbiosis. Using σEcfG-activity reporter strains, we further showed that both HhkA and HhkE activate the GSR in free-living cells exposed to salt and hyperosmotic stress. In conclusion, our data suggest that HhkA and HhkE trigger GSR activation in response to osmotically stressful conditions which B. diazoefficiens encounters during soybean host infection.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Secondary Analysis of Walking Activities During the Acute Stroke Hospital Stay and Cerebrovascular Health
Authors: Whitaker Alicen A. , Henry Madison L. , Morton Allegra , Ward Jaimie L. , Eickmeyer Sarah M. , Abraham Michael G. , Billinger Sandra A.
Published: March 2022

Purpose:

Physical activity within the hospital poststroke is recommended for cardiovascular and musculoskeletal health, but no studies have examined cerebrovascular health. We hypothesized that individuals who walked farther distances (FARhigh) during the acute phase of stroke recovery in a hospital setting would have a higher resting middle cerebral artery blood velocity (MCAv) and a greater cerebrovascular response (CVR) to moderate-intensity exercise at 3 months poststroke, compared with individuals who walked shorter distances (FARlow).

Methods:

At 3 months poststroke, we recorded 90 seconds of resting baseline (BL) MCAv, followed by 6 minutes of moderate-intensity exercise. We calculated CVR as the change in MCAv from BL to steady-state exercise. We retrospectively collected the farthest distance walked within the hospital poststroke from the electronic medical record. Participants were classified as FARhigh or FARlow based on the average farthest walking distance.

Results:

Twenty participants completed the study, aged 63 (15) years. Baseline MCAv was not different between groups (P = .07). In comparison with FARlow, we report a higher CVR in FARhigh's ipsilesional (

= 7.38 [5.42] vs

= 2.19 [3.53], P = .02)and contralesional hemispheres (

= 8.15 [6.37] vs

= 2.06 [4.76], P = .04).

Conclusions:

Physical activity during the hospital stay poststroke may support cerebrovascular health after discharge. Prospective studies are needed to support this finding.
RPNI, TMR, and Reset Neurectomy/Relocation Nerve Grafting after Nerve Transection in Headache Surgery
Authors: Gfrerer Lisa , Wong Frankie K. , Hickle Kelli , Eberlin Kyle R. , Valerio Ian L. , Austen William G.
Published: March 2022

Background:

In the context of headache surgery, greater occipital nerve (GON) transection is performed when the nerve appears severely damaged, if symptoms are recurrent or persistent, and when neuromas are excised. Lesser occipital nerve (LON) excision is commonly performed during the primary decompression surgery. Advanced techniques to address the proximal nerve stump after nerve transection such as regenerative peripheral nerve interface (RPNI), targeted muscle reinnervation (TMR), relocation nerve grafting, and reset neurectomy have been shown to improve chronic pain and neuroma formation. These techniques have not been described in the head and neck region.

Methods:

This article describes RPNI, TMR, and reset neurectomy with GON autograft relocation to prevent chronic pain and neuroma formation after GON/LON transection.

Results:

RPNI and TMR are feasible options in patients undergoing GON/LON transection. Further, relocation nerve grafting with GON autograft relocation is a method that is beneficial in patients with diffuse nerve injury requiring proximal nerve division.

Conclusion:

Advanced nerve reconstruction techniques should be considered in headache surgery following GON/LON transection.
ATYPICAL ENDOGENOUS FUNGAL ENDOPHTHALMITIS CAUSED BY CANDIDA RUGOSA
Authors: Koide Ryohei , Yamamoto Soichiro , Kobayashi Yoshiyuki , Irie Junji , Enaida Hiroshi
Published: March 2022

Purpose:

The purpose of this study was to report a case of atypical endogenous fungal endophthalmitis caused by Candida rugosa, a rare species of nonalbicans Candida.

Methods:

This report describes a case of a 45-year-old woman who presented with a reduced visual acuity in the right eye in addition to vitreous opacity during breast cancer treatment, which was suspected as fungal endophthalmitis from medical examination and history. Various tests were performed for diagnosis.

Results:

Blood test results were normal, including the blood beta-D-glucan level, and blood cultures were negative. Diagnosis could not be made using systemic computed tomography and magnetic resonance imaging results. Therefore, a lesion sample was collected by using vitrectomy. C. rugosa was identified through DNA (extracted from the lesion sample) analysis using Basic Local Alignment Search Tool. The visual acuity of the right eye improved after vitrectomy.

Conclusion:

We encountered a rare case of atypical endogenous fungal endophthalmitis caused by C. rugosa. Clinicians sometimes encounter invasive candidiasis caused by rare nonalbicans Candida species. DNA analysis using Basic Local Alignment Search Tool is effective for diagnosing such cases.
Corneal Biomechanics and Intraocular Pressure Following Scleral Lens Wear in Penetrating Keratoplasty and Keratoconus
Authors: Kumar Mukesh , Shetty Rohit , Lalgudi Vaitheeswaran G. , Roy Abhijit S. , Khamar Pooja , Vincent Stephen J.
Published: March 2022

Objective:

To compare corneal biomechanics and intraocular pressure (IOP) in keratoconus and penetrating keratoplasty eyes before and after nonfenestrated scleral lens wear.

Methods:

Twenty-three participants were enrolled, and 37 eyes were included in the analysis (11 penetrating keratoplasty and 26 keratoconus). A range of corneal biomechanical parameters and IOP were measured using the CORVIS ST before and after 8 hr of nonfenestrated scleral lens wear (Keracare, Acculens, Denver, CO).

Results:

Before lens wear, penetrating keratoplasty eyes displayed significantly greater median values for central corneal thickness (97 μm thicker, P=0.02), IOP (3.89 mm Hg higher, P=0.01), and biomechanical parameter A2 length (0.48 mm longer, P=0.003) compared with keratoconic eyes. No significant changes in corneal biomechanical parameters or IOP were observed after scleral lens wear in either group (all P>0.05).

Conclusion:

Although nonfenestrated scleral contact lenses can induce a subatmospheric pressure after lens settling and compress tissue surrounding the limbus, no significant changes were detected in the corneal biomechanical parameters studied using CORVIS ST after scleral lens wear in eyes with penetrating keratoplasty and keratoconus.
Outcomes of a multicenter U.S. clinical trial of a new monofocal single-piece hydrophobic acrylic IOL
Authors: Schallhorn Steven C. , Bonilla Michael , Pantanelli Seth M.
Published: March 2022

Purpose:

To evaluate the safety and effectiveness of the CT LUCIA 611P intraocular lens (IOL) in patients with cataracts.

Setting:

23 surgeons at 15 different clinical sites.

Design:

Prospective single-arm clinical trial.

Methods:

The study was conducted under an Investigational Device Exemption for premarket approval of a new hydrophobic acrylic IOL in the United States. Patients were followed for 12 months, and the main measured variables included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, manifest refraction, and adverse events.

Results:

In total, 339 eyes of 339 patients were implanted with the study device, of which 310 (91.4%) reached the 12-month visit. The percentage of eyes within ±0.50 diopter (D) and ±1.00 D of emmetropia was 85.8% (266/310) and 96.8% (300/310), respectively. Manifest refraction spherical equivalent (MRSE) remained stable over the first year with the mean 12-month MRSE of −0.03 ± 0.45 D. The mean 12-month UDVA and CDVA were 0.09 ± 0.15 (≈20/25) and −0.02 ± 0.09 (≈20/19) logMAR, respectively. Of all patients, 99.4% (308/310) achieved postoperative CDVA ≥20/40. The incidence of Nd:YAG capsulotomy within the first year was 3.5% (11/310). Only 2 eyes had IOL tilt present at the 12-month postoperative visit with no associated visual symptoms. There were 2 cases of IOL decentration; one required removal of the IOL, whereas the other had no visual side effects related to decentration. There were no findings of glistening at any visit.

Conclusions:

The CT LUCIA 611P IOL demonstrated excellent safety, efficacy, and stability of refractive outcomes. No significant issues related to the biocompatibility of the IOL material were observed.
Telemedicine Across the Cancer Care Continuum
Authors: Nekhlyudov Larissa , Fleisher Lee A. , Jacobsen Paul B.
Published: March 2022

In this commentary, we provide an overview about the surge of telemedicine services during the COVID-19 pandemic, describe the cancer care continuum and existing evidence regarding the use of telemedicine across the continuum, and offer our perspective on existing opportunities to advance the use of telemedicine in clinical care, research, and policy. While research implications are relevant to an international audience, our focus pertains specifically to health care delivery and policy in the United States.
3D-printed nails for aesthetic silicone prostheses
Authors: Lee Felix Austin , Leow Michael EL , Chiuan YEN Ching , Wang Wilson
Published: March 2022

Background and aim:

The nail is a crucially important part that needs to be closely reproduced in aesthetic silicone prostheses. The traditional method of producing prosthetic nails is a laborious process often fraught with errors and rejects. In this article, additive manufacturing or 3D printing intervention was sought to make this process less time-consuming and more exacting.

Study design and technique:

With a focus on finger prosthesis, the process involves reverse engineering a patient’s hand using a 3D scanner to obtain a digital blue print for referencing. 3D models of the nail shapes were created using CAD software. Colors sampling is obtained using image processing software from 2D digital images. Using specifically the inkjet technology from Stratasys, batches of nails of different sizes and colors were printed, which were then used for manual adhesion to silicone finger prostheses.

Results and conclusions:

This article has demonstrated that 3D printing is able to produce nails of comparable quality with those produced by traditional methods in size, shape, curvature, and thickness. More consistent thickness, better size, and shape-matching using 3D files also minimize rejects and grinding time when finishing a prosthesis, leading to significant time savings. However, 3D-printed nails fall short in color match, surface texture, and life-likeness. Traditionally produced nails that are made using a more translucent grade of acrylic than that used in the 3D-printed nails are better able to reproduce the life-like coloration of the translucent human nail. The limitations encountered with 3D printing as applied to prosthetic nails production relate to camera settings, digital image color capture and display, differences in color system used in the printer and monitor, ambient lighting, and suitability of acrylic grade used with the proprietary 3D printing system for material translucency or opacity.
Nocardioides mangrovi sp. nov., a novel endophytic actinobacterium isolated from root of Kandelia candel
Authors: Chen Ming-Sheng , Chen Feng , Chen Xiao-Hui , Zheng Zhou-Qing , Ma Xiao , Tuo Li
Published: March 2022

A novel species of endophytic actinobacterium, designated strain GBK3QG-3T, was isolated from surface-sterilized root of Kandelia candel collected from Beilun Estuary, Guangxi Zhuang Autonomous Region, PR China. Cells of strain GBK3QG-3T were Gram-stain-positive, aerobic, non-spore-forming and rod-shaped. Growth of GBK3QG-3T was observed at 10–40 °C (optimum, 30 °C), pH 5.0–9.0 (optimum, pH 7.0) and in the presence of 0–3 % (w/v) NaCl (optimum, 0 %). The G+C content of genomic DNA was determined to be 72.2 mol%. On the basis of 16S rRNA gene sequence analysis, strain GBK3QG-3T was most related to the type strain of

Nocardioides agrisoli

CCTCC AB 2017058T (97.7 % 16S rRNA gene sequence similarity), followed by

Nocardioides ginkgobilobae

SYP-A7303T (97.0 %) and

Nocardioides aquiterrae

GW-9T (96.9 %). Average nucleotide identity and digital DNA–DNA hybridization values between strain GBK3QG-3T and some strains of the genus

Nocardioides

with publicly available genomes were below 84.3 and 30.0 %, respectively. The cell-wall peptidoglycan contained ll-diaminopimelic acid. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unknown phospholipid and an unknown lipid. The major menaquinone was identified as MK-8(H4), and the major fatty acids were identified as iso-C16 : 0, iso-C17 : 0 and anteiso-C17 : 0. Based on evidence collected from the phenotypic, genotypic and phylogenetic analyses, we propose a novel species named Nocardioides mangrovi sp. nov. The type strain is GBK3QG-3T (=CGMCC 4.7708T=JCM 34553T).
COVID-19 Vaccine Effectiveness against the Omicron BA.2 variant in England
Authors: Kirsebom Freja C. M. , Andrews Nick , Stowe Julia , Toffa Samuel , Sachdeva Ruchira , Gallagher Eileen , Groves Natalie , O’Connell Anne-Marie , Chand Meera , Ramsay Mary , Bernal Jamie Lopez
Published: March 2022

The BA.1 sub-lineage of the Omicron (B.1.1.529) variant, first detected in the UK in mid-November 2021, rapidly became the dominant strain partly due to reduced vaccine effectiveness. An increase in a second Omicron sub-lineage BA.2 was observed in early January 2022. In this study we use a test-negative case control study design to estimate vaccine effectiveness against symptomatic disease with BA.1 and BA.2 after one or two doses of BNT162b2, ChAdOx1-S or mRNA-1273, and after booster doses of BNT162b2 or mRNA-1273 during a period of co-circulation. Overall, there was no evidence that vaccine effectiveness against symptomatic disease is reduced following infection with the BA.2 sub-lineage as compared to BA.1. Furthermore, similar rates of waning were observed after the second and booster dose for each sub-lineage. These data provide reassuring evidence of the effectiveness of the vaccines currently in use against symptomatic disease caused by BA.2.
Inverse proportionality between height and duration of epidemic peaks not observed for the COVID-19 epidemic in Japan
Authors: Tomie Toshihisa
Published: March 2022

The height of the epidemic peaks varied ten-fold, but the duration was almost constant independent of the peak height in the six times COVID-19 epidemics in Japan over the past two years. The observed relation between the peak height and duration contradicts the inverse proportionality, which is the essential conclusion derived from mathematical models for infectious diseases. We found that the peak height was inversely proportional to the number of rhinovirus patients. The literature has revealed the mechanism behind our found power of rhinovirus suppressing COVID-19. We discuss that the critical flaw of current mathematical models originates in the absence of the 0th power term of the number of infected people in the Kermack and McKendrick equation.
How the West(ern) Was Won: Solutions for Immunoblotting Large and Small Proteins
Authors: Llabata Paula , Llinàs-Arias Pere
Published: March 2022

Relative protein quantification is a well-established technique in the vast majority of the molecular biology laboratories. However, western blot standard protocols may be unable to detect certain proteins depending on their size. When the protein of interest is out of 10-250 KDa range, its migration through the gel or transfer to the membrane are compromised, thus making its detection difficult. Here we present a set of modifications of the standard working procedure for western blotting based on the experience working with Small VCP Interacting Protein (SVIP) and Max-Gene Associated Protein (MGA), whose molecular weight are 8 and 350 kDa, respectively. We expect that these adaptations may help researchers to improve their experiments in a cost-effective manner.
The lectin LecB induces patches with basolateral characteristics at the apical membrane to promote Pseudomonas aeruginosa host cell invasion
Authors: Thuenauer Roland , Kühn Katja , Guo Yubing , Kotsis Fruzsina , Xu Maokai , Trefzer Anne , Altmann Silke , Wehrum Sarah , Heshmatpour Najmeh , Faust Brian , Landi Alessia , Diedrich Britta , Dengjel Jörn , Kuehn E. Wolfgang , Imberty Anne , Römer Winfried
Published: March 2022

The opportunistic bacterium Pseudomonas aeruginosa can infect mucosal tissues of the human body. To persist at the mucosal barrier, this highly adaptable pathogen has evolved many strategies, including invasion of host cells. Here, we show that the P. aeruginosa lectin LecB binds and cross-links fucosylated receptors at the apical plasma membrane of epithelial cells. This triggers a signaling cascade via Src kinases and PI3K leading to the formation of patches enriched with the basolateral marker PIP3 at the apical plasma membrane. This identifies LecB as causative bacterial factor for activating this well-known host cell response that is elicited upon apical binding of P. aeruginosa. Downstream of PI3K, Rac1 is activated to cause actin rearrangement and the outgrowth of protrusions at the apical plasma membrane. LecB-triggered PI3K activation also results in aberrant recruitment of caveolin-1 to the apical domain. In addition, we reveal a positive feedback loop between PI3K activation and apical caveolin-1 recruitment, which provides a mechanistic explanation for the previously observed implication of caveolin-1 in P. aeruginosa host cell invasion. Interestingly, LecB treatment also reversibly removes primary cilia. To directly prove the role of LecB for bacterial uptake, we coated bacteria-sized beads with LecB, which drastically enhanced their endocytosis. Furthermore, LecB deletion and LecB inhibition with L-fucose diminished the invasion efficiency of P. aeruginosa bacteria. Taken together, our study identifies LecB as missing link that can explain how PI3K signaling and caveolin-1 recruitment are triggered to facilitate invasion of epithelial cells from the apical side by P. aeruginosa.

Importance

An intriguing feature of the bacterium P. aeruginosa is its ability to colonize highly diverse niches. P. aeruginosa can, besides biofilm formation, also enter and proliferate within epithelial host cells. Moreover, research during recent years has shown that P. aeruginosa possesses many different mechanisms to invade host cells. In this study we identify LecB as novel invasion factor. In particular, we show that LecB activates PI3K signaling, which is connected via a positive feedback loop to apical caveolin-1 recruitment, and leads to actin rearrangement at the apical plasma membrane. This provides a unifying explanation for the previously reported implication of PI3K and caveolin-1 in P. aeruginosa host cell invasion. In addition, our study adds a further function to the remarkable repertoire of the lectin LecB, which is all brought about by the capability of LecB to recognize fucosylated glycans on many different niche-specific host cell receptors.
International Travel-Related Control Measures to contain The Covid-19 Pandemic: An update to a Cochrane Rapid Review
Authors: Hohlfeld Ameer , Abdullahi Leila , Abou-Setta Ahmed M. , Engel Mark E
Published: March 2022

Background

COVID-19 has proven to be more difficult to manage for many reasons including its high infectivity rate. One of the potential ways to limit its spread is by controlling international travel. The objective of this systematic review is to identify, critically-appraise and summarize evidence on international travel-related control measures.

Methods

This review is based on the Cochrane review: International travel-related control measures to contain the COVID-19 pandemic and followed the same methods. In brief, we searched for clinical and modelling studies in general health and COVID-19-specific bibliographic databases. The primary outcome categories were (i) cases avoided, (ii) a shift in epidemic development and, (iii) cases detected. Secondary outcomes were other infectious disease transmission outcomes, healthcare utilisation, resource requirements and adverse effects if identified in studies assessing at least one primary outcome.

Results

We assessed 66 full-text articles that met with our inclusion criteria. Seventeen new studies (modelling = 9, observational = 8) were identified in the updated search. Most studies were of critical to moderate risk of bias. The added studies did not change the main conclusions of the Cochrane review nor the quality of the evidence (very low to low certainty). However, it did add to the evidence base for most outcomes.

Conclusions

Weak evidence supports the use of international travel-related control measures to limit the spread of COVID-19 via air travel. Real-world studies are required to support these conclusions.
Relative Effectiveness of Four Doses Compared to Three Dose of the BNT162b2 Vaccine in Israel
Authors: Gazit Sivan , Saciuk Yaki , Perez Galit , Peretz Asaf , Pitzer Virginia E. , Patalon Tal
Published: March 2022

Objectives

The rapid spread of the Omicron variant (B.1.1.529) alongside evidence of a relatively rapid waning of the third dose prompted Israel to administer a fourth dose of the BNT162b2 vaccine on January 2022. Thus far, sufficient real-world evidence demonstrating the effectiveness of a fourth dose against infection and severe COVID-19 are lacking. This study examined the short-term effectiveness of a fourth dose compared to three doses over the span of 10 weeks.

Design

A retrospective test-negative case-control study, performing both a matched analysis and an unmatched multiple-tests analysis.

Setting

Nationally centralized database of Maccabi Healthcare Services (MHS), an Israeli national health fund that covers 2.5 million people.

Participants

The study population included 97,499 MHS members aged 60 or older who were eligible to receive a fourth vaccine dose and performed at least one PCR test during the study period. Of them, 27,876 received the fourth dose and 69,623 received only three doses.

Main outcomes and measures

Analyses focused on the period from January 10, 2022 (7 days after the fourth dose was first administered to eligible individuals) to March 13, 2022, an Omicron-dominant period in Israel. We evaluated two SARS-CoV-2-related outcomes: (1) breakthrough infection, defined as a positive PCR test performed 7 or more days after inoculation with the BNT162b2 vaccine; and (2) breakthrough infection resulting in a severe disease, defined as COVID-19-related hospitalization or COVID-19 associated mortality.

Results

A fourth dose provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, vaccine effectiveness against infection varied over time, peaking during the third week with a VE of 64% (95% CI: 62.0%-65.9%) and declining to 29.2% (95% CI: 17.7%-39.1%) by the end of the 10-week follow-up period. Unlike VE against infection, the relative effectiveness of a fourth dose against severe COVID-19 was maintained at high level (>73%) throughout the 9-week follow-up period. Importantly, severe disease was a relatively rare event, occurring in <1% of both fourth dose and third dose only recipients.

Conclusions

A fourth dose of the BNT162b2 vaccine provided considerable additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, effectiveness of the fourth dose against infection wanes sooner than that of the third dose.
Production of anti-spike antibodies in response to COVID vaccine in lymphoma patients
Authors: Pia Alexandra Della , (Geeny) Kim Gee Youn , Ip Andrew , Ahn Jaeil , Liu Yanzhi , Kats Simone , Koropsak Michael , Lukasik Brittany , Contractor Anamta , Amin Krushna , Ayyagari Lakshmi , Zhao Charles , Gupta Amolika , Batistick Mark , Leslie Lori A. , Goy Andre , Feldman Tatyana
Published: March 2022

Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. There is limited data on the efficacy of the COVID vaccines in lymphoma patients, and to suggest the optimal timing of vaccination to elicit immunity in patients receiving immunochemotherapy. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody titer following the primary COVID vaccination series. The primary series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher’s exact test, and unadjusted and adjusted logistic regression models were used for univariate (UVA) and multivariate (MVA) analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt’s, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); and 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p=0.04). Lymphoma patients are capable of mounting a humoral response to the COVID mRNA vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.
The modified COVID-19 Yorkshire Rehabilitation Scale (C19-YRSm) patient-reported outcome measure for Long Covid or Post-COVID syndrome
Authors: Sivan Manoj , Preston Nick , Parkin Amy , Makower Sophie , Gee Jeremy , Ross Denise , Tarrant Rachel , Davison Jennifer , Halpin Stephen , O’Connor Rory J , Horton Mike
Published: March 2022

Background

The C19-YRS was the first validated scale reported in the literature for patient assessment and monitoring in Long Covid or Post-COVID syndrome. The 22-item scale contains four subscales measuring symptom severity, functional disability, overall health and additional symptoms.

Objectives

This study aimed to modify and refine the scale based on psychometric properties, emerging evidence on additional Long Covid symptoms, and feedback from a working group of patients and healthcare professionals.

Methods

Data were collected from 370 patients who completed the C19-YRS scale in a community Long COVID service. The psychometric properties of the Symptom Severity and Functional Disability subscales were assessed using a Rasch Measurement Theory framework, where all individual scale items were assessed for model fit, local dependency, response category functioning and differential item functioning (DIF) by age group and sex. Additionally, the subscales were assessed for targeting, reliability and unidimensionality. The overall health subscale is a single item, and the additional symptoms subscale is not intended to be summed, therefore neither is appropriate for Rasch analyses. Psychometric results and implications were relayed back to the working group for discussion, alongside clinical evidence of emerging and relevant symptoms not covered by the original C19-YRS.

Results

Rasch analysis revealed promising psychometric properties of the symptom severity and functional disability subscales, with both displaying good targeting and reliability, although some individual measurement anomalies were noted. The original 0-10 item response category structure did not operate as intended for both the subscales. Post-hoc rescoring suggested that a 4-point response category structure would be more appropriate for both the subscales, and this aligned with patient feedback. This scoring change was implemented, alongside changes in the item composition of the symptom severity and additional symptoms subscales. The functional disability item set, and the overall health single-item subscale remained unchanged.

Conclusion

A modified version of the C19-YRS was developed based on a combination of psychometric evidence, clinical relevance of the content and feedback from the working group (comprising patients and healthcare professionals). Future studies including NIHR funded LOCOMOTION study will undertake large-scale, multi-centre validation of the modified C19-YRS.
Changes in m6A RNA methylation of goat lung following PPRV infection
Authors: Nabi Khan Raja Ishaq , Praharaj Manas Ranjan , Malla Waseem Akram , Hosamani Neelima , Saxena Shikha , Mishra Bina , Rajak Kaushal Kishor , Dhanavelu Muthuchelvan , Tiwari Ashok Kumar , Mishra B P , Sajjanar Basavaraj , Gandham Ravi Kumar
Published: March 2022

Peste des petits ruminants (PPR) is an acute, highly contagious viral disease of goats and sheep, caused by the Peste des petits ruminants virus (PPRV). Earlier studies suggest the involvement of diverse regulatory mechanisms in PPRV infection. Methylation at N6 of Adenosine called m6A is one such RNA modification that influences various physiological and pathological phenomena. As the lung tissue represents the primary target organ of PPRV, the present study explored the m6A changes and their functional significance in PPRV disease pathogenesis. m6A-seq analysis revealed 1289 m6A peaks to be significantly altered in PPRV infected lung in comparison to normal lung, out of which 975 m6A peaks were hypomethylated and 314 peaks were hypermethylated. Importantly, hypomethylated genes were enriched in Interleukin-4 and Interleukin-13 signaling and various processes associated with extracellular matrix organization. Further, of the 843 differentially m6A containing cellular transcripts, 282 transcripts were also found to be differentially expressed. Functional analysis revealed that these 282 transcripts are significantly enriched in signaling by Interleukins, extracellular matrix organization, cytokine signaling in the immune system, signaling by receptor tyrosine kinases, and Toll-like Receptor Cascades. We also found m6A reader HNRNPC and the core component of methyltransferase complex METTL14 to be highly upregulated than the m6A readers – HNRNPA2B1 and YTHDF1 at the transcriptome level. These findings suggest that alteration in m6A landscape following PPRV is implicated in diverse processes including the Interleukin signaling.
Distinct bile salt hydrolase substrate preferences dictate C. difficile pathogenesis
Authors: Foley Matthew H. , Walker Morgan E. , Stewart Allison K. , O’Flaherty Sarah , Gentry Emily C. , Allen Garrison , Patel Shakshi , Pan Meichen , Beaty Violet V. , Vanhoy Molly E. , Dougherty Michael K. , McGill Sarah K. , Gulati Ajay , Dorrestein Pieter C. , Baker Erin S. , Redinbo Matthew R. , Barrangou Rodolphe , Theriot Casey M.
Published: March 2022

Summary paragraph

Bile acids (BAs) mediate the crosstalk between human and microbial cells and influence intestinal diseases including Clostridioides difficile infection (CDI). While bile salt hydrolases (BSHs) shape the BA pool by deconjugating conjugated BAs, the basis for their substrate preferences and impact on C. difficile remain elusive. Here, we survey the diversity of Lactobacillus BSHs and unravel the structural basis of their substrate preference. We show that leveraging BSH activity and specificity is an effective strategy to prevent C. difficile growth in clinically relevant CDI models. A range of non-canonical conjugated BAs is also identified, comprising unique BSH substrates that also inhibit C. difficile spore germination. These findings establish BSHs as intestinal enzymes essential to BA homeostasis and colonization resistance against C. difficile.

One sentence summary

Bile salt hydrolase activity inhibits C. difficile by shaping the conventional and non-canonical conjugated bile acid pools
B cell receptor repertoire analysis unveils dynamic antibody response and severity markers in COVID-19 patients
Authors: Rao Soumya , Srivastava Kriti , Verma Anupriya , Das Achintya
Published: March 2022

Humoral and cell mediated immunity are critical against viral infections. The knowledge of composition, diversity, gene usage of the B cell repertoires helps in determining the immune response to SARS-CoV-2 infection. Examining B cell response provides insights on therapeutic antibodies, disease severity markers and aids in predicting vaccine response. We have analyzed public domain immunoglobulin sequencing data from PBMCs of SARS-CoV-2 infected individuals to gain a better understanding of B cell repertoire in patients. Public clonotypes showed increased usage of IGHV3, IGHV4, IGKV1, IGKV3, IGLV3 and IGLV2 family genes during the acute phase infection. Identical CDR3 sequences were identified for heavy (H), kappa (K) and lambda (L) chains across individuals, indicating the convergence of B cell selection during SARS-CoV-2 infection. While the immune repertoire dynamically changed over the course of convalescence, there were persistent clones across early and late timepoints. The diversity of antibody repertoire, measured by Shannon-Weiner diversity index for H and K chains, reduced during the acute phase of infection. In addition, the repertoire diversity was low in severe patients compared to patients with mild or moderate symptoms. Increased usage of IGHV4-59 gene was observed in COVID-19 patients with severe symptoms requiring ventilator support at 2 weeks and 3 weeks post symptom onset. IGHV4-59 is reported to have rheumatoid factor (RF) activity with high affinity for IgG and the elevated level of IGHV4-59 provides a potential mechanism for the increased autoimmune responses in severe patients. Correlation of the clinical features with the B cell receptor repertoire dynamics elucidated public antibody clonotypes and disease severity markers for COVID-19.
Target class profiling of small molecule methyltransferases
Authors: Hanson Quinlin M , Shen Min , Guo Hui , Cho Ig-Jun , Hall Matthew D
Published: March 2022

Target class profiling (TCP) is a chemical biology approach to investigating understudied biological target classes. TCP is achieved by developing a generalizable assay platform and screening curated compound libraries to interrogate the chemical biological space of members of an enzyme family with clinical and biological importance. In this work we took a TCP approach to investigate inhibitory activity across a set of small molecule methyltransferases, a subclass of methyltransferase enzymes, with the goal of creating a launchpad to explore this largely understudied target class. Using the representative enzymes nicotinamide N-methyltransferase (NNMT), phenylethanolamine N-methyltransferase (PNMT), histamine N-methyltransferase (HNMT), glycine N-methyltransferase (GNMT), catechol O-methyltransferase (COMT), and guanidinoacetate N-methyltransferase (GAMT), we optimized high-throughput screening (HTS)-amenable assays to screen 27,574 unique small molecules against all targets. From this dataset we identified a novel inhibitor which selectively inhibits the small molecule methyltransferase HNMT, and demonstrated how this platform approach can be leveraged for a targeted drug discovery campaign using the example of HNMT.
Using genome scans to identify genes used repeatedly for adaptation
Authors: Booker Tom R. , Yeaman Sam , Whitlock Michael C.
Published: March 2022

Adaptation occurring in similar genes or genomic regions in distinct lineages provides evolutionary biologists with a glimpse at the fundamental opportunities for and constraints to diversification. With the widespread availability of high throughput sequencing technologies and the development of population genetic methods to identify the genetic basis of adaptation, studies have begun to compare the evidence for adaptation at the molecular level among distinct lineages. However, methods to study repeated adaptation are often oriented towards genome-wide testing to identify a set of genes with signatures of repeated use, rather than evaluating the significance at the level of an individual gene. In this study, we propose PicMin, a novel statistical method derived from the theory of order statistics that can test for repeated molecular evolution to estimate significance at the level of an individual gene, using the results of genome scans. This method is generalizable to any number of lineages and indeed, statistical power to detect repeated adaptation increases with the number of lineages that have signals of repeated adaptation of a given gene in multiple lineages. An implementation of the method written for R can be downloaded from https://github.com/TBooker/PicMin.
A cell cycle-linked mechanism for the glutamine driven establishment of stem cell fate
Authors: Xiao Michael , Wu Chia-Hua , Meek Graham , Kelly Brian , Young Lyndsay E.A. , Martire Sara , Castillo Dara Buendia , Saha Purbita , Dube Altair L. , Gentry Matthew S. , Banaszynski Laura A. , Sun Ramon C. , Kikani Chintan K.
Published: March 2022

The cell cycle offers a unique opportunity for stem cells to sample metabolic and signaling cues to establish cell fate. Molecular pathways that integrate and convey these signals to cell cycle machinery to license cell fate transitions and drive terminal differentiation remain unknown. Here, we describe a signaling role of mitochondrial glutamine metabolism in driving exit from cell cycle-linked self-renewal to generate differentiation competent progenitors. In proliferating stem cells, mitochondrial glutamine metabolism opposes the WDR5-linked self-renewal network via acetylation and nuclear translocation of its upstream regulator, PASK. Nuclear PASK disrupts the mitotic WDR5-anaphase-promoting complex (APC/C) interaction to drive exit from self-renewal. Consistent with these roles, loss of PASK or inhibition of glutamine metabolism preserves stemness in vitro and in vivo during muscle regeneration. Our results suggest a mechanism whereby the proliferative functions of glutamine metabolism are co- opted by stem cells to establish cell fate.
Nonlinear EEG signatures of mind wandering during breath focus meditation
Authors: Lu Yiqing , Rodriguez-Larios Julio
Published: March 2022

In meditation practices that involve focused attention to a specific object, novice practitioners often experience moments of distraction (i.e., mind wandering). Previous studies have investigated the neural correlates of mind wandering during meditation practice through Electroencephalography (EEG) using linear metrics (e.g., oscillatory power). However, their results are not fully consistent. Since the brain is known to be a chaotic/nonlinear system, it is possible that linear metrics cannot fully capture complex dynamics present in the EEG signal. In this study, we assess whether nonlinear EEG signatures can be used to characterize mind wandering during breath focus meditation in novice practitioners. For that purpose, we adopted an experience sampling paradigm in which 25 participants were iteratively interrupted during meditation practice to report whether they were focusing on the breath or thinking about something else. We compared the complexity of EEG signals during mind wandering and breath focus states using three different algorithms: Higuchi’s fractal dimension (HFD), Lempel-Ziv complexity (LZC), and Sample entropy (SampEn). Our results showed that EEG complexity was generally reduced during mind wandering relative to breath focus states. We conclude that EEG complexity metrics are appropriate to disentangle mind wandering from breath focus states in novice meditation practitioners, and therefore, they could be used in future EEG neurofeedback protocols to facilitate meditation practice.
π-Hole bonding in a new co-crystal hydrate of gallic acid and pyrazine: static and dynamic charge density analysis
Authors: Pal Rumpa , Jelsch Christian , Momma Koichi , Grabowsky Simon
Published: March 2022

A new cocrystal hydrate of gallic acid with pyrazine (4GA, Py, 4H2O; GA4PyW4) was obtained and characterized by single crystal X-ray diffraction. In addition to structure determination, experimental charge density analysis was carried out in terms of Multipole Modelling (MP), X-ray wavefunction refinement (XWR) and maximum entropy method (MEM). As a part of XWR, the structural refinement via Hirshfeld atom refinement was carried out and resulted in O—H bond lengths close to values from neutron diffraction. A systematic comparison of molecular conformations and aromatic interactions in this new cocrystal hydrate was performed with other existing polymorphs of gallic acid. In GA4PyW4, the two symmetry-independent gallic acid molecules have a syn COOH orientation and form the common (COOH)2 dimeric synthon. The carboxyl C atom displays the characteristics of π-holes with electropositive regions above and below the molecular plane and engages in acceptor–donor interactions with oxygen atoms of acidic O—H groups and phenol groups of neighbouring gallic acid molecules. The signature of the π-hole was identified from experimental charge density analysis, both in static density maps in MP and XWR as well as dynamic density in MEM, but it cannot be pinned down to a specific atom–atom interaction. This study presents the first comparison between an XWR and a MEM experimental electron-density determination.
Leverage-value nexus in Italian small-medium enterprises: further evidence using dose-response function
Authors: Harasheh Murad , De Vincenzo Francesca
Published: March 2022

Purpose

The study introduces a new approach to leverage-value relationship. Besides applying the classical regression models, the study deals with leverage as a continuous treatment variable implemented on the firm’s value using the dose-response function (DFR).

Design/methodology/approach

After proper model calibration and splitting the treatment (leverage) into ten doses, a response function is generated, which enables the realization of the dose level at which the firm’s value is maximized. Furthermore, the study tests the pecking order theory (POT) and the trade-off theory (TOT) using the threshold model to see whether firms are under or over-indebted. The analysis is carried out on panel data from small-medium enterprises (SMEs), providing more valuable insights than large and mature companies.

Findings

The study used two leverage measures: total liabilities ratio and bank debt ratio. Value is measured by the market capitalization and Tobin’s Q. In general, the study finds a positive relationship between leverage and value; POT is not strongly supported, firms are below their optimal leverage and there is a certain leverage dose that would maximize firms’ value.

Practical implications

Since the threshold model and DRF show that SMEs are under-indebted, firms could benefit from extra leverage doses without affecting the firm’s risk profile, especially in a low-interest rate regime, and the potential increase in public-private expenditure after Italy obtained the European Recovery Funds.

Originality/value

The study contributes to new knowledge and understanding of financial leverage from new methodological perspectives, offering valuable insights from SMEs using novel approaches.