bluuebunny/crossref_metadata_2025 huggingface dataset:
A Case of Endocarditis Following Endophthalmitis After XEN45 Gel Stent Implantation
Authors: Wisdorf Martin , Kowalski Radoslaw , Kiessling David , Roessler Gernot F. , Widder Randolf A.
Published: May 2021

Introduction:

We report a case of endophthalmitis and endocarditis that developed after stent perforation following a XEN45 Gel Stent implantation 10 months ago.

Case Report:

A 79-year-old man was referred to our hospital because of endophthalmitis of the right eye. The patient had undergone XEN45 Gel Stent implantation in the same eye 10 months ago. On examination, the conjunctiva was perforated by the stent, and it was no longer covered by the conjunctiva. A 27-G pars plana vitrectomy with intravitreal antibiotic injection was performed. Moreover, the patient received intravenous antibiotic treatment and local anti-inflammatory and anti-infectious therapy. Streptococcus gordonii was identified as a bacterial cause of the endophthalmitis. Therefore, transesophageal echocardiography was performed, which revealed aortic valve endocarditis.

Discussion:

Although not proven, it is possible that the exposed XEN45 Gel Stent served as an entry point for S. gordonii, which caused the exogenous endophthalmitis and subsequent endocarditis. S. gordonii belongs to the viridans group streptococci, which is the etiological agent for endocarditis which is a severe and potentially life-threatening infection. Ophthalmologists should therefore consider the risk of systemic infections as endocarditis after endophthalmitis, particularly caused by the viridans group streptococci, which are known etiological agents of endocarditis.
Reliability of iCare ic100 Rebound Tonometry and Agreement With Goldmann Applanation Tonometry in Healthy and Post-myopic LASIK Patients
Authors: Gómez-Gómez Alicia , Talens-Estarelles Cristian , Alcocer-Yuste Pablo , Nieto Juan C.
Published: May 2021

Precis:

Rebound tonometry offers excellent reliability for obtaining intraocular pressure (IOP) measurements in healthy and post-myopic laser-assisted in situ keratomileusis (LASIK) patients regardless of corneal parameters and axial length and regardless of the instillation of ocular topical anesthesia.

Purpose:

The purpose of this study was to assess the reliability of rebound tonometry, its agreement with Goldmann applanation tonometry (GAT) and its concordance after topical anesthesia in a group of nonoperated healthy patients and a group of post-myopic LASIK patients.

Patients and Methods:

Fifty-four patients were included in this prospective observational, case-control study. Patients were divided into 2 groups: control (n=32, 26.7±6.1 y) and LASIK (n=22, 35.8±7.6 y). Measurements of IOP were carried out using the iCare ic100 tonometer and GAT. The repeatability, intersession and interobserver reproducibility, GAT interchangeability and concordance after topical anesthesia of the iCare ic100 tonometer were assessed.

Results:

Clinical reliability of the iCare ic100 was excellent in terms of repeatability [intraclass correlation coefficient (ICC)=0.909 and 0.951 in control and ICC=0.938 and 0.961 in LASIK] as well as interobserver reproducibility (ICC=0.896 in control and 0.916 in LASIK) and concordance after anesthesia (ICC=0.910 in control and 0.972 in LASIK) in both groups. Intersession reproducibility was clinically good in nonoperated patients (ICC=0.758 and 0.849) and excellent in LASIK patients (ICC=0.878 and 0.904), although statistically significant differences were obtained in the control group for both examiners (P=0.003 for examiner 1 and P=0.04 for examiner 2). Agreement with GAT was good in both groups (ICC=0.805 in control and 0.790 in LASIK), although statistically different (P<0.001 and P=0.02, respectively). Finally, the iCare ic100 reliability was independent of corneal parameters and axial length in both groups (P>0.05 for all parameters).

Conclusions:

Rebound tonometry offers good or excellent clinical reliability in both healthy and post-myopic LASIK patients. This article highlights the efficacy of iCare ic100 rebound tonometry as a reliable tool for the measurement of IOP and the management of glaucoma in healthy patients and patients undergoing myopic LASIK surgery.
Long-term Results of Ahmed Valve Implantation With Mitomycin-C in Pediatric Glaucoma
Authors: Promelle Veronique , Lyons Christopher J.
Published: May 2021

Precis:

Mitomycin was used with Ahmed valve implantation in 81 eyes of 63 children. After 5 years, probability of intraocular pressure (IOP) control without glaucoma medication was 35±6%; 57% achieved IOP control with topical medications after 10 years.

Purpose:

The purpose of this study was to determine the long-term outcomes of Ahmed glaucoma valve (AGV) implantation with intraoperative application of mitomycin-C (MMC) for the treatment of childhood glaucoma.

Methods:

Retrospective review of children undergoing AGV implantation with subtenon application of MMC between 2000 and 2019. We defined surgical success as a final IOP of 5 to 21 mm Hg with no glaucoma medication, no subsequent glaucoma surgery, and no severe complication. Qualified success was defined if the above criteria were met with topical antiglaucoma medication.

Results:

Eighty-one eyes of 63 patients were included. The probability of complete success was 72±5% (63% to 83%) at 1 year, 58±6% (48% to 70%) at 2 years, and 35±6% (25% to 48%) at 5 years. The probability of qualified success was 92±3% (87% to 98%) at 1 year, 79±5% (70% to 89%) at 5 years, 57±7% (44% to 73%) at 10 years, and 39±9% (24% to 62%) at 14 years. The IOP was reduced by an average of 10.7±9 mm Hg from preoperative visit to the last follow-up, and the number of medications decreased from 3.0±1.4 to 1.5±1.4 after implantation.

Conclusions:

A significant proportion of patients achieved long-term IOP control without glaucoma medication. The majority achieved IOP control with additional topical antiglaucoma medications. When compared with existing AGV implantation in childhood literature, the use of MMC appears to lengthen the drop-free (complete success) duration, as well as the long-term IOP control with topical medications.
Intraocular Pressure According to Eye Gaze by iCare Rebound Tonometry in Normal Participants and Glaucoma Patients
Authors: Kim Yu Jeong , Moon Yeji , Kwon Amy M. , Lim Han Woong , Lee Won June
Published: May 2021

Precis:

We investigated changes of intraocular pressure (IOP) according to eye gaze. IOP was significantly elevated in adduction, abduction, and supraduction. However, there was no significant difference between glaucoma and control groups.

Purpose:

We assessed changes in IOP according to eye gaze and identified their correlations with various risk factors of glaucoma.

Patients and Methods:

In this prospective observational study that included 56 glaucoma patients and 34 healthy participants, we measured IOP in the primary position with a Goldmann applanation tonometry and rebound tonometer. Then, this IOP was measured in abduction, adduction, supraduction using a rebound tonometer. IOP changes according to eye gaze were measured based on the baseline IOP, and IOP changes between glaucoma and the control groups were compared. Correlations between IOP changes and risk factors of glaucoma were evaluated.

Results:

The baseline IOP was not significantly different between glaucoma and the control groups. Compared with the IOP in the primary position, a significant increase in IOP was 2.3±2.7 mm Hg during abduction (P<0.0001), 0.7±2.7 mm Hg during adduction (P<0.0001), and 1.2±2.8 mm Hg during supraduction (P<0.0001). However, there was no significant difference in the amount of IOP elevation or the ratio of IOP change between glaucoma and the control groups in all gazes. The baseline IOP measured by Goldmann applanation tonometry and IOP changes according to eye gaze showed a significant negative correlation in all gazes.

Conclusions:

IOP was significantly elevated in adduction, abduction, and supraduction than in the primary position in both the normal and glaucoma groups. However, there was no significant difference of IOP changes between glaucoma and normal groups.
Surgical Results of Ahmed Glaucoma Valve Implantation in One-chamber Eyes
Authors: Tanito Masaki , Tsutsui Aika , Manabe Kaoru , Matsuoka Yotaro
Published: May 2021

Precis:

Ahmed glaucoma valve (AGV) implantation in eyes with damaged iris-lens diaphragms (“1-chamber” eyes) resulted in mean intraocular pressure (IOP) and antiglaucoma medications decreases of 66% and 59% (P<0.0001 for both), respectively, at the mean 23-month follow-up.

Purpose:

The purpose of this study was to report the results of AGV implantation with pars plana tube insertion to control IOP in glaucomatous eyes with damaged iris-lens diaphragms (“1-chamber” eyes).

Methods:

The medical records of 52 consecutive glaucomatous 1-chamber eyes (48 Japanese patients, mean age±SD, 76.0±11.2 y) were retrospectively reviewed. Other than aphakic eyes, eyes were defined as having 1 chamber if intraocular lenses (IOLs) were sclerally or intrasclerally fixated, IOLs were fixed on-the-bag due to posterior capsular defects, vitreous collapse into the anterior chamber resulted from Zinn zonular dialysis, and phacodonesis or IOL-donesis required lens/IOL explantation during AGV implantation. The data collected were preoperative/postoperative IOPs, numbers of antiglaucoma medications, visual acuity, anterior chamber flare, visual field mean deviation, corneal endothelial cell density, and surgical complications/interventions.

Results:

The preoperative IOP (28.5±9.4 mm Hg) and a number of antiglaucoma medications (3.2±1.2) decreased significantly (P<0.0001 for both) to 9.8±3.3 mm Hg and 1.3±1.3, respectively, at the final visit (mean follow-up, 23 mo). The success rates of IOP control (6 to 21 mm Hg and >20% reduction irrespective of medication use) were 82.5% and 79.0%, respectively, at postoperative years 1 and 2. The most common postoperative complications were macular edema (n=9, 17%), choroidal detachment (n=8, 15%), vitreous hemorrhage (n=7, 13%), and hyphema (n=7, 13%). The most common postoperative intervention was tubal repositioning/reopening (n=6, 12%). Compared with preoperative values, the visual acuity, anterior chamber flare, mean deviation, corneal endothelial cell density remained unchanged postoperatively.

Conclusion:

Choice of pars plana AGV tube insertion with simultaneous vitrectomy is reasonable to achieve IOP reduction and minimize vision-threatening complication in glaucomatous eyes with a damaged iris-lens diaphragm.
Defining Vasoplegia Following Durable, Continuous Flow Left Ventricular Assist Device Implantation
Authors: Swan Joshua T. , Iso Tomona , Rizk Elsie , Trachtenberg Barry H. , Krisl Jill , Varnado Sara , Suki Wadi N. , Frost Adaani E. , Suarez Erik , Uddin Faisal S. , Kassi Mahwash , Giesecke Noel Martin , Bhimaraj Arvind , Masud Faisal N.
Published: May 2021

This study aimed to develop a definition of vasoplegia that reliably predicts clinical outcomes. Vasoplegia was evaluated using data from the electronic health record for each 15-minute interval for 72 hours following cardiopulmonary bypass. Standardized definitions considered clinical features (systemic vascular resistance [SVR], mean arterial pressure [MAP], cardiac index [CI], norepinephrine equivalents [NEE]), threshold strategy (criteria occurring in any versus all measurements in an interval), and duration (criteria occurring over multiple consecutive versus separated intervals). Minor vasoplegia was MAP < 60 mm Hg or SVR < 800 dynes⋅sec⋅cm−5 with CI > 2.2 L/min/m2 and NEE ≥ 0.1 µg/kg/min. Major vasoplegia was MAP < 60 mm Hg or SVR < 700 dynes⋅sec⋅cm−5 with CI > 2.5 L/min/m2 and NEE ≥ 0.2 µg/kg/min. The primary outcome was incidence of vasoplegia for eight definitions developed utilizing combinations of these criteria. Secondary outcomes were associations between vasoplegia definitions and three clinical outcomes: time to extubation, time to intensive care unit discharge, and nonfavorable discharge. Minor vasoplegia detected anytime within a 15-minute period (MINOR_ANY_15) predicted the highest incidence of vasoplegia (61%) and was associated with two of three clinical outcomes: 1 day delay to first extubation (95% CI: 0.2 to 2) and 7 day delay to first intensive care unit discharge (95% CI: 1 to 13). The MINOR_ANY_15 definition should be externally validated as an optimal definition of vasoplegia.
Hydrodynamic Approach for Revealing Venous Anastomotic Stenosis Formation Within a Dialysis Arteriovenous Graft
Authors: Sano Yoshihiko , Ugawa Toyomu , Takeda Ayato , Hyakutake Toru , Nakazawa Takashi , Yanase Shinichiro , Shigemitsu Hidenobu , Arai Hirokuni
Published: May 2021

A conventional arteriovenous graft in patients on dialysis often leads to anastomotic stenosis, which decreases the blood flow rate and increases the risk of complications. In this study, based on hydrodynamics, the pulsatile pressure at the blood vessel graft–vein junction was investigated experimentally and numerically for revealing the causes of stenosis formation and inward remodeling. In the experiments, the pulsatile pressure and displacement at the anastomotic connection were measured at a branched collapsible tube. It was revealed that the pressure becomes negative between pressure peaks of the pulsatile flow; furthermore, tube diameter changes in accordance with the pressure pulsation. Subsequently, numerical simulations revealed that a relatively large pressure difference occurs at the anastomotic connection because of flow collision and separation as compared with the other part, and the pulsatile pressure. Therefore, it is possible that vein at an anastomotic connection may change its shape under pulsating flow. Furthermore, it was found that the pressure difference slightly increased with the anastomosis angle, but the anastomosis angle did not affect the flow rate. Clinical trials in the next step are required to reveal the causal relationship between stenosis and the pulsatile pressure, but the pulsatile flow and its pressure are likely to be one factor in stenosis and inward remodeling.
Are diabetes microvascular complications risk factors for fragility fracture?
Authors: Almutlaq Nourah , Neyman Anna , DiMeglio Linda A.
Published: May 2021

Purpose of review

We describe relationships between microvascular complications and bone fragility fracture in the context of diabetes. We highlight gaps in knowledge and suggest areas of further study.

Recent findings

Evidence in type 1 diabetes (T1D) demonstrates that low bone mineral density (BMD) is associated with microvascular complications and linked to increased fracture risk. Of note, the low BMD does not solely explain bone fragility. Microvascular disease also has been linked to compromised bone microarchitecture and poorer bone quality. Moreover, microvascular complications may indirectly increase the rate of fragility fracture through increasing fall propensity; however, to date no conclusive studies have assessed microvascular disease and fracture risk independent of falls.

In the other hand, individuals with type 2 diabetes (T2D) have increased fracture risk despite high BMD. Data suggest microvascular disease mediates microarchitectural changes by increasing cortical porosity and is associated with lower bone turnover. There is no direct evidence linking microangiopathy to fracture incidence.

Taken together present evidence suggests associations between diabetic bone disease, fragility fracture, and microvascular disease. Data are more convincing for T1D than T2D. Further studies are required to confirm whether microvascular disease is itself causative of fracture or merely a contributory factor to fragility fracture for persons with diabetes.
Impact of COVID-19 on New Graduate Nurses' Transition to Practice
Authors: Smith Susan M. , Buckner Martha , Jessee Mary Ann , Robbins Veronica , Horst Tessa , Ivory Catherine H.
Published: May 2021

Background

The COVID-19 pandemic disrupted nursing education and required modification of instructional methods and clinical experiences. Given the variation in education, rapid transition to virtual platforms, and NCLEX-RN testing stressors, this cohort faced unique losses and gains influencing their transition into clinical practice.

Purpose

This study examined the impact of COVID-19 and preparedness for professional practice of 340 new graduate nurses (NGNs) at an academic medical center.

Methods

This was a mixed-methods descriptive study focusing on how clinical experience loss or gains in the final semester affected the fears, concerns, and recommendations for NGNs.

Results

More than half (67.5%, n = 295) of NGNs reported changes to clinical experiences, ranging from 0 to 240 hours transitioned to virtual (n = 187; median, 51; interquartile range, 24-80). NGNs fear missing important details or doing something wrong in providing patient care. They identified the need for preceptor support, guidance, teaching, and continued practice of skills.

Conclusion

Recommendations are clear communication with leadership, advocacy from the nurse residency program, and targeted clinical and emotional support for NGNs.
Laboratory Markers of Acidosis and Mortality in Cardiogenic Shock: Developing a Definition of Hemometabolic Shock
Authors: Jentzer Jacob C. , Kashani Kianoush B. , Wiley Brandon M. , Patel Parag C. , Baran David A. , Barsness Gregory W. , Henry Timothy D. , Van Diepen Sean
Published: May 2021

Background:

Acidosis and higher lactate predict worse outcomes in cardiogenic shock (CS) patients. We sought to determine whether overall acidosis severity on admission predicted in-hospital mortality in CS patients.

Methods:

This retrospective descriptive analysis included CS patients admitted to a single academic tertiary cardiac intensive care unit from 2007 to 2015. Admission arterial pH, base excess, and anion gap values were used to generate a Composite Acidosis Score (range 0–5, with a score ≥2 defining Severe Acidosis). Adjusted in-hospital mortality was analyzed using multivariable logistic regression.

Results:

We included 1,065 patients with median age of 68.9 (59.0, 77.2) years (36.4% females). Concomitant diagnoses included cardiac arrest in 38.1% and acute coronary syndrome in 59.1%. Severe Acidosis was present in 35.2%, and these patients had worse shock and more organ failure. In-hospital mortality occurred in 34.1% and was higher among patients with Severe Acidosis (54.9% vs. 22.4%, adjusted odds ratio [OR] 2.01, 95% CI 1.43–2.83, P < 0.001). Increasing Composite Acidosis Score was associated with higher in-hospital mortality (adjusted OR 1.25 per point, 95% CI 1.11–1.40, P < 0.001). Severe Acidosis was associated with higher hospital mortality at every level of shock severity and organ failure (all P < 0.05). Admission lactate level had equivalent discrimination for in-hospital mortality as the Composite Acidosis Score (0.69 vs. 0.66; P = 0.32 by De Long test).

Conclusion:

Given its incremental association with higher in-hospital mortality among CS patients beyond shock severity and organ failure, we propose Severe Acidosis as a marker of hemometabolic shock. Lactate levels performed as well as a composite measure of acidosis for predicting mortality.
The effect of long-term awareness on active and passive tobacco smokers
Authors: Köksoy Serkan , Kara Fatih
Published: May 2021

Background and objective

Tobacco addiction is a major public health problem. Numerous scientific studies have been conducted on the harms of tobacco products. However, the number of intervention studies investigating the effect of long-term awareness of the harm of tobacco products on the Fagerström nicotine addiction test (FTND), carbon monoxide (CO), carboxyhemoglobin (COHb) and respiratory function test (RFT) are limited. Our goal is to investigate the impact of long-term scientific awareness on these parameters.

Participant and Method

The study was designed an intervention study on active and passive smoking participants and their control groups. Intervention groups were given seminar program (up-to-date literature information and images on the harms of tobacco products) for eight weeks. Control groups were not given any training on the harms of tobacco products. Intervention groups were measured 8 times (FNBT, CO, COHb and SFT). Control groups were measured only in the first and last week.

Result

When comparing the first and last weeks in active smoker intervention group (ASIG), the difference between FTND, FEV1, CO, and COHb parameters was observed to be statistically significant. The highest decrease in ASIG was in CO (60%) parameter and the highest increase was in the FEV1(%10) parameter. There was a significant difference between FEV1, FVC, FEV1/FVC, and CO parameters of passive smokers intervention group (PSIG). The highest decrease in PSIG was in the CO parameter (%65.8) and the highest increase was in the FVC (%10) parameter.

Conclusion

Awareness programs may reduce the severity of addiction in active smokers and may help protect passive smokers. In the absence of any awareness, it may not positively change. As awareness increases, positive changes in some vital parameters may be possible. Up-to-date programs and policies are needed to make easy and sustainable awareness of both active and passive smoking.
SARS-CoV-2 naïve and recovered individuals show qualitatively different antibody responses following mRNA vaccination
Authors: Vaquero Sonia Tejedor , de Campos-Mata Leire , María Ramada José , Díaz Pilar , Navarro-Barriuso Juan , Ribas-Llaurado Clara , Melero Natalia Rodrigo , Carolis Carlo , Cerutti Andrea , Gimeno Ramon , Magri Giuliana
Published: May 2021

mRNA-based vaccines effectively induce protective neutralizing antibody responses against SARS-CoV-2, the etiological agent of COVID-19. The specific compositional patterns of these responses remain largely unknown. We found that SARS-CoV-2-naïve individuals receiving the first dose of an mRNA vaccine developed a SARS-CoV-2-specific antibody response with a subclass profile comparable to that induced by the natural infection, except IgA2, which did not increase. SARS-CoV-2-naïve subjects also mounted a robust virus-specific recall response after receiving the second dose. This response increased all IgG subclasses, but boosted neither IgM nor IgA1 and IgA2 subclasses. In contrast, individuals recovered from COVID-19 mounted peak virus-specific antibody responses upon primary immunization and did not further augment such responses following secondary immunization. Remarkably, compared to SARS-CoV-2-naïve subjects, individuals with pre-existing immunity showed increased levels of all virus-specific antibodies but IgG3 following primary vaccination. By dissecting the heterogeneity of mRNA vaccine-induced humoral responses to SARS-CoV-2, our findings indicate that the induction of optimal immune protection may require the development of personalized vaccination programs.
First comparison of conventional activated sludge versus root-zone treatment for SARS-CoV-2 RNA removal from wastewaters: statistical and temporal significance
Authors: Kumar Manish , Kuroda Keisuke , Joshi Madhvi , Bhattacharya Prosun , Barcelo Damia
Published: May 2021

In the initial pandemic phase, effluents from wastewater treatment facilities were reported mostly free from Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) RNA, and thus conventional wastewater treatments were generally considered effective. However, there is a lack of first-hand data on i) comparative efficacy of various treatment processes for SARS-CoV-2 RNA removal; and ii) temporal variations in the removal efficacy of a given treatment process in the backdrop of active COVID-19 cases. This work provides a comparative account of the removal efficacy of conventional activated sludge (CAS) and root zone treatments (RZT) based on weekly wastewater surveillance data, consisting of forty-four samples, during a two-month period. The average genome concentration was higher in the inlets of CAS-based wastewater treatment plant in the Sargasan ward (1.25 x 103 copies/ L), than that of RZT plant (7.07 x 102 copies/ L) in an academic institution campus of Gandhinagar, Gujarat, India. ORF 1ab and S genes appeared to be more sensitive to treatment i.e., significantly reduced (p <0.05) than N genes (p>0.05). CAS treatment exhibited better RNA removal efficacy (p=0.014) than RZT (p=0.032). Multivariate analyses suggested that the effective genome concentration should be calculated based on the presence/absence of multiple genes. The present study stresses that treated effluents are not always free from SARS-CoV-2 RNA, and the removal efficacy of a given WWTPs is prone to exhibit temporal variability owing to variations in active COVID-19 cases in the vicinity and genetic material accumulation over time. Disinfection seems less effective than the adsorption and coagulation processes for SARS-CoV-2 removal. Results stress the need for further research on mechanistic insight on SARS-CoV-2 removal through various treatment processes taking solid-liquid partitioning into account.

Graphical Abstract

Highlights

Wastewater treatments may not completely remove the SARS-CoV-2 RNA.

The activated sludge process exhibited better RNA removal efficacy than root-zone treatment.

ORF 1ab and S genes appeared more sensitive to treatment than N genes.

Temporal variability is observed in the removal efficacy of wastewater treatment plants.
A linear Mixed Model to Estimate COVID-19-induced Excess Mortality
Authors: Verbeeck Johan , Faes Christel , Neyens Thomas , Hens Niel , Verbeke Geert , Deboosere Patrick , Molenberghs Geert
Published: May 2021

Summary

The Corona Virus Disease (COVID-19) pandemic has increased mortality in countries worldwide. To evaluate the impact of the pandemic on mortality, excess mortality has been suggested rather than reported COVID-19 deaths. Excess mortality, however, requires estimation of mortality under non-pandemic conditions. Although many methods exist to forecast mortality, they are either complex to apply, require many sources of information, ignore serial correlation, and/or are influenced by historical excess mortality. We propose a linear mixed model that is easy to apply, requires only historical mortality data, allows for serial correlation, and down-weighs the influence of historical excess mortality. Appropriateness of the linear mixed model is evaluated with fit statistics and forecasting accuracy measures for Belgium and the Netherlands. Unlike the commonly used 5-year weekly average, the linear mixed model is forecasting the subject-specific mortality, and as a result improves the estimation of excess mortality for Belgium and the Netherlands.
Interrupted time series analyses to assess the impact of alcohol control policy on socioeconomic inequalities in mortality in Lithuania: a study protocol
Authors: Manthey Jakob , Jasilionis Domantas , Jiang Huan , Mesceriakova-Veliuliene Olga , Petkeviciene Janina , Radisauskas Ricardas , Rehm Jurgen , Stelemekas Mindaugas
Published: May 2021

Introduction
Alcohol use is a major risk factor for mortality. Previous studies suggest that the alcohol-attributable mortality burden is higher in lower socioeconomic strata. This project will test the hypothesis, that the 2017 increase of alcohol excise taxes for beer and wine, which was linked to lower all-cause mortality rates in previous analyses, will reduce socioeconomic mortality inequalities.
Methods and analysis
Data on all causes of deaths will be obtained from Statistics Lithuania. Record linkage will be implemented using personal identifiers combining data from 1) the 2011 whole-population census, 2) death records between March 1, 2011 (census date) and December 31, 2019, and 3) emigration records, for individuals aged 30 to 70 years. The analyses will be performed separately for all-cause and for alcohol-attributable deaths. Monthly age-standardized mortality rates will be calculated by sex, education, and three measures of socioeconomic status. Inequalities in mortality will be assessed using absolute and relative indicators between low and high SES groups. We will perform interrupted time series analyses, and test the impact of the 2017 rise in alcohol excise taxation using generalized additive mixed models. In these models, we will control for secular trends for economic development.
Ethics and dissemination
This work is part of project grant 1R01AA028224-01 by the National Institute on Alcohol Abuse and Alcoholism. It has been granted research ethics approval 050/2020 by CAMH Research Ethics Board on April 17, 2020, renewed on March 30, 2021.
Transmission roles of symptomatic and asymptomatic COVID-19 cases: a modeling study
Authors: Tan Jianbin , Ge Yang , Martinez Leonardo , Sun Jimin , Li Changwei , Westbrook Adrianna , Chen Enfu , Pan Jinren , Li Yang , Ling Feng , Chen Zhiping , Huang Hui , Shen Ye
Published: May 2021

Key Points

Question

What is the transmissibility of COVID-19 asymptomatic and symptomatic cases, respectively? To date, they have not been well quantified in existing literature.

Findings

The transmissibility of asymptomatic and symptomatic COVID-19 increases with patient age. The asymptomatic cases had a 66.72% lower transmissibility rate than symptomatic cases.

Meaning

The transmissibility of asymptomatic COVID-19 cases is not low. Asymptomatic cases are harder to detect compared to symptomatic cases. Consequently, the burden of asymptomatic transmission could potentially dominate the spreading in certain scenarios.
Genetic estimates of correlation and causality between blood-based biomarkers and psychiatric disorders
Authors: Reay William R. , Kiltschewskij Dylan J. , Geaghan Michael P. , Atkins Joshua R. , Carr Vaughan J. , Green Melissa J. , Cairns Murray J.
Published: May 2021

There is a long-standing interest in exploring the relationship between blood-based biomarkers of biological exposures and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable biochemical traits measured from serum to refine our understanding of causal effect in biochemical-psychiatric trait parings. In accordance with expectation we observed widespread evidence of positive and negative genetic correlation between psychiatric disorders and biochemical traits. We then implemented causal inference to distinguish causation from correlation and found strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders, along with other putatively causal relationships involving urate and glucose. Strikingly, these analyses suggested CRP has a protective effect on three disorders including anorexia nervosa, obsessive-compulsive disorder, and schizophrenia, whilst being a risk factor for major depressive disorder. Multivariable models that conditioned CRP effects on interleukin-6 signalling and body mass index suggested that CRP-schizophrenia relationship was not likely mediated by those factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness, including factors such as CRP that are likely to constitute a causal effect and could be targets for therapeutic intervention and precision medicine.
Cardiovascular vulnerability predicts hospitalisation in primary care clinically suspected and confirmed COVID-19 patients: a model development and validation study
Authors: van Royen Florien S. , Joosten Linda P.T. , van Smeden Maarten , Slottje Pauline , Rutten Frans H. , Geersing Geert-Jan , van Doorn Sander
Published: May 2021

Objectives

Cardiovascular conditions were shown to be predictive of clinical deterioration in hospitalised patients with coronavirus disease 2019 (COVID-19). Whether this also holds for outpatients managed in primary care is yet unknown. The aim of this study was to determine the incremental value of cardiovascular vulnerability in predicting the risk of hospital referral in primary care COVID-19 outpatients.

Design

Analysis of anonymised routine care data extracted from electronic medical records from three large Dutch primary care registries.

Setting

Primary care.

Participants

Consecutive adult patients seen in primary care for COVID-19 symptoms in the ‘first wave’ of COVID-19 infections (March 1 2020 to June 1 2020) and in the ‘second wave’ (June 1 2020 to April 15 2021) in the Netherlands.

Outcome measures

A multivariable logistic regression model was fitted to predict hospital referral within 90 days after first COVID-19 consultation in primary care. Data from the ‘first wave’ was used for derivation (n=5,475 patients). Age, sex, the interaction between age and sex, and the number of cardiovascular conditions and/or diabetes (0, 1, or ≥2) were pre-specified as candidate predictors. This full model was (i) compared to a simple model including only age and sex and its interaction, and (ii) externally validated in COVID-19 patients during the ‘second wave’ (n=16,693).

Results

The full model performed better than the simple model (likelihood ratio test p<0.001). Older male patients with multiple cardiovascular conditions and/or diabetes had the highest predicted risk of hospital referral, reaching risks above 15-20%, whereas on average this risk was 5.1%. The temporally validated c-statistic was 0.747 (95%CI 0.729-0.764) and the model showed good calibration upon validation.

Conclusions

For patients with COVID-19 symptoms managed in primary care, the risk of hospital referral was on average 5.1%. Older, male and cardiovascular vulnerable COVID-19 patients are more at risk for hospital referral.
The effect of recent habitat change on genetic diversity at putatively adaptive and neutral loci inPrimula verisin semi-natural grasslands
Authors: Träger S. , Rellstab C. , Reinula I. , Zemp N. , Helm A. , Holderegger R. , Aavik T.
Published: May 2021

Recent habitat change in semi-natural grasslands due to a lack of management has been shown to affect the genetic diversity of grassland plants. However, it is unknown how a change in local environment affects genetic diversity at adaptive loci. We applied RADseq (restriction-site associated DNA sequencing) to extract > 3,000 SNPs across 568 individuals from 32 Estonian populations ofPrimula veris, a plant species common to semi-natural grasslands. We evaluated the effect of recent grassland overgrowth following management abandonment on the genetic diversity at putatively neutral and adaptive loci, which we distinguished by applying three methods, i.e., linear and categorical environmental association analyses, and anFSToutlier test. For validation, we randomised the genotype to sample assignments. Effects of recent habitat change on genetic diversity differed between neutral and adaptive SNP sets. Genetic diversity assessed at putatively neutral loci was similar in open and overgrown habitats but showed a significant difference between these habitat types at putatively adaptive loci: overgrown (i.e. newly established) habitats exhibited higher genetic diversity at putatively adaptive loci than open (i.e. old) habitats, likely due to the exertion of novel selection pressures imposed by new habitat conditions. This increase in genetic diversity at putatively adaptive loci in the new environment points to currently ongoing selection processes where genetic adaptation to the old habitat is potentially lost through altered allele frequencies. Our study suggests that a recent change in local habitat conditions may not be reflected in neutral loci whereas putatively adaptive loci can inform about potential selection processes.
Generalizability in White Blood Cells’ Classification Problem
Authors: Tavakoli Sajad , Ghaffari Ali , Kouzehkanan Zahra Mousavi
Published: May 2021

Counting and classifying white blood cells (WBCs) in blood samples helps the early diagnosis of the disease. Many works have been done to develop machine learning-based methods to count WBCs. However, most of these works have low generalizability, and their accuracy decreases sharply as the dataset changes. In this paper, a new method is presented that helps to increase the generalization power. In this method, first, the WBC’s nucleus is segmented, and then its convex hull is obtained. By subtracting the nucleus from the convex hull, a new image is created called the representative of the convex hull (ROC). Then, by Training a convolutional neural network (CNN) with the cells’ RGB image as well as the binary images of the nucleus and ROC, the generalization power is increased. The proposed method was first trained on the Raabin-WBC dataset, then its performance was evaluated on the LISC dataset without retraining. The proposed method’s accuracy on the Raabin-WBC and LISC datasets is 93.97% and 51.57 %, respectively. Besides, the generalization power of four well-known CNNs named VGG16, ResNext50, MobileNet-V2, and MnasNet1 was investigated. It was found that VGG16 has more generalization power among these models.
Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis
Authors: Saclier Marielle , Temponi Giulia , Bonfanti Chiara , Messina Graziella
Published: May 2021

Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as muscular dystrophies. Here we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct murine models of muscular dystrophies. Plus, we showed that the deletion of Nfix in macrophages in dystrophic mice delays fibrosis establishment and muscle wasting until 6 months of life. Indeed, macrophages lacking Nfix express more TNFα and less TGFβ1 thus promoting apoptosis of fibro-adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with ROCK inhibitor accelerates fibrosis through the increase of Nfix expression by macrophages. Thus, we identify Nfix as a macrophage profibrotic actor in muscular dystrophies, whose inhibition could be a therapeutic way to rescue the dystrophic disease.
LaminaRGeneVis: a tool to visualize gene expression across the laminar architecture of the human neocortex
Authors: Kim Ethan , Howard Derek , Chen Yuxiao , Tripathy Shreejoy J. , French Leon
Published: May 2021

Application of RNA sequencing has enabled the characterization of genome-wide gene expression in the human brain, including distinct layers of the neocortex. Neuroanatomically, the molecular patterns that underlie the laminar organization of the neocortex can help link structure to circuitry and function. To advance our understanding of cortical architecture, we created LaminaRGeneVis, a web application that displays across-layer cortical gene expression from multiple datasets. These datasets were collected using bulk, single-nucleus, and spatial RNA sequencing methodologies and these data were harmonized to facilitate comparisons between datasets. The online resource facilitates single- and multi-gene analyses by providing figures and statistics for user-friendly assessment of laminar gene expression patterns in the adult human neocortex.

Availability and implementation

LaminaRGeneVis is available at https://ethanhkim.shinyapps.io/laminargenevis. The source code and data is accessible at https://github.com/ethanhkim/laminargenevis.
Genome-wide Imputation Using the Practical Haplotype Graph in the Heterozygous Crop Cassava
Authors: Long Evan M , Bradbury Peter J. , Romay M. Cinta , Buckler Edward S. , Robbins Kelly R
Published: May 2021

Genomic applications such as genomic selection and genome-wide association have become increasingly common since the advent of genome sequencing. Genotype imputation makes it possible to infer whole genome information from limited input data, making large sampling for genomic applications more feasible, especially in non-model species where resources are less abundant. Imputation becomes increasingly difficult in heterozygous species where haplotypes must be phased. The Practical Haplotype Graph is a recently developed tool that can accurately impute genotypes, using a reference panel of haplotypes. The Practical Haplotype Graph is a haplotype database that implements a trellis graph to predict haplotypes using minimal input data. Genotyping information is aligned to the database and missing haplotypes are predicted from the most likely path through the graph. We showcase the ability of the Practical Haplotype Graph to impute genomic information in the highly heterozygous crop cassava (Manihot esculenta). Accurately phased haplotypes were sampled from runs of homozygosity across a diverse panel of individuals to populate the graph, which proved more accurate than relying on computational phasing methods. At 1X input sequence coverage, the Practical Haplotype Graph achieves a high concordance between predicted and true genotypes (R=0.84), as compared to the standard imputation tool Beagle (R=0.69). This improved accuracy was especially visible in the prediction of rare and heterozygous alleles. We validate the Practical Haplotype Graph as an accurate imputation tool in the heterozygous crop cassava, showing its potential for application in heterozygous species.
Chromosome length and gene density contribute to micronuclear membrane stability
Authors: Mammel Anna E , Huang Heather Z , Gunn Amanda L , Choo Emma , Hatch Emily M
Published: May 2021

Micronuclei are derived from missegregated chromosomes and frequently lose membrane integrity, leading to DNA damage, innate immune activation, and metastatic signaling. Here we demonstrate that two characteristics of the trapped chromosome, length and gene density, are key contributors to micronuclei membrane stability in human cells. Chromosome length is proportional to micronuclei size, and gene density has an additive effect with micronucleus size on membrane stability. We demonstrate that these results are not due to chromosome-specific differences in spindle position or initial nuclear pore complex recruitment during post-mitotic nuclear envelope assembly. We find that chromosome length and micronuclei size strongly correlate with lamin B1 and nuclear pore density in intact micronuclei. Unexpectedly, lamin B1 levels do not predict nuclear lamina organization and membrane stability. Instead, small gene-dense micronuclei have decreased nuclear lamina gaps compared to large micronuclei, despite very low levels of lamin B1. Our data strongly suggest that nuclear envelope composition defects previously correlated with membrane rupture only partly explain membrane stability in micronuclei. We propose that an unknown factor linked to gene density has a separate function that inhibits the appearance of nuclear lamina gaps and delays membrane rupture until late in the cell cycle.
Live-Cell Imaging of (p)ppGpp with RNA-based Fluorescent Sensors
Authors: Sun Zhining , Wu Rigumula , Zhao Bin , Zeinert Rilee , Chien Peter , You Mingxu
Published: May 2021

Guanosine tetra- and pentaphosphate, (p)ppGpp, are important alarmone nucleotides that regulate bacterial survival in stressful environment. A direct detection of (p)ppGpp in living cells is critical for our understanding of the mechanism of bacterial stringent response. However, it is still challenging to directly image and measure cellular (p)ppGpp. Here, we report a type of RNA-based fluorescent sensors for live-cell imaging of (p)ppGpp. Our sensor is engineered by conjugating a recently identified (p)ppGpp-specific riboswitch with a fluorogenic RNA aptamer, Broccoli. These sensors can be genetically encoded and enable direct monitoring of cellular (p)ppGpp accumulation. Unprecedented information on cell-to-cell variation and cellular dynamics of (p)ppGpp levels can now be obtained under different nutritional conditions. We predict that these RNA-based sensors will be broadly adapted to study bacterial stringent response.
Rapid Estimation of SNP Heritability using Predictive Process approximation in Large scale Cohort Studies
Authors: Seal Souvik , Datta Abhirup , Basu Saonli
Published: May 2021

With the advent of high throughput genetic data, there have been attempts to estimate heritability from genome-wide SNP data on a cohort of distantly related individuals using linear mixed model (LMM). Fitting such an LMM in a large scale cohort study, however, is tremendously challenging due to its high dimensional linear algebraic operations. In this paper, we propose a new method named PredLMM approximating the aforementioned LMM motivated by the concepts of genetic coalescence and gaussian predictive process. PredLMM has substantially better computational complexity than most of the existing LMM based methods and thus, provides a fast alternative for estimating heritability in large scale cohort studies. Theoretically, we show that under a model of genetic coalescence, the limiting form of our approximation is the celebrated predictive process approximation of large gaussian process likelihoods that has well-established accuracy standards. We illustrate our approach with extensive simulation studies and use it to estimate the heritability of multiple quantitative traits from the UK Biobank cohort.
Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy
Authors: Shroff Rachna T. , Chalasani Pavani , Wei Ran , Pennington Daniel , Quirk Grace , Schoenle Marta V. , Peyton Kameron L. , Uhrlaub Jennifer L. , Ripperger Tyler J. , Jergović Mladen , Dalgai Shelby , Wolf Alexander , Whitmer Rebecca , Hammad Hytham , Carrier Amy , Scott Aaron J. , Nikolich-Žugich Janko , Worobey Michael , Sprissler Ryan , Dake Michael , LaFleur Bonnie J. , Bhattacharya Deepta
Published: May 2021

Vaccines against SARS-CoV-2 have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. We compared immune responses to the Pfizer/BioNTech mRNA vaccine in solid tumor patients (n=53) on active cytotoxic anti-cancer therapy to a control cohort (n=50) as an observational study. Using live SARS-CoV-2 assays, neutralizing antibodies were detected in 67% and 80% of cancer patients after the first and second immunizations, respectively, with a 3-fold increase in median titers after the booster. Similar trends were observed in serum antibodies against the receptor-binding domain (RBD) and S2 regions of Spike protein, and in IFNγ+ Spike-specific T cells. Yet the magnitude of each of these responses was diminished relative to the control cohort. We therefore quantified RBD- and Spike S1-specific memory B cell subsets as predictors of anamnestic responses to additional immunizations. After the second vaccination, Spike-specific plasma cell-biased memory B cells were observed in most cancer patients at levels similar to those of the control cohort after the first immunization. We initiated an interventional phase 1 trial of a third booster shot (NCT04936997); primary outcomes were immune responses with a secondary outcome of safety. After a third immunization, the 20 participants demonstrated an increase in antibody responses, with a median 3-fold increase in virus-neutralizing titers. Yet no improvement was observed in T cell responses at 1 week after the booster immunization. There were mild adverse events, primarily injection site myalgia, with no serious adverse events after a month of follow-up. These results suggest that a third vaccination improves humoral immunity against COVID-19 in cancer patients on active chemotherapy with no severe adverse events.