bluuebunny/crossref_metadata_2025 huggingface dataset:
Influential factors of subacromial impingement syndrome after hook plate fixation for acromioclavicular joint dislocation
Authors: Xu Ding , Shi Yulong , Luo Peng , Wang Weikang , Guo Weijun , Lou Weigang , Chen Jianming
Published: June 2021

Subacromial impingement syndrome (SIS) after hook plate fixation for acromioclavicular joint (AC) dislocation was the most common complication. However, the researches on its’ influential factors were rare. The purpose of this study was to identify the risk factors by analyzing the influencing factors of postoperative SIS and minimize the incidence of SIS in clinical surgery.

We retrospectively analyzed the prospectively collected data from 330 consecutive patients with AC joint dislocation between August 2014 and August 2017 at our institute. The SIS was presented as the dependent variable at the last follow-up when the internal fixation was removed. The independent variables included age, gender, body-mass index (BMI), smoking status, alcohol consumption, type of injury, Rockwood Classification, site of injury, operation time, injury-to-surgery, the distance between the hook body and the acromion (DBA), the depth of hook tip (DHT), the distance between the hook plate and the humeral head (DHH), the distance between the acromion and the humeral head (DAH), the hook plate angle (AHP) and acromial shape. Logistic regression analysis was performed to identify independent influential factors of SIS.

A total of 312 cases were included and 18 cases were lost. The follow-up rate was 94.5%. In without SIS group, there were 225 cases (123 males and 102 females). In with SIS group, a total of 87 cases were included (56 males and 31 females). The incidence of SIS was 27.8%. DHT (OR = 9.385, 95% CI = 4.883 to 18.040, P < .001) and DBA (OR = 2.444, 95% CI = 1.591 to 3.755, P < .001) were the significant independent risk factor for SIS of AC dislocation treat with hook plate. DAH (OR = 0.597, 95% CI = 0.396 to 0.900, P = .014) and acromial shape with flat and straight (OR = 0.325, 95% CI = 0.135 to 0.785, P = .012) were also independent factors of SIS, but they were all protective.

The SIS had a high incidence in fixation of clavicular hook plate for AC dislocation. DHT and DBA were two independent risk factors, DAH and acromial shape with flat and straight were two independent protective factors for SIS. In clinical surgery, we should avoid risk factors to reduce the incidence of SIS.
Inter-rater reliability and predictive accuracy of the Shkuratova Assessment of Falls-risk in Rehabilitation (SAFER) tool
Authors: Shkuratova Nataylia , Blatsis Erene , Khaw Damien , Redley Bernice , Botti Mari , Hutchinson Anastasia F.
Published: June 2021

Despite the recognised importance of falls prevention in rehabilitation settings, there is limited research focusing on falls risk assessment tools designed to guide both patient screening and therapy. This study evaluated the predictive accuracy and inter-rater reliability of the Shkuratova Assessment of Falls-risk in Rehabilitation settings (SAFER) tool. The study was conducted at a subacute rehabilitation facility in Australia. Patient assessments were performed on admission to subacute care by trained physiotherapists, and the incidence of falls was documented prospectively. Of the 147 patients, 45 had at least one fall and were compared to 102 who had no falls. The inter-rater reliability of the SAFER tool when used by trained physiotherapists was high with the level of agreement for individual items ranging from 74 to 99%. Thirty-two (76%) patients who experienced a fall during their admission and 46 (44%) who did not fall were identified as having a high falls-risk. Using a SAFER tool cut-off of 12/26: sensitivity is 69%, specificity is 66%, area under the curve 0.71 (95% confidence interval: 0.62–0.80). The high negative predictive values at a range of cut-offs provided strong evidence that patients identified as having a low falls-risk were unlikely to experience a fall. Performing a comprehensive assessment of specific deficits in gait, balance and mobility on admission provided a streamlined approach to identification of patients who would benefit from tailored falls prevention interventions.
Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV
Authors: Rolle Charlotte-Paige , Berhe Mezgebe , Singh Tulika , Ortiz Roberto , Wurapa Anson , Ramgopal Moti , Leone Peter A. , Matthews Jessica E. , Dalessandro Marybeth , Underwood Mark R. , Angelis Konstantinos , Wynne Brian R. , Merrill Deanna , Nguyen Christopher , van Wyk Jean , Zolopa Andrew R.
Published: June 2021

Objectives:

Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting.

Design:

The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting.

Methods:

Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed).

Results:

Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred.

Conclusion:

These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].
Microfinance, retention in care, and mortality among patients enrolled in HIV care in East Africa
Authors: Genberg Becky L. , Wilson-Barthes Marta G. , Omodi Victor , Hogan Joseph W. , Steingrimsson Jon , Wachira Juddy , Pastakia Sonak , Tran Dan N. , Kiragu Zana W. , Ruhl Laura J. , Rosenberg Molly , Kimaiyo Sylvester , Galárraga Omar
Published: June 2021

Objective:

To measure associations between participation in community-based microfinance groups, retention in HIV care, and death among people with HIV (PWH) in low-resource settings.

Design and methods:

We prospectively analyzed data from 3609 patients enrolled in an HIV care program in western Kenya. HIV patients who were eligible and chose to participate in a Group Integrated Savings for Health Empowerment (GISHE) microfinance group were matched 1 : 2 on age, sex, year of enrollment in HIV care, and location of initial HIV clinic visit to patients not participating in GISHE. Follow-up data were abstracted from medical records from January 2018 through February 2020. Logistic regression analysis examined associations between GISHE participation and two outcomes: retention in HIV care (i.e. >1 HIV care visit attended within 6 months prior to the end of follow-up) and death. Socioeconomic factors associated with HIV outcomes were included in adjusted models.

Results:

The study population was majority women (78.3%) with a median age of 37.4 years. Microfinance group participants were more likely to be retained in care relative to HIV patients not participating in a microfinance group [adjusted odds ratio (aOR) = 1.31, 95% confidence interval (CI) 1.01–1.71; P = 0.046]. Participation in group microfinance was associated with a reduced odds of death during the follow-up period (aOR = 0.57, 95% CI 0.28–1.09; P = 0.105).

Conclusion:

Participation in group-based microfinance appears to be associated with better HIV treatment outcomes. A randomized trial is needed to assess whether microfinance groups can improve clinical and socioeconomic outcomes among PWH in similar settings.
18F-FET PET/CT as a Diagnostic Tool for Brain Abscess
Authors: Kang Seo Young , Jang Yunejeong , Cho Min-Sun , Park Soo Jeong , Moon Byung Seok , Kim Hye Ok , Yoon Hai-Jeon , Kim Bom Sahn
Published: June 2021

A 49-year-old man presented with sudden right-sided weakness and seizure. Brain MRI identified a lobulated mass with diffusion restriction and irregular wall enhancement in the left parietal lobe. 18F-FET (O-(2-[18F]fluoroethyl)-l-tyrosine) PET/CT was performed, which identified a cystic mass in the left parietal lobe accompanied by FET uptake. Compartmentalized uptake was also confirmed throughout the left parietal lobe. Considering the relatively low target-to-background ratio and uptake observed in the entire left parietal lobe, the lesion was more likely to be a brain abscess than a tumor. The pathologic diagnosis after mass removal was acute and chronic inflammation with abscess.
Visualization of Fibroblast Activation After Myocardial Infarction Using 68Ga-FAPI PET
Authors: Kessler Lukas , Kupusovic Jana , Ferdinandus Justin , Hirmas Nader , Umutlu Lale , Zarrad Fadi , Nader Michael , Fendler Wolfgang P. , Totzeck Matthias , Wakili Reza , Schlosser Thomas , Rassaf Tienush , Rischpler Christoph , Siebermair Johannes
Published: June 2021

Aims

The aim of this retrospective analysis was to examine the pattern of cardiac 68Ga-fibroblast-activation protein-α inhibitor (FAPI) uptake in patients after acute myocardial infarction (AMI) using PET and to investigate its association with results of coronary angiography. We correlated FAPI uptake with biomarkers of myocardial damage including left ventricular function.

Methods and Results

A cohort of 10 patients with no history of coronary artery disease underwent PET 18 ± 20.6 days after AMI (ST-segment elevation myocardial infarction [n = 5] and non–ST-segment elevation infarction [n = 5]), respectively. SUVmax, SUVmean, and SUVpeak of localized tracer uptake were calculated; tracer uptake volume was reported as fibroblast activation volume (FAV), with imaging data being correlated with clinical parameters. Focal FAPI uptake was observed in all patients. Average uptake at 10 minutes postinjection was 8.9 ± 4.4 (SUVmax), 7.6 ± 4.0 (SUVpeak), and 5.3 ± 2.8 (SUVmean), respectively. Affected myocardium showed a partial to complete match between tracer uptake and confirmed culprit lesion by coronary angiography in 44.4% and 55.6% of patients, respectively. A strong correlation between FAV and peak creatine kinase level (r = 0.90, P < 0.01) and inverse correlation of FAV with left ventricular function (r = −0.69, P < 0.05) was observed.

Conclusions

This analysis demonstrates in vivo visualization of fibroblast activation after AMI. The uptake area showed a very good agreement with the affected coronary territory. A strong correlation of the de novo established parameter FAV with left ventricular function and peak creatine kinase was observed. This imaging modality may provide important insights into mechanisms of structural remodeling after AMI at an early stage.
Thyroid Metastasis in Whole-Body 18F-FDG PET/CT Restaging of Small Cell Lung Cancer
Authors: Vogel Jonas , Tenev Alina , Solass Wiebke , Schwenck Johannes , Dittmann Helmut
Published: June 2021

Incidental findings of thyroid lesions, some of which show increased FDG uptake, are common in whole-body FDG PET/CT imaging of oncological patients. As metastases to the thyroid are extremely rare, it is often a matter of debate, whether thyroid lesions should be considered as benign goiter or evaluated further. Here, we present the case of a 65-year-old woman with history of small cell lung cancer and multiple thyroid lesions, classified as benign nodular goiter. Because in restating using18F-FDG PET/CT these lesions showed an increased FDG uptake and growth progression, decision was made for fine-needle aspiration, which revealed small cell lung cancer metastasis 14 months after first tumor diagnosis.
Pineal Yolk Sac Tumor Producing α-Fetoprotein Detected by 68Ga-FAPI PET/MRI
Authors: Dai Yaqing , Pang Yizhen , Bao Weiqi , Cheng Yuanyuan , Chen Haojun
Published: June 2021

Pineal yolk sac tumors (YSTs) are a rare type of extragonadal YST. They make up a small fraction of all intracranial germ cell tumors and an even small fraction of pineal masses overall. This study reported a case of pineal YST with α-fetoprotein production revealed by 18F-FDG and 68Ga-FAPI PET/MRI. In the PET images, 68Ga-FAPI showed a far better tumor-to-background ratio than 18F-FDG in the pineal YST because there is little 68Ga-FAPI uptake in the brain. This case indicates that 68Ga-FAPI PET/MRI may be a useful tool for evaluating intracranial YST and other types of tumors in central nervous system.
68Ga-PSMA-11 PET/CT in Isolated Bilateral Adrenal Metastases From Prostate Adenocarcinoma
Authors: Zhao Qian , Yang Bo , Dong Aisheng , Zuo Changjing
Published: June 2021

A 65-year-old man with treated prostate adenocarcinoma underwent68Ga-PSMA-11 PET/CT scan for restaging due to significantly increased serum PSA levels. PET/CT showed bilateral adrenal masses with high68Ga-PSMA-11 uptake. There was no other lesion suspicious for metastasis. The laboratory and imaging findings were consisted with isolated bilateral adrenal metastases from prostate adenocarcinoma. The patient received docetaxel chemotherapy in combination with androgen deprivation therapy. PSA levels gradually decreased during chemotherapy. Follow-up MRI showed the bilateral adrenal masses significantly decreased in size. This case demonstrates the usefulness of68Ga-PSMA-11 PET/CT in identifying atypical metastasis from prostate adenocarcinoma.
The Impact of Obesity on Critical Illnesses
Authors: Ayalon Itay , Bodilly Lauren , Kaplan Jennifer
Published: June 2021

In the last few decades, obesity became one of the world's greatest health challenges reaching a size of global epidemic in virtually all socioeconomic statuses and all age groups. Obesity is a risk factor for many health problems and as its prevalence gradually increases is becoming a significant economic and health burden. In this manuscript we describe how normal respiratory and cardiovascular physiology is altered by obesity. We review past and current literature to describe how obesity affects outcomes of patients facing critical illnesses and discuss some controversies related to this topic.
T-cell Exhaustion in Organ Transplantation
Authors: Angeletti Andrea , Cantarelli Chiara , Riella Leonardo V. , Fribourg Miguel , Cravedi Paolo
Published: June 2021

Exhaustion of T cells occurs in response to long-term exposure to self and foreign antigens. It limits T cell capacity to proliferate and produce cytokines, leading to an impaired ability to clear chronic infections or eradicate tumors. T-cell exhaustion is associated with a specific transcriptional, epigenetic, and metabolic program and characteristic cell surface markers’ expression. Recent studies have begun to elucidate the role of T-cell exhaustion in transplant. Higher levels of exhausted T cells have been associated with better graft function in kidney transplant recipients. In contrast, reinvigorating exhausted T cells by immune checkpoint blockade therapies, while promoting tumor clearance, increases the risk of acute rejection. Lymphocyte depletion and high alloantigen load have been identified as major drivers of T-cell exhaustion. This could account, at least in part, for the reduced rates of acute rejection in organ transplant recipients induced with thymoglobulin and for the pro-tolerogenic effects of a large organ such as the liver. Among the drugs that are widely used for maintenance immunosuppression, calcineurin inhibitors have a contrasting inhibitory effect on exhaustion of T cells, while the influence of mTOR inhibitors is still unclear. Harnessing or encouraging the natural processes of exhaustion may provide a novel strategy to promote graft survival and transplantation tolerance.
Correlation between the ankle–brachial index and microalbuminuria with certain risk factors in type 2 diabetes patients
Authors: Nguyen Van Tuan , Phan Ha Linh , Hoang Thi Minh , Dam Thi Phuong Lan , Ho Thi Hang , Huynh Quang Thuan
Published: June 2021

Background

The ankle–brachial index (ABI) is a fast, simple, noninvasive method that provides accurate results in the early diagnosis of peripheral artery disease. Microalbuminuria is considered a predictor of renal and cardiovascular complications in patients with diabetes. This study was conducted to determine the correlation between ABI and microalbuminuria with certain risk factors in patients with type 2 diabetes.

Subjects and research methods

A cross-sectional descriptive study was performed on 62 inpatients with type 2 diabetes. All patients were measured for ABI as well as microalbuminuria, HbA1c, glucose and lipidemia in the blood.

Results

The study results showed that in patients with dyslipidemia, the risk of having microalbuminuria (+) increased 5.7 times and ABI ≤0.90 increased 8.6 times (P = 0.004 and 0.021, respectively). Fasting blood glucose >7.2 mmol/L had 5.7 times higher microalbuminuria (+) risk and 8.6 times higher ABI ≤0.90 (P = 0.004 and 0.021, respectively). Patients with HbA1c ≥7% were 2.9 times more likely to have microalbuminuria (+) and ABI ≤0.90 (P = 0.043 and 0.048, respectively).

Conclusions

Peripheral vascular disease risk factors such as hypertension, dyslipidemia and waist circumference and the effectiveness of fasting blood glucose and HbA1c control increased the risk of high microalbuminuria and ABI in patients with type 2 diabetes.
A runtime alterable epidemic model with genetic drift, waning immunity, and vaccinations
Authors: Getz Wayne M. , Salter Richard , Vissat Ludovica Luisa , Koopman James S. , Simon Carl P.
Published: June 2021

In this paper, we present methods for building a Java Runtime-Alterable-Model Platform (RAMP) of complex dynamical systems. We illustrate our methods by building a multivariant SEIR (epidemic) RAMP. Underlying our RAMP is an individual-based model that includes adaptive contact rates, pathogen genetic drift, waning and cross immunity. Besides allowing parameter values, process descriptions, and scriptable runtime drivers to be easily modified during simulations, our RAMP is easily integrated into other computational platforms, such as our illustrated example with R-Studio. Processes descriptions that can be runtime altered within our SEIR RAMP include pathogen variant-dependent host shedding, environmental persistence, host transmission, and within-host pathogen mutation and replication. They also include adaptive social distancing and adaptive application of vaccination rates and variant-valency of vaccines. We present simulation results using parameter values and process descriptions relevant to the current COVID-19 pandemic. Our results suggest that if waning immunity outpaces vaccination rates, then vaccination rollouts may fail to contain the most transmissible variants, particularly if vaccine valencies do not adapt to escape mutations. Our SEIR RAMP is designed for easy-use by individuals and groups involved in formulating social-distancing and adaptive vaccination rollout policies. More generally, our RAMP concept facilitates construction of highly flexible complex systems models of all types, which can then be easily shared among researchers and policymakers as stand alone applications programs.
Reproducibility of global electrical heterogeneity measurements on 12-lead ECG: The Multi-Ethnic Study of Atherosclerosis
Authors: Haq Kazi T. , Lutz Katherine J. , Peters Kyle , Craig Natalie , Mitchell Evan , Desai Anish K. , Stencel Nathan W. L. , Soliman Elsayed Z. , Lima João A.C. , Tereshchenko Larisa G.
Published: June 2021

Objective

Vectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics.

Methods

GEH was measured on two 10-second 12-lead ECGs recorded on the same day in 4,316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4±9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradient’s (SVG’s) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi).

Results

Two N ECGs with heart rate (HR) bias of -0.64 (95% limits of agreement [LOA] - 5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of -0.12 (95%LOA -14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA -15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA -33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA -3.0 to 3.5) showed aQRST bias of -1.03 (95%LOA -11.9 to 9.9). After excluding premature arial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA -0.092 to 0.092).

Conclusion

GEH measurements on N, S, and VP median beats are reproducible. SVG’s scalar can be measured as either SAIQRST or VMQTi.

Significance

Satisfactory reproducibility of GEH metrics supports their implementation.

Highlights

VCG metrics are reliably reproducible, which supports their implementation.

GEH is reproducible if measured during atrial fibrillation or ventricular pacing.

Scalar of spatial ventricular gradient can be measured as either SAIQRST or VMQTi.
Using structurally fungible biosensors to evolve improved alkaloid biosyntheses
Authors: d’Oelsnitz Simon , Kim Wantae , Burkholder Nathaniel T. , Javanmardi Kamyab , Thyer Ross , Zhang Yan , Alper Hal , Ellington Andrew D.
Published: June 2021

A key bottleneck in the microbial production of therapeutic plant metabolites is identifying enzymes that can greatly improve yield. The facile identification of genetically encoded biosensors can overcome this limitation and become part of a general method for engineering scaled production. We have developed a unique combined screening and selection approach that quickly refines the affinities and specificities of generalist transcription factors, and using RamR as a starting point we evolve highly specific (>100-fold preference) and sensitive (EC50<30 μM) biosensors for the alkaloids tetrahydropapaverine, papaverine, glaucine, rotundine, and noscapine. High resolution structures reveal multiple evolutionary avenues for the fungible effector binding site, and the creation of new pockets for different chemical moieties. These sensors further enabled the evolution of a streamlined pathway for tetrahydropapaverine, an immediate precursor to four modern pharmaceuticals, collapsing multiple methylation steps into a single evolved enzyme. Our methods for evolving biosensors now enable the rapid engineering of pathways for therapeutic alkaloids.
Dengue and Zika virus capsid proteins bind to membranes and self-assemble into liquid droplets with nucleic acids
Authors: Ambroggio Ernesto E. , Navarro Guadalupe Soledad Costa , Socas Luis Benito Pérez , Bagatolli Luis A. , Gamarnik Andrea V.
Published: June 2021

Liquid-liquid phase separation is prone to occur when positively charged proteins interact with nucleic acids. Here, we studied biophysical properties of Dengue (DENV) and Zika (ZIKV) virus capsid proteins to understand the process of RNA genome encapsidation. In this route, the capsid proteins efficiently recruit the viral RNA at the ER membrane to yield nascent viral particles. However, little is known either about the molecular mechanisms by which multiple copies of capsid proteins assemble into nucleocapsids or how the nucleocapsid is recruited and wrapped by the ER membrane during particle morphogenesis. Here, we measured relevant interactions concerning the viral process using purified DENV and ZIKV capsids proteins, membranes mimicking the ER lipid composition and nucleic acids at in vitro conditions. We found that both ZIKV and DENV capsid proteins bound to liposomes at liquid-disordered phase regions and docked exogenous membranes and RNA molecules. When the proteins bound nucleic acids, droplet liquid-liquid phase separation was observed. We characterized these liquid condensates by measuring nucleic acid partition constant and the extent of water dipolar relaxation observing a cooperative process for the formation of the new phase that involves a distinct water organization. Our data supports a new model in which capsid-RNA complexes directly bind the ER membrane, seeding the process of RNA recruitment for viral particle assembly. These results contribute to understand the viral nucleocapsid formation as a stable liquid-liquid phase transition, which could be relevant for Dengue and Zika gemmation, opening new avenues for antiviral intervention.
Prenatal Acetaminophen, Adverse Birth Outcomes, and ADHD: Mediation Analysis in a Prospective Cohort
Authors: Baker Brennan H. , Burris Heather H. , Bloomquist Tessa R. , Boivin Amélie , Gillet Virginie , Larouche Annie , Bellenger Jean-Philippe , Pasquier Jean-Charles , Baccarelli Andrea A. , Takser Larissa
Published: June 2021

Structured Abstract

Background

Although we previously reported an association of prenatal acetaminophen exposure with more than two-fold increased odds of child ADHD, it is unknown whether prenatal acetaminophen is associated with adverse birth outcomes, and if birth outcomes may mediate the association of prenatal acetaminophen with ADHD.

Methods

This birth cohort from Sherbrooke, Québec, Canada, included 773 live births. Mothers with no thyroid disease enrolled at their first prenatal care visit or delivery. Acetaminophen was measured in meconium for 393 children at delivery. Physician diagnosis of ADHD was determined when children were 6-7 years old. We first tested associations of prenatal acetaminophen with birthweight, preterm birth, gestational age, and small and large for gestational age. Then we assessed whether these birth outcomes mediate the association of prenatal acetaminophen with ADHD. We imputed missing data via multiple imputation and used inverse probability weighting to account for confounding and selection bias.

Results

Acetaminophen was detected in 222 meconium samples (56.5%). Prenatal acetaminophen exposure was associated with decreased birthweight by 136 grams (β = -136; 95%CI [-229, - 43]), 20% increased weekly hazard of delivery (hazard ratio = 1.20; 95%CI [1.00, 1.43]), and over 60% decreased odds of being born large for gestational age (odds ratio = 0.38; 95%CI [0.20, 0.75]). There was no evidence for adverse birth outcomes mediating the association of prenatal acetaminophen with child ADHD.

Conclusions

Although unobserved confounding and confounding by indication are possible, these results warrant further investigation into adverse perinatal effects of prenatal acetaminophen exposure.
Identification of novel human derived influenza viruses in pigs with zoonotic potential
Authors: Tapia Rodrigo , Brito Bárbara , Saavedra Marco , Mena Juan , García-Salum Tamara , Rathnasinghe Raveen , Barriga Gonzalo , Tapia Karla , García Victoria , Bucarey Sergio , Jang Yunho , Wentworth David , Torremorell Montserrat , Neira Víctor , Medina Rafael A.
Published: June 2021

In 2009, a novel swine influenza A virus (IAV) emerged causing a global pandemic that highlighted the role of swine as a reservoir. To date, there is limited information about swine IAV circulating in Latin America. We identified two swine H1N2 and one divergent swine H3N2 viruses that co-circulated in Chilean swine together with the 2009 H1N1 pandemic strain (A(H1N1)pdm09). Phylogenetic analysis revealed several human-to-swine IAV introductions occurring as early as the mid-1980s, and since 2009, several introductions of the A(H1N1)pdm09 strain. Antigenic cartography confirmed that these viruses were antigenically unique and identified drifted variants within the clusters. Human sera from the Chilean general population showed an age dependent mid to low-level antibody mediated protection against swine H1N2 and A(H1N1)pdm09-like viruses and a poor protection against the swine H3N2 virus, highlighting the zoonotic potential of this strain. Our results underscore the epidemiological importance of studying swine IAV in Latin America for epidemic and pandemic preparedness.
Alzheimer’s disease BIN1 coding variants increase intracellular Aβ by interfering with BACE1 recycling
Authors: Perdigão Catarina , Barata Mariana , Burrinha Tatiana , Almeida Cláudia Guimas
Published: June 2021

Genetics identified BIN1 as the second most important risk locus associated with late-onset Alzheimer’s disease, after APOE4. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid accumulation (iAbeta) and early endosome enlargement, two interrelated early cytopathological Alzheimer’s disease phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates beta-amyloid production by decreasing BACE1 recycling and enlarging early endosomes. Here, we demonstrate that the expression of the two LOAD mutant forms of Bin1 did not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. The LOAD coding variants reduced Bin1 interaction with BACE1 likely causing a dominant-negative effect since Bin1 mutants, but not wild-type Bin1, overexpression increased iAbeta42 due to defective BACE1 recycling and accumulation in early endosomes. Endocytic recycling of transferrin was similarly affected by Bin1 wild-type and mutants, indicating that Bin1 is a general regulator of endocytic recycling. These data show that the LOAD mutations in Bin1 lead to a loss of function, suggesting that endocytic recycling defects are an early causal mechanism of Alzheimer’s disease.
Transmission distortion and genetic incompatibilities between alleles in a multigenerational mouse advanced intercross line
Authors: Arends Danny , Kärst Stefan , Heise Sebastian , Korkuc Paula , Hesse Deike , Brockmann Gudrun A.
Published: June 2021

Background/Objectives

While direct additive and dominance effects on complex traits have been mapped repeatedly, additional genetic factors contributing to the heterogeneity of complex traits have been scarcely investigated. To assess genetic background effects, we investigated transmission ratio distortions (TRDs) of alleles from parent to offspring using an advanced intercross line (AIL) of an initial cross between the mouse inbred strains C57BL/6NCrl (B6N) and BFMI860-12 (BFMI).

Subjects/Methods

341 males of generation 28 and their respective 61 parents and 66 grandparents were genotyped using Mega Mouse Universal Genotyping Arrays (MegaMUGA). TRDs were investigated using allele transmission asymmetry tests, and pathway overrepresentation analysis was performed. Sequencing data was used to test for overrepresentation of non-synonymous SNPs in TRD regions. Genetic incompatibilities were tested using the Bateson-Dobzhansky-Muller two-locus model.

Results

62 TRD regions were detected, many in close proximity to the telocentric centromere. TRD regions contained 44.5% more non-synonymous SNPs than randomly selected regions (182 vs. 125.9 ± 17.0, P < 1×10−4). Testing for genetic incompatibilities between TRD regions identified 29 genome-wide significant incompatibilities between TRD regions (P(BF) < 0.05). Pathway overrepresentation analysis of genes in TRD regions showed that DNA methylation, epigenetic regulation of RNA, and meiotic/meiosis regulation pathways were affected independent of the parental origin of the TRD. Paternal BFMI TRD regions showed overrepresentation in the small interfering RNA (siRNA) biogenesis and in the metabolism of lipids and lipoproteins. Maternal B6N TRD regions harbored genes involved in meiotic recombination, cell death, and apoptosis pathways. The analysis of genes in TRD regions suggests the potential distortion of protein-protein interactions influencing obesity and diabetic retinopathy as a result of disadvantageous combinations of allelic variants in Aass, Pgx6 and Nme8.

Conclusions

Using an AIL significantly improves the resolution at which we can investigate TRD. Our analysis implicates distortion of protein-protein interactions as well as meiotic drive as the underlying mechanisms leading to the observed TRD in our AIL. Furthermore, genes with large amounts of non-synonymous SNPs located in TRD regions are more likely to be involved in pathways that are related to the phenotypic differences between the parental strains. Genes in these TRD regions provide new targets for investigating genetic adaptation, protein-protein interactions, and determinants of complex traits such as obesity.
Recurrent erosion ofCOA1/MITRAC15demonstrates gene dispensability in oxidative phosphorylation
Authors: Shinde Sagar Sharad , Sharma Sandhya , Teekas Lokdeep , Sharma Ashutosh , Vijay Nagarjun
Published: June 2021

Skeletal muscle fibers rely upon either oxidative phosphorylation or glycolytic pathway to achieve muscular contractions that power mechanical movements. Species with energy-intensive adaptive traits that require sudden bursts of energy have a greater dependency on fibers that use the glycolytic pathway. Glycolytic fibers have decreased reliance on OXPHOS and lower mitochondrial content compared to oxidative fibers. Hence, we hypothesized that adaptive gene loss might have occurred within the OXPHOS pathway in lineages that largely depend on glycolytic fibers. The protein encoded by theCOA1/MITRAC15gene with conserved orthologs found in budding yeast to humans promotes mitochondrial translation. We show that gene disrupting mutations have accumulated within theCOA1/MITRAC15gene in the cheetah, several species of galliforms, and rodents. The genomic region containingCOA1/MITRAC15is a well-established evolutionary breakpoint region in mammals. Careful inspection of genome assemblies of closely related species of rodents and marsupials suggests two independentCOA1/MITRAC15gene loss events co-occurring with chromosomal rearrangements. Besides recurrent gene loss events, we document changes inCOA1/MITRAC15exon structure in primates and felids. The detailed evolutionary history presented in this study reveals the intricate link between skeletal muscle fiber composition and dispensability of the chaperone-like role of theCOA1/MITRAC15gene.
Time-resolved secretome analysis of threeColletotrichumspecies identifies copper radical alcohol oxidases for the production of fatty aldehydes
Authors: Ribeaucourt David , Saker Safwan , Navarro David , Bissaro Bastien , Drula Elodie , Correia Lydie Oliveira , Haon Mireille , Grisel Sacha , Lapalu Nicolas , Henrissat Bernard , O’Connell Richard J. , Lambert Fanny , Lafond Mickaël , Berrin Jean-Guy
Published: June 2021

Copper Radical Alcohol Oxidases (CRO-AlcOx), which have been recently discovered among fungal phytopathogens are attractive for the production of fragrant fatty aldehydes. To investigate the secretion of CRO-AlcOx by natural fungal strains, we undertook time-course analyses of the secretomes of threeColletotrichumspecies (C. graminicola, C. tabacumandC. destructivum) using proteomics. The addition of a copper-manganese-ethanol mixture toColletotrichumcultures unexpectedly induced the secretion of up to 400 proteins, 29-52% of which were carbohydrate-active enzymes (CAZymes), including a wide diversity of copper-containing oxidoreductases from the auxiliary activities (AA) class (AA1, AA3, AA5, AA7, AA9, AA11-AA13, AA16). Under these specific conditions, while a CRO-glyoxal oxidase from the AA5_1 subfamily was among the most abundantly secreted proteins, the targeted AA5_2 CRO-AlcOx were secreted at lower levels, suggesting heterologous expression as a more promising strategy for CRO-AlcOx production and utilization.C. tabacumandC. destructivumCRO-AlcOx were expressed inPichia pastorisand their preference toward both aromatic and aliphatic primary alcohols was assessed. The CRO-AlcOx fromC. destructivumwas further investigated in applied settings, revealing a full conversion of C6 and C8 alcohols into their corresponding fragrant aldehydes.

IMPORTANCE

In the context of the industrial shift toward greener processes, the biocatalytic production of aldehydes is of utmost interest owing to their importance as intermediates in preparative chemistry and for their use as flavors and fragrances ingredients. In the search for new biocatalysts, CRO-AlcOx have the potential to become platform enzymes for the oxidation of alcohols to aldehydes. The use of crude fungal secretomes is often seen has an appealing approach by industries since alleviating various costs pertaining to biocatalysts production. However, the secretion of CRO-AlcOx by natural fungal strains has never been explored. This study showed thatColletotrichumspecies can secrete a broad diversity of copper-containing enzymes, but only little amount of CRO-AlcOx. Thus, recombinant expression remains the most promising approach. The potential of CRO-AlcOx as biocatalyst for flavor and fragrance applications was confirmed through the production of two new enzymes with activity on fatty alcohols.
A deep learning approach to capture the essence ofCandida albicansmorphologies
Authors: Bettauer V , Costa ACBP , Omran RP , Massahi S , Kirbizakis E , Simpson S , Dumeaux V , Law C , Whiteway M , Hallett MT
Published: June 2021

We present deep learning-based approaches for exploring the complex array of morphologies exhibited by the opportunistic human pathogenC. albicans. Our system entitled Candescence automatically detectsC. albicanscells from Differential Image Contrast microscopy, and labels each detected cell with one of nine vegetative, mating-competent or filamentous morphologies. The software is based upon a fully convolutional one-stage object detector and exploits a novel cumulative curriculum-based learning strategy that stratifies our images by difficulty from simple vegetative forms to more complex filamentous architectures. Candescence achieves very good performance on this difficult learning set which has substantial intermixing between the predicted classes. To capture the essence of eachC. albicansmorphology, we develop models using generative adversarial networks and identify subcomponents of the latent space which control technical variables, developmental trajectories or morphological switches. We envision Candescence as a community meeting point for quantitative explorations ofC. albicansmorphology.
Autonomic and respiratory components of orienting behaviors are mediated by descending pathways originating from the superior colliculus
Authors: Lynch Erin , Dempsey Bowen , Saleeba Christine , Monteiro Eloise , Turner Anita , Burke Peter GR , Allen Andrew M , Dampney Roger AL , Hildreth Cara M , Cornish Jennifer L , Goodchild Ann K , McMullan Simon
Published: June 2021

The ability to discriminate competing, external stimuli, and initiate contextually appropriate behaviors, is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting and attention, behaviors which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear and persisted under urethane anesthesia, indicating independence from emotional stress. Moreover, autonomic responses were replicated by selective stimulation of dSC inputs to a subregion in the ventromedial medulla containing spinally-projecting premotor neurons. This putative disynaptic pathway from the dSC represents a likely substrate for autonomic components of orienting.
Greenland’s thaw pushes the biodiversity crisis
Authors: Ureta Carolina , Ramírez-Barahona Santiago , Calderón-Bustamante Óscar , Cruz-Santiago Pedro , Gay-García Carlos , Swingedouw Didier , DeFrance Dimitri , Cuervo-Robayo Angela P.
Published: June 2021

Anthropogenic greenhouse gas emissions have led to sustained global warming over the last decades1. This is already reshaping the distribution of biodiversity across the world and can lead to the occurrence of large-scale singular events, such as the melting of polar ice sheets2,3. The potential impacts of such a melting event on species persistence across taxonomic groups – in terms of magnitude and geographic extent – remain unexplored. Here we assess impacts on biodiversity of global warming and melting of Greenland’s ice sheet on the distribution of 21,146 species of vascular plants and tetrapods across twelve megadiverse countries. We show that high global warming would lead to widespread reductions in species’ geographic ranges (median range loss, 35–78%), which are magnified (median range loss, 95–99%) with the added contribution of Greenland’s melting and its potentially large impact on oceanic circulation and regional climate changes. Our models project a decline in the geographical extent of species hotspots across countries (median reduction, 48–95%) and a substantial alteration of species composition in the near future (mean temporal dissimilarity, 0.26–0.89). These results imply that, in addition to global warming, the influence of Greenland’s melting can lead to the collapse of biodiversity across the globe, providing an added domino in its cascading effects.
The Candida albicans Cdk8-dependent phosphoproteome reveals repression of hyphal growth through a Flo8-dependent pathway
Authors: Hollomon Jeffrey M. , Liu Zhongle , Rusin Scott F. , Jenkins Nicole P. , Smith Allia K. , Koeppen Katja , Kettenbach Arminja N. , Myers Lawrence C. , Hogan Deborah A.
Published: June 2021

Ssn3, also known as Cdk8, is a member of the four protein Cdk8 submodule within the multi-subunit Mediator complex involved in the co-regulation of transcription. In Candida albicans, the loss of Ssn3 kinase activity affects multiple phenotypes including cellular morphology, metabolism, nutrient acquisition, immune cell interactions, and drug resistance. In these studies, we generated a strain in which Ssn3 was replaced with a functional variant of Ssn3 that can be rapidly and selectively inhibited by the ATP analog 3-MB-PP1. Consistent with ssn3 null mutant and kinase dead phenotypes, inhibition of Ssn3 kinase activity promoted hypha formation. Furthermore, the increased expression of hypha-specific genes was the strongest transcriptional signal upon inhibition of Ssn3 in transcriptomics analyses. Rapid inactivation of Ssn3 was used for phosphoproteomic studies performed to identify Ssn3 kinase substrates associated with filamentation potential. Both previously validated and novel Ssn3 targets were identified. Protein phosphorylation sites that were reduced specifically upon Ssn3 inhibition included two sites in Flo8 which is a transcription factor known to positively regulate C. albicans morphology. Mutation of the two Flo8 phosphosites (threonine 589 and serine 620) was sufficient to increase Flo8-HA levels and Flo8 dependent activity, suggesting that Ssn3 kinase activity negatively regulates Flo8. Previous work has also shown that loss of Ssn3 activity leads to increased alkalinization of medium with amino acids. Here, we show that FLO8 and STP2, a transcription factor involved in amino acid utilization, are required for ssn3Δ/Δ phenotype, but that loss of the Ssn3 phosphosites identified in Flo8 was not sufficient to phenocopy the ssn3Δ/Δ mutant. These data highlight the spectrum of processes affected by the modulation of Ssn3 activity and underscore the importance of considering Ssn3 function in the control of transcription factor activities.
A DNA Replication-Independent Function of the pre-Replication Complex during Cell Invasion in C. elegans
Authors: Lattmann Evelyn , Deng Ting , Walser Michael , Widmer Patrizia , Rexha-Lambert Charlotte , Prasad Vibhu , Eichhoff Ossia , Daube Michael , Dummer Reinhard , Levesque Mitchell P. , Hajnal Alex
Published: June 2021

Cell invasion is an initiating event during tumor cell metastasis and an essential process during development. A screen of C. elegans orthologs of genes over-expressed in invasive human melanoma cells has identified several components of the conserved DNA pre-replication complex (pre-RC) as positive regulators of anchor cell (AC) invasion. The pre-RC functions cell-autonomously in the G1-arrested AC to promote invasion, independently of its role in licensing DNA replication origins in proliferating cells. While the helicase activity of the pre-RC is necessary for AC invasion, the downstream acting DNA replication initiation factors are not required. The pre-RC promotes the invasive fate by regulating the expression of extracellular matrix genes and components of the PI3K signaling pathway. Increasing PI3K pathway activity partially suppressed the AC invasion defects caused by pre-RC depletion, suggesting that the PI3K pathway is one critical pre-RC target. We propose that the pre-RC acts in the non-proliferating AC as a transcriptional regulator that facilitates the switch to an invasive phenotype.
MGEnrichment: a web application for microglia gene list enrichment analysis
Authors: Jao Justin , Ciernia Annie Vogel
Published: June 2021

Gene expression analysis is becoming increasingly utilized in neuro-immunology research, and there is a growing need for non-programming scientists to be able to analyze their own genomic data. MGEnrichment is a web application developed both to disseminate to the community our curated database of microglia-relevant gene lists, and to allow non-programming scientists to easily conduct statistical enrichment analysis on their gene expression data. Users can upload their own gene IDs to assess the relevance of their expression data against gene lists from other studies. We include example datasets of differentially expressed genes (DEGs) from human postmortem brain samples from Autism Spectrum Disorder (ASD) and matched controls. We demonstrate how MGEnrichment can be used to expand the interpretations of these DEG lists in terms of regulation of microglial gene expression and provide novel insights into how ASD DEGs may be implicated specifically in microglial development, microbiome responses and relationships to other neuropsychiatric disorders. This tool will be particularly useful for those working in microglia, autism spectrum disorders, and neuro-immune activation research. MGEnrichment is available at https://ciernialab.shinyapps.io/MGEnrichmentApp/ and further online documentation and datasets can be found at https://github.com/ciernialab/MGEnrichmentApp. The app is released under the GNU GPLv3 open source license.