bluuebunny/crossref_metadata_2025 huggingface dataset:
The Achilles’ Heel of Pancreatic Cancer: Targeting pancreatic cancer's unique immunologic characteristics and metabolic dependencies in clinical trials
Authors: Siolas Despina , Morrissey Christy , Oberstein Paul E.
Published: August 2020

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and is notoriously refractory to multiple cancer treatments. In recent years, cancer therapy has expanded beyond traditional cytotoxic chemotherapy to targeted agents and immunotherapy which have been successfully implemented in many cancers. Despite robust pre-clinical research, these novel therapies have only had a small impact on PDAC. However, there have been successes with emerging clinical data supporting a potential role for checkpoint inhibitor therapy and targeted therapy with poly (ADP-ribose) polymerase inhibitors for select subsets of PDAC patients. In this clinical review, we discuss recent pre-clinical evidence for targeting metabolic pathways as well as prevalent intratumoral immune subsets, and focus on clinical trials designed to test novel agents in PDAC. The challenge of translating pre-clinical findings to patients remains substantial and many clinical trials yield negative results, but collaborative efforts and renewed focus on novel clinical trials have led to optimism that we will identify additional options for PDAC patients and change outcomes for this deadly disease.
Factors associated with the performance of primary dental health care in Brazil
Authors: Reis Clarice Magalhães Rodrigues dos , Mendes Suellen da Rocha , Matta-Machado Antônio Thomaz Gonzaga da , Mambrini Juliana Vaz de Melo , Werneck Marcos Azeredo Furquim , Abreu Mauro Henrique Nogueira Guimarães de
Published: August 2020

This study evaluated the factors associated with the performance of Brazilian Oral Health Teams (OHTs).

This is multilevel research that used data from 12,386 Brazilian OHTs in 2012. The OHTs performance was estimated in previous research by using Item Response Theory model, which employed 20 questions about dental procedures in Primary Care. The first level covariates were based on OHTs procedures such as: the record of pregnant woman dental appointment, provision of dentistry home care, dental appointments scheduled choices, and OHTs in charge for more than 5000 individuals. Moreover, the use of guidelines was accessed concerning delivering prostheses in primary care, referring to secondary care, referring to suspected oral cancer, and providing care towards patients with special needs. Variables included in level 2 were GINI and Human Development Index. Multilevel linear regression models were constructed, estimating linear regression coefficients, 95% confidence intervals, and P values.

OHTs performance was different among the 3,613 municipalities analyzed (P < .001), with 36.7% of the variation in the performance of the OHTs being attributed to the variability between municipalities. The adjusted model showed that higher performance OHTs reported attention to pregnant women, dentistry home care and use of dental care guidelines (P < .001). There were lower performance scores for those OHTs with more restricted scheduling (P < .05), compared to those that reported scheduling appointments at any day and time. The best OHTs and population ratio led to a better performance score (P = .010). At the municipal level, better socioeconomic status was associated with better performance of the OHTs (P < .001).

OHTs with higher performance are associated with oral health services organizations and municipalities’ socioeconomic status.
Optimized Trientine‐dihydrochloride Therapy in Pediatric Patients With Wilson Disease
Authors: Mayr Toni , Ferenci Peter , Weiler Markus , Fichtner Alexander , Mehrabi Arianeb , Hoffmann Georg Friedrich , Mohr Isabelle , Pfeiffenberger Jan , Weiss Karl Heinz , Teufel‐Schäfer Ulrike
Published: August 2020

Objectives:

The aim of the study was to investigate the efficacy and safety of trientine‐dihydrochloride (TD) in pediatric patients with Wilson disease (WD) and the effect of different weight‐based dosages on their clinical and biochemical outcome.

Methods:

We retrospectively reviewed the clinical data of 31 children with WD receiving TD therapy ages under 18 years at the time of diagnosis. Outcome measures included parameters of copper metabolism and liver function tests. To examine the impact of different weight‐based dosages, 2 dosage subgroups were analyzed. Group 1 received less than 20 mg/kg TD per day, group 2 more than 20 mg · kg−1 · day−1.

Results:

Median follow‐up was 60 (5–60) months in the total study group. During TD therapy, nonceruloplasmin‐bound copper was reduced from mean 1.53 (0.01–6.95) at baseline to 0.62 (0.01–4.57) μmol/l. 24h‐urinary copper excretion diminished to 1.85 (0.8–9.6) μmol/day approximating the therapeutic goal of 1.6 μmol/day. Seven of 31 patients (22.6%) required discontinuation of TD treatment, in 4 cases it was because of adverse events (ulcerative colitis, gingival and breast hypertrophy, hirsutism, elevation of transaminases).

Investigations about weight‐based dosage showed no significant difference of any laboratory parameter between the 2 cohorts. But in terms of clinical safety, adverse effects because of TD were only found in 6.7% of children in group 1 (<20 mg · kg−1 · day−1, median follow‐up 60 [9–60] months), whereas in group 2 (>20 mg · kg−1 · day−1, median follow‐up 60 [14–60] months), it was 63.6%.

Conclusions:

TD proves to be an efficacious alternative chelating agent for children with WD. Weight‐based dosages above the recommended 20 mg · kg−1 · day−1 may increase the rate of adverse effects in pediatric patients.
Development and Validation of a Self‐management Skills Assessment Tool for Children With Inflammatory Bowel Disease
Authors: Vernon‐Roberts Angharad , Frampton Chris , Gearry Richard B. , Day Andrew S.
Published: August 2020

Objectives:

For children with inflammatory bowel disease (IBD), the development of self‐management skills has the potential to improve disease outcomes. No assessment tools are aimed at measuring self‐management skills in this population. A tool was developed called the IBD‐Skills Tasks and Abilities Record (IBD‐STAR) which measures children's allocation of responsibility for specific skills. IBD‐STAR contains 18 items, scored whether completed independently (score 2), with help (score 1) or not at all (score 0).

Methods:

Children with IBD completed IBD‐STAR; one parent and a gastroenterologist completed a series of visual analogue scales that corresponded with each IBD‐STAR section. Children's IBD‐STAR scores were examined against independent variables and compared with the parent and clinician visual analogue scale scores. Reliability was calculated using Cronbach's alpha.

Results:

Twenty‐five Cronbach's alpha with IBD participated, mean age 14 years (standard deviation (SD) 1.7), 14 (56%) were boys, and 21 (84%) had Crohn's disease. The mean IBD‐STAR score was 27.1 (SD 5.7), equivalent to a score of 75%. Age was the only independent variable significantly associated with scores (P = 0.017). Parents consistently underestimated their children in all sections, but clinician assessments were more closely aligned. Reliability for IBD‐STAR was good with an overall Cronbach's alpha of 0.84.

Conclusion:

IBD‐STAR reports the allocation of responsibility for self‐management skills with good agreement between children and clinician, and with comprehensible differences with their parents. Such a tool may be used to identify children with IBD in need of support or to measure the efficacy of targeted interventions.
Infliximab Level Between Venous and Capillary Blood Using Novel Device Strongly Correlate in Paediatric Inflammatory Bowel Disease Patients
Authors: Zijlstra Marieke , Jongsma Maria M.E. , de Vries Annick , Schaap Tiny , Bloem Karien , de Ridder Lissy
Published: August 2020

Objectives:

Blood to measure infliximab (IFX) levels is typically obtained with venipuncture. Dried blood sampling (DBS), using capillary blood obtained from a finger prick, would be an alternative to measure IFX blood levels while being more patient friendly. The aim of this study is to compare IFX blood level measured by venipuncture versus DBS in patients with paediatric inflammatory bowel disease (PIBD) to assure accuracy.

Methods:

A prospective clinical pilot study was performed in patients with PIBD. Before IFX infusion, blood was collected simultaneously through venipuncture and DBS from a finger prick, using Mitratips (Neoteryx). All IFX concentrations were measured by an enzyme‐linked immunosorbent assay. The Bland‐Altman analysis was used to measure limits of agreement. The interrater reliability was measured with the interclass correlation coefficient and Cohen kappa. To calculate Cohen kappa, IFX levels were categorized into 3 groups; low <5 μg/mL, adequate 5 to 10 μg/mL, and high >10 μg/mL.

Results:

Twenty patients were included. Median age was 12.1 year (interquartile range 8–16 year). The mean difference between the 2 methods was −0.14 as calculated with Bland‐Altman plot. The limits of agreement were between −1.39 and 1.12. The interclass correlation coefficient was with 0.998 excellent. The Cohen kappa between 3 IFX level categories was strong K = 0.911 (P = 0.0001). There was a strong correlation between venous IFX serum levels and DBS (r = 0.991, P = 0.0001) in the included patients.

Conclusions:

This is the first study in patients with PIBD to show that bloodspot technology is a patient friendly alternative method to measure IFX blood levels in PIBD.
Switch to Efavirenz Attenuates Lipoatrophy in Girls With Perinatal HIV
Authors: Su Junwei , Shiau Stephanie , Arpadi Stephen M. , Strehlau Renate , Burke Megan , Patel Faeezah , Kuhn Louise , Coovadia Ashraf , Yin Michael T. ,   CHANGES Bone Study Team
Published: August 2020

Objectives:

Children with HIV (CHIV) have lifetime exposure to antiretrovirals (ART); therefore, optimizing their regimens to have the least impact on fat redistribution is a priority.

Methods:

This is a cross‐sectional study of 219 perinatally infected CHIV and 219 HIV‐uninfected controls from similar socioeconomic backgrounds in Johannesburg, South Africa. We compared total body and regional fat distribution in CHIV on suppressive ART regimens with controls and, among CHIV, between ritonavir‐boosted lopinavir (LPV/r)‐based and efavirenz (EFV)‐based regimens.

Results:

The mean age of the 219 uninfected children (45% girls) and the 219 CHIV (48% girls) was 7.0 and 6.4 years, respectively. CHIV had lower adjusted total body fat (P = 0.005) and lower percentage fat at the trunk (P = 0.020), arms (P = 0.001), and legs (P < 0.001) than uninfected children. CHIV on LPV/r had similar body composition as those on EFV, except for arm fat mass (P = 0.030). When stratified by sex, girls with HIV on LPV/r had lower adjusted total (P = 0.007), trunk (P = 0.002), arms (P = 0.008), legs (P = 0.048) fat mass; trunk‐to‐total body fat (P = 0.044); and higher legs‐to‐total body fat (P = 0.011) than those on EFV.

Conclusions:

South African CHIV receiving ART had lower global and partial fat mass and percentage fat than healthy controls. In girls with HIV with sustained virologic suppression on ART, switching from LPV/r to EFV could attenuate fat mass loss, indicating that EFV‐based regimen may be a better option in this group of individuals.
Self-Efficacy, Pain Intensity, Rheumatic Disease Duration, and Hand Functional Disability on Activities of Daily Living
Authors: Rodríguez-García Estefanía , Barnes-Ortiz Samuel , Pérez-Mármol José Manuel
Published: August 2020

Background

Knowledge regarding the possible influence of self-efficacy, pain intensity and disease duration on hand functional disability could promote new intervention strategies for activities of daily living (ADLs) in patients with rheumatic disease (RD). These approaches could prevent the health problems and socioeconomic costs associated with these diseases.

Objective

The aims of this study were to evaluate if there are differences between the levels of perceived self-efficacy, pain intensity and disease duration among people with RD and non-RD diseases, and to analyze if hand functional disability in ADLs is related to self-efficacy, pain intensity and disease duration in a sample of patients with RD.

Methods

A multicenter, observational, cross-sectional study was conducted on a total sample of 335 participants over 50 years old (176 patients with RD and 159 individuals with non-RD). The Duruöz Hand Index, the General Perceived Self-Efficacy Scale, the Rheumatic Diseases Self-Efficacy Scale (RDS-ES), the Visual Analog Scale (VAS), and the mean time of evolution in years of the disease (disease duration) were used to analyze the possible relationships surrounding hand functional disability in ADLs.

Results

The comparison analysis showed significant differences between the RD/non-RD sample for the General Perceived Self-Efficacy Scale, RDS-ES, and VAS scores (p < .001). The multiple regression results showed that age, General Perceived Self-Efficacy Scale scores, RDS-ES scores, VAS scores, and disease duration (or a combination of some of them) explained the variability of hand functional disability in almost 68% of kitchen tasks, 44% of dressing tasks, 46% of hygiene and other tasks, and 47% of office tasks.

Discussion

Our study shows that general and domain-specific self-efficacy, pain intensity, and disease duration are predictors of the dimensions of hand functional disability in patients with RD. Early evaluation of these components with an interdisciplinary approach would help to manage hand disability properly.
Collection of Gender Identity in National Case Notifications of Chlamydia, Gonorrhea, and Primary and Secondary Syphilis, 2018
Authors: Torrone Elizabeth , Grier LaZetta , Gadsden-Knowles Kim , Weinstock Hillard , Stenger Mark
Published: August 2020

In 2018, 21 (41%) jurisdictions had begun reporting gender identity for sexually transmitted disease case notifications sent to the Centers for Disease Control and Prevention. Among jurisdictions with ≥70% of cases with reported gender identity and sex, 1.0% of primary and secondary syphilis cases were identified as transgender and 71% of transgender women with syphilis were concurrently coded as being male sex.
Desmoplastic Small Round Cell Tumor of the Kidney: Report of a Case, Literature Review, and Comprehensive Discussion of the Distinctive Morphologic, Immunohistochemical, and Molecular Features in the Differential Diagnosis of Small Round Cell Tumors Affecting the Kidney
Authors: Galliani Carlos A. , Bisceglia Michele , Del Giudice Antonio , Cretì Giuseppe
Published: August 2020

Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive neoplasm typically presenting with widespread involvement of the abdominopelvic peritoneum of adolescent males, usually without organ-based primary. Although it is believed to originate from the serous (mainly peritoneal) membranes, intracranial, sinonasal, intraosseous, and other soft tissue sites are also documented. A chromosomal translocation t(11:22)(p13;q12) signature that fuses EWSR1 and WT1 genes results in the production of a chimeric protein with transcriptional regulatory activity that drives oncogenesis. Integration of clinical, morphologic, immunohistochemical, and genetic data is necessary to arrive at the correct diagnosis, especially when the tumor arises in an atypical site. A 15-year-old male presented with hematuria and was found to have a large renal tumor associated with adrenal, liver, lung, and bone metastases. Histopathologic and immunophenotypic features were distinctive for DSRCT. This diagnosis was confirmed by means of fluorescence in situ hybridization and cytogenetic analysis, which documented the pathognomonic t(11;22) translocation, and by reverse transcription polymerase chain reaction on snap-frozen tissue, which revealed the EWSR1/WT1-specific chimeric transcript. Despite high-dose chemotherapy and radiation therapy targeted to a single T11 vertebral metastasis, the disease progressed, and the patient died 4 years after the diagnosis. A search of electronic databases for DSRCT yielded 16 cases of well-documented renal primaries out of around 1570 cases from all sites gathered from the global literature. Desmoplastic small round blue cell tumor and other primary renal tumors considered in the differential diagnosis with DSRCT are discussed.
Technology-Based Closed-Loop Tracking for Improving Communication and Follow-up of Pathology Results
Authors: Rajan Suja S. , Baldwin Jessica L. , Giardina Traber D. , Singh Hardeep
Published: August 2020

Objective

Failure to follow-up on laboratory test results can lead to missed diagnoses, diagnostic delays, patient harm, and potential malpractice claims against providers. State-of-the-art tracking technologies such as the radio frequency identification (RFID) can potentially improve laboratory order processing and test result communication. We conducted a comparative evaluation of differences in completion rates for 5 testing process milestones and time to reach these process milestones, with and without RFID order tracking for skin biopsy orders.

Methods

This observational study analyzed 48,515 orders from 20 dermatology providers, sent to 8 pathology laboratories in 2016 to 2017. Descriptive t tests and multiple Cox proportional hazard regressions were used to examine the differences in completion rates and times to the 5 testing process milestones, namely, (1) provider receipt of results, (2) provider review of results, (3) patient notification, (4) follow-up scheduling, and (5) order case closure, for orders processed with and without RFID order tracking.

Results

Descriptive statistics illustrated that all 5 testing process milestone completion rates were statistically higher for RFID tracked orders compared with non-RFID tracked orders, and RFID tracked orders took 3 to 5 days lesser than non-RFID tracked orders to reach the 5 testing process milestones. Multiple cox proportional hazard regressions showed that the process milestones were achieved faster if orders were RFID tracked versus not (hazard ratios ranged from 1.3 to 4.9).

Conclusions

The RFID tracking technology considerably improved test result communication timeliness and reliability. Such technologies can be beneficial for laboratory order processing, and their effectiveness should be explored in other practice settings.
Factitious Disorder (Munchausen Syndrome) in Plastic Surgery
Authors: Evans Rhian Louise , Tew Jennifer Catherine , Yates Gregory Peter , Feldman Marc
Published: August 2020

Introduction

Patients with factitious disorder (FD) or “Munchausen syndrome” intentionally fabricate or induce medical problems for psychological gratification. They may deceive plastic surgeons into performing multiple unnecessary procedures. We undertook the first systematic review of FD case reports in plastic surgery. Our aims were 2-fold: (1) describe the adverse outcomes associated with these cases and (2) identify strategies for their prevention by surgeons.

Methods

MEDLINE, EMBASE, and SCOPUS databases were searched. We included cases in which an adult with FD presented to a plastic surgeon. Our search returned a total of 42 eligible cases reported from North America (43%), Europe (37%), and Asia (20%).

Results

Seventy-six percent of patients were women, and 62% worked in health care. Sixty percent had a comorbid psychiatric disorder, the most common (50%) being depression. Ninety-three percent of our sample presented with self-induced lesions. The average delay in diagnosis of FD was 54 months, with 46% of patients receiving multiple surgical procedures in this time, including debridement (36%) and skin grafts (39%). Surgical wounds were frequently exploited by patients to remain in, or return to, hospital: 50% contaminated or manipulated their wounds to prevent healing. Thirty-six percent of cases resulted in significant long-term disability (24%) or disfigurement (12%). Ten percent of patients received an amputation. Outcomes were improved when patients were confronted by surgeons, however, and 62% were willing to see a psychiatrist. Surgeons were able to support recovery in 33% of cases—for example, by using occlusive wound dressings.

Conclusions

Patients with FD who present to plastic surgeons are high risk: the majority require surgical intervention for severe self-injury, and many engage in harmful behaviors, such as “doctor-shopping.” Early recognition of FD in plastic surgery is, therefore, crucial and may be achieved via careful examination of lesions for unusual morphology. Medical records may reveal extensive health care service use and negative investigations. Finally, plastic surgeons may play an important role in managing such patients. Management strategies include direct observation by nursing staff in the postoperative period and use of strict occlusive dressings to prevent access to surgical wounds.
Managing dissociative symptoms following the use of esketamine nasal spray: a case report
Authors: Pereira Sophia , Brennan Emily , Patel Anjali , Moran Melissa , Wallier Jenny , Liebowitz Michael R.
Published: August 2020

Patients with treatment-resistant depression (TRD) treated with esketamine nasal spray commonly experience transient symptoms of dissociation. Manifestations of dissociation, such as feelings of detachment from the environment, can cause considerable anxiety for patients. Nonpharmacologic interventions may help clinicians to manage associated anxiety and confusion due to dissociation following administration of esketamine nasal spray. We present the case of a 64-year-old woman with major depressive disorder who participated in a clinical trial evaluating the efficacy and safety of esketamine nasal spray in conjunction with an oral antidepressant for TRD. The patient received flexible doses of esketamine nasal spray (56 or 84 mg) twice weekly for 4 weeks. On treatment day 1, the patient was administered 56 mg of esketamine nasal spray using two nasal spray devices (28 mg per device). Twenty minutes after the first esketamine nasal spray device was administered, the patient experienced a dissociative episode lasting 40 minutes that caused anxiety and confusion. The patient was encouraged to listen to music during treatment sessions, which resulted in notable improvement of her symptoms. Listening to music of choice immediately following esketamine nasal spray administration along with reassurance from staff may help manage confusion and anxiety associated with dissociation.
Efficient Deep Network Architecture for COVID-19 Detection Using Computed Tomography Images
Authors: Goel Chirag , Kumar Abhimanyu , Dubey Satish Kumar , Srivastava Vishal
Published: August 2020

Globally the devastating consequence of COVID-19 or Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV-2) has posed danger on the life of living beings. Doctors and scientists throughout the world are working day and night to combat the proliferation or transmission of this deadly disease in terms of technology, finances, data repositories, protective equipment, and many other services. Rapid and efficient detection of COVID-19 reduces the rate of spreading this deadly disease and early treatment improve the recovery rate. In this paper, we proposed a new framework to exploit powerful features extracted from the autoencoder and Gray Level Co-occurence Matrix (GLCM), combined with random forest algorithm for the efficient and fast detection of COVID-19 using computed tomographic images. The model’s performance is evident from its 97.78% accuracy, 96.78% recall, and 98.77% specificity.
SARS-Coronavirus-2 nucleocapsid protein measured in blood using a Simoa ultra-sensitive immunoassay differentiates COVID-19 infection with high clinical sensitivity
Authors: Shan Dandan , Johnson Joseph M , Fernandes Syrena C. , Mendes Muriel , Suib Hannah , Holdridge Marcella , Burke Elaine M , Beauregard Katie , Zhang Ying , Cleary Megan , Xu Samantha , Yao Xiao , Patel Purvish , Plavina Tatiana , Wilson David , Chang Lei , Kaiser Kim M , Natterman Jacob , Schmidt Susanne V , Latz Eicke , Hrusovsky Kevin , Mattoon Dawn , Ball Andrew J.
Published: August 2020

The COVID-19 pandemic continues to have an unprecedented impact on societies and economies worldwide. Despite rapid advances in diagnostic test development and scale-up, there remains an ongoing need for SARS-CoV-2 tests which are highly sensitive, specific, minimally invasive, cost-effective and scalable for broad testing and surveillance. Here we report development of a highly sensitive single molecule array (Simoa) immunoassay on the automated HD-X platform for the detection of SARS-CoV-2 Nucleocapsid protein (N-protein) in venous and capillary blood (fingerstick). In pre-pandemic and clinical sample sets, the assay has 100% specificity and 97.4% sensitivity for serum / plasma samples. The limit of detection (LoD) estimated by titration of inactivated SARS-CoV-2 virus is 0.2 pg/ml, corresponding to 0.05 Median Tissue Culture Infectious Dose (TCID50) per ml, > 2000 times more sensitive than current EUA approved antigen tests. No cross-reactivity to other common respiratory viruses, including hCoV229E, hCoVOC43, hCoVNL63, Influenza A or Influenza B, was observed. We detected elevated N-protein concentrations in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals using capillary blood from a finger-stick collection device. The Simoa SARS-CoV-2 N-protein assay has the potential to detect COVID-19 infection via antigen in blood with performance characteristics similar to or better than molecular tests, while also enabling at home and point of care sample collection.

One Sentence Summary

SARS-CoV-2 nucleocapsid protein (N-protein) measured in serum, plasma, and dried blood spots (DBS) via ultrasensitive immunoassay can be used to differentiate PCR+ from PCR- patients, even if asymptomatic.
Functional analysis of genome-wide dataset from 17000 individuals identifies multiple candidate malaria resistance genes enriched in malaria pathogenic pathways
Authors: Damena Delesa , Agamah Francis , Kimathi Peter O. , Kabongo Ntumba E. , Girma Hundaol , Choga Wonderful T. , Golassa Lemu , Chimusa Emile R.
Published: August 2020

Recent genome-wide association studies (GWASs) of severe malaria have identified several association variants. However, much about the underlying biological functions are yet to be discovered. Here, we systematically predicted plausible candidate genes and pathways from functional analysis of severe malaria resistance GWAS summary statistics (N = 17,000) metaanalyzed across eleven populations in malaria endemic regions. We applied positional mapping, expression quantitative trait locus (eQTL), chromatin interaction mapping and gene-based association analyses to identify candidate severe malaria resistance genes. We performed network and pathway analyses to investigate their shared biological functions. We further applied rare variant analysis to raw GWAS datasets (N = 11,000) of three malaria endemic populations including Kenya, Malawi and Gambia and performed various population genetic structures of the identified genes in the three populations and global populations.

Our functional mapping analysis identified 57 genes located in the known malaria genomic loci while our gene-based GWAS analysis identified additional 125 genes across the genome. The identified genes were significantly enriched in malaria pathogenic pathways including multiple overlapping pathways in erythrocyte-related functions, blood coagulations, ion channels, adhesion molecules, membrane signaling elements and neuronal systems. Our population genetic analysis revealed that the minor allele frequencies (MAF) of the single nucleotide polymorphisms (SNPs) residing in the identified genes are generally higher in the three malaria endemic populations compared to global populations. Overall, our results suggest that severe malaria resistance trait is attributed to multiple genes; highlighting the possibility of harnessing new malaria therapeutics that can simultaneously target multiple malaria protective host molecular pathways.
Socioeconomic Inequalities in Adult Mortality across Small Areas in Brazil: Exploration Analysis Using Machine Learning Models
Authors: Arruda Natália Martins , Carvalho Tiago José de , Alves Luciana Correia
Published: August 2020

Future progress in life expectancy in all countries depends, to some degree, on a reduction in adult mortality. Significant regional differences are found in Brazil, with high adult mortality rates in some areas. The aim of the present study was to investigate associations between the probability of adult deaths in microregions of Brazil in 2010 and socioeconomic, structural, contextual and health-related factors. The analyses were based on data from the 2010 demographic census and the Mortality Information System. The machine learning model was used to establish determinants of the probability of adult deaths. Machine learning methods have considerable potential for this type of analysis, enabling a better understanding of the interactions among different factors. The algorithms employed (Random Forest, Extreme Gradient Boosted Trees and Support Vector Machine) obtained a good performance and proved to be effective at analyzing the variables and correlations with the outcome (probability of adult death). The results showed the mortality due to external causes, the employment rate, sex ratio, vaccine coverage, proportion of blacks, poverty rate, aging index and proportion of whites had the best predictive power regarding the probability of adult deaths using the algorithm with the best performance (Extreme Gradient Boosted Trees).
SARS-CoV-2 Antibody Responses Correlate with Resolution of RNAemia But Are Short-Lived in Patients with Mild Illness
Authors: Röltgen Katharina , Wirz Oliver F. , Stevens Bryan A. , Powell Abigail E. , Hogan Catherine A. , Najeeb Javaria , Hunter Molly , Sahoo Malaya K. , Huang ChunHong , Yamamoto Fumiko , Manalac Justin , Otrelo-Cardoso Ana R. , Pham Tho D. , Rustagi Arjun , Rogers Angela J. , Shah Nigam H. , Blish Catherine A. , Cochran Jennifer R. , Nadeau Kari C. , Jardetzky Theodore S. , Zehnder James L. , Wang Taia T. , Kim Peter S. , Gombar Saurabh , Tibshiran Robert , Pinsky Benjamin A. , Boyd Scott D.
Published: August 2020

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, could offer protective immunity, and may affect clinical outcomes of COVID-19 patients. We analyzed 625 serial plasma samples from 40 hospitalized COVID-19 patients and 170 SARS-CoV-2-infected outpatients and asymptomatic individuals. Severely ill patients developed significantly higher SARS-CoV-2-specific antibody responses than outpatients and asymptomatic individuals. The development of plasma antibodies was correlated with decreases in viral RNAemia, consistent with potential humoral immune clearance of virus. Using a novel competition ELISA, we detected antibodies blocking RBD-ACE2 interactions in 68% of inpatients and 40% of outpatients tested. Cross-reactive antibodies recognizing SARS-CoV RBD were found almost exclusively in hospitalized patients. Outpatient and asymptomatic individuals’ serological responses to SARS-CoV-2 decreased within 2 months, suggesting that humoral protection may be short-lived.
Rapid, sensitive and high-throughput screening method for detection of SARS-CoV-2 antibodies by bio layer interferometry
Authors: Lokireddy Sudarshan Reddy , Kunchala Sridhar Rao , Godavarthy Ranga Pratyusha , Kona Venkata Sri Krishna , Avula Laxmaiah , Mishra Rakesh Kumar , Nalam Madhusudhana Rao
Published: August 2020

Present pandemic scenario, there exists an unmet global need for the development of a rapid and sensitive method for the detection of SARS-CoV-2 infection. The available options for identification of SARS-CoV-2 infection are detection of viral RNA by qRT-PCR, Antigen or Antibody testing by serological methods. Even though many kits available commercially but none of them are rapid, sensitive and high throughput. ‘OnCovid total antibody assay’ is a diagnostic method developed by us uses the principle of bio-layer Interferometry to detect IgM, IgA and IgG antibodies against SARS-CoV-2 antigens. This method overcomes many of the limitations normally faced in antibody detection by other methods and offers a superior platform for a rapid, sensitive and specific detection of SARS-CoV-2 infection. The test is economical, and the results can be obtained in as short as 30 seconds per test. In addition to its standalone use in early diagnosis of SARS-CoV-2, ‘OnCovid total antibody assay’ can be used to therapeutic monitoring of antiviral therapies used in clinical management and to estimate the antibody titers during convalescent plasma donation.
Role of Sugar Stereochemistry on Structural and Free Energy Landscape of Double-Stranded Nucleic Acids
Authors: Kumar Anuj , Singh Reman Kumar , Tagad Amol , Patwari G. Naresh
Published: August 2020

The conformational landscape of 29-mer long four stereo variants of furanosal nucleic acids and their C2’ deoxy counterparts were explored using molecular dynamics and well-tempered metadynamics simulations. The ribose containing double-stranded nucleic acids exhibit helical structure, however inversion of C3’ and/or C2’ stereocentre of ribose results in structural modification. The free energy surfaces relative to the average twist angle and end-to-end distances suggests that the configuration at the C3’ position plays a pivotal role in determining the helicity. The C3’ stereocentre acts as toggle-switch for helix to non-helical structures in double-stranded nucleic acids. Thus, the ribose containing double-stranded nucleic acids result in well-organized helical structures, while those containing xylose and lyxose show a variety of structures, which include (circular) ladder configurations. Based on the present set of results, it can be inferred that ribose containing double-stranded nucleic acids form well-defined helical structures in contrast to their C2’ and C3’ epimers.
In vitro culture of aberrant basal-like cells from fibrotic lung tissue
Authors: Khan Petra , Roux Julien , Blumer Sabrina , Fang Lei , Savic Spasenija , Knudsen Lars , Jonigk Danny , Kuehnel Mark P. , Gazdhar Amiq , Geiser Thomas , Tamm Michael , Hostettler Katrin E.
Published: August 2020

Rationale

In idiopathic pulmonary fibrosis (IPF) atypical epithelial cells are present in the alveolar compartment. Their origin and contribution to IPF pathogenesis is unknown. We recently cultured a distinct population of cells, which readily grew from fibrotic lung tissue, but only rarely from non-fibrotic tissue. Here we aimed to characterize these fibrosis-enriched cells and determine transcriptomic differences between cells derived from IPF and patients with other interstitial lung diseases (ILD).

Methods

Cells were cultured from peripheral lung tissue of ILD patients and analysed by bulk or single cell RNA sequencing (scRNA-seq), TaqMan-PCR, immunofluorescence (IF), immunoblotting or electron microscopy (EM).

Results

scRNA-seq demonstrated an overall homogeneity and epithelial origin of the cells. The majority of cells expressed basal cell markers (Cytokeratin (KRT) 5 and 17, TP63), of which a fraction co-expressed mesenchymal cell markers (VIM, FN1, CDH2), alveolar (SLC34A2, ABCA3, LPCAT1, EMP2, HOPX) and/or secretory epithelial cell markers (SCGB1A1, MUC4). Interestingly, most of the cells showed closest transcriptomic similarity to recently described aberrant basal-like cells. Cells derived from IPF versus other ILD patients revealed significant transcriptomic differences with an up-regulation of fibrosis-associated and a down-regulation of inflammatory pathways in IPF cells.

Conclusion

We here confirm the presence of aberrant basal-like cells in fibrotic lung tissue and, importantly, are the first to describe theirin vitrocharacteristics and a way of culturing these cellsin vitro. Cultured basal-like cells co-express epithelial and mesenchymal markers, suggesting a partial epithelial to mesenchymal transition (EMT). A subset of cells co-express alveolar, ciliated or secretory epithelial cell markers, possibly indicating differentiation towards these cell linages. Furthermore, cultured basal-like cells display a disease-specific transcriptome, possibly induced by their specific microenvironment. Our findings will contribute to a better understanding of the cells origin and their potential contribution to IPF pathogenesis.
LipidFinder 2.0: advanced informatics pipeline for lipidomics discovery applications
Authors: Alvarez-Jarreta Jorge , Rodrigues Patricia R.S. , Fahy Eoin , O’Connor Anne , Price Anna , Gaud Caroline , Andrews Simon , Benton Paul , Siuzdak Gary , Hawksworth Jade I. , Valdivia-Garcia Maria , Allen Stuart M. , O’Donnell Valerie B.
Published: August 2020

We present LipidFinder 2.0, incorporating four new modules that apply artefact filters, remove lipid and contaminant stacks, in-source fragments and salt clusters, and a new isotope deletion method which is significantly more sensitive than available open-access alternatives. We also incorporate a novel false discovery rate (FDR) method, utilizing a target-decoy strategy, which allows users to assess data quality. A renewed lipid profiling method is introduced which searches three different databases from LIPID MAPS and returns bulk lipid structures only, and a lipid category scatter plot with color blind friendly pallet. An API interface with XCMS Online is made available on LipidFinder’s online version. We show using real data that LipidFinder 2.0 provides a significant improvement over non-lipid metabolite filtering and lipid profiling, compared to available tools.

Availability

LipidFinder 2.0 is freely available athttps://github.com/ODonnell-Lipidomics/LipidFinderandhttp://lipidmaps.org/resources/tools/lipidfinder.

Contact

lipidfinder@cardiff.ac.uk

Supplementary information

Supplementary data are available atBioinformaticsonline.
Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency
Authors: Li Yongzheng , Xue Boxin , Zhang Liwei , Su Qian Peter , Zhang Mengling , Long Haizhen , Wang Yao , Jin Yanyan , Hou Yingping , Cao Yuan , Li Guohong , Sun Yujie
Published: August 2020

Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Despite various genetic and epigenetic signatures are found to be related with active origins, it remains elusive how the selection of origins is determined. The classic Rosette model proposes that the origins clustered in a chromatin domain are preferentially and simultaneously fired, but direct imaging evidence has been lacking due to insufficient spatial resolution. Here, we applied dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We found that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase, in contrary to the Rosette model. Intriguingly, while both active and dormant origins are distributed homogeneously in the TAD during the G1 phase, active origins relocate to the TAD periphery before entering the S phase. We proved that such origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observed that the replication machinery protein PCNA forms immobile clusters around the TADs at the G1/S transition, which explains why origins at the TAD periphery are preferentially fired. Thus, we propose a “Chromatin Re-organization Induced Selective Initiation” (CRISI) model that the transcription-coupled chromatin structural re-organization determines the selection of replication origins, which transcends the scope of specific genetic and epigenetic signatures for origin efficiency. Ourin situsuper-resolution imaging unveiled coordination among DNA replication, transcription, and chromatin organization inside individual TADs, providing new insights into the biological functions of sub-domain chromatin structural dynamics.
The Structural Basis of Rubisco Phase Separation in the Pyrenoid
Authors: He Shan , Chou Hui-Ting , Matthies Doreen , Wunder Tobias , Meyer Moritz T. , Atkinson Nicky , Martinez-Sanchez Antonio , Jeffrey Philip D. , Port Sarah A. , Patena Weronika , He Guanhua , Chen Vivian K. , Hughson Frederick M. , McCormick Alistair J. , Mueller-Cajar Oliver , Engel Benjamin D. , Yu Zhiheng , Jonikas Martin C.
Published: August 2020

Approximately one-third of global CO2fixation occurs in a phase separated algal organelle called the pyrenoid. Existing data suggest that the pyrenoid forms by the phase-separation of the CO2-fixing enzyme Rubisco with a linker protein; however, the molecular interactions underlying this phase-separation remain unknown. Here we present the structural basis of the interactions between Rubisco and its intrinsically disordered linker protein EPYC1 (Essential Pyrenoid Component 1) in the model algaChlamydomonas reinhardtii. We find that EPYC1 consists of five evenly-spaced Rubisco-binding regions that share sequence similarity. Single-particle cryo-electron microscopy of one of these regions in complex with Rubisco indicates that each Rubisco holoenzyme has eight binding sites for EPYC1, one on each Rubisco small subunit. Interface mutations disrupt binding, phase separation, and pyrenoid formation. Cryo-electron tomography supports a model where EPYC1 and Rubisco form a co-dependent multivalent network of specific low-affinity bonds, giving the matrix liquid-like properties. Our results advance the structural and functional understanding of the phase separation underlying the pyrenoid, an organelle that plays a fundamental role in the global carbon cycle.
Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages
Authors: Babagana Mahamat , Oh Kyu-Seon , Chakraborty Sayantan , Pacholewska Alicja , Aqdas Mohammad , Sung Myong-Hee
Published: August 2020

Age-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues.In vivosuppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, whilein vitroactivation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.
Multidimensional single-cell benchmarking of inducible promoters for precise dynamic control in budding yeast
Authors: Gligorovski Vojislav , Sadeghi Ahmad , Rahi Sahand Jamal
Published: August 2020

For quantitative systems biology, simultaneous readout of multiple cellular processes as well as precise, independent control over different genes’ activities are essential. In contrast to readout systems such as fluorescent proteins, control systems such as inducible transcription-factor-promoter systems have only been characterized in anad hocfashion, impeding precise system-level manipulations of biological systems and reliable modeling.

We designed and performed systematic benchmarks involving easy-to-communicate units to characterize and compare inducible transcriptional systems. We built a comprehensive single-copy library of inducible systems controlling standardized fluorescent protein expression in budding yeast, includingGAL1pr,GALL,MET3pr,CUP1pr,PHO5pr,tetOpr,terminator-tetOpr, Z3EV system, the blue-light optogenetic systems El222-LIP, El222-GLIPand the red-light inducible PhyB-PIF3 system. To analyze these systems’ dynamic properties, we performed high-throughput time-lapse microscopy. The analysis of >100 000 cell images was made possible by the recently developed convolutional neural network YeaZ. We report key kinetic parameters, scaling of noise levels, impacts on growth, and, crucially, the fundamental leakiness of each system. Our multidimensional benchmarking additionally uncovers unexpected disadvantages of widely used tools, e.g., nonmonotonic activity of theMET3andGALLpromoters, slow off kinetics of the doxycycline and estradiol-inducible systemstetOprand Z3EV, and high variability ofPHO5prand red-light activated PhyB-PIF3 system. We introduce two new tools for controlling gene expression: strongLOV, a more light-sensitive El222 mutant, andARG3prthat functions as an OR gate induced by the lack of arginine or presence of methionine. To demonstrate the ability to finely control genetic circuits, we experimentally tuned the time between cell cycle Start and mitotic entry in budding yeast, artificially simulating near-wild-type timing.

The characterizations presented here define the compromises that need to be made for quantitative experiments in systems and synthetic biology. To calibrate perturbations across laboratories and to allow new inducible systems to be benchmarked, we deposited single-copy reporter yeast strains, plasmids, and computer analysis code in public repositories. Furthermore, this resource can be accessed and expanded through the websitehttps://promoter-benchmark.epfl.ch/.
Quantitative PCR assays to detect humpback whale (Megaptera novaeangliae), shortbelly rockfish (Sebastes jordani), and common murre (Uria aalge) in marine water samples
Authors: Andruszkiewicz Elizabeth A. , Yamahara Kevan M. , Closek Collin J. , Boehm Alexandria B.
Published: August 2020

Monitoring aquatic species by identification of environmental DNA (eDNA) is becoming more common. In order to obtain quantitative datasets for individual species, species-specific quantitative PCR (qPCR) assays are required. Here, we present detailed methodology of qPCR assay design and testing, includingin silico, in vitro, andin vivotesting, and comment on the challenges associated with assay design and performance. We use the presented methodology to design assays for three important marine organisms common in the California Current Ecosystem (CCE): humpback whale (Megaptera novaeangliae), shortbelly rockfish (Sebastes jordani), and common murre (Uria aalge). All three assays have excellent sensitivity and high efficiencies ranging from 92% to 99%. However, specificities of the assays varied from species-specific in the case of common murre to the genus-specific shortbelly rockfish assay, to the humpback whale assay which cross-amplified with other two other whale species, including one in a different family. All assays detected their associated targets in complex environmental water samples.