bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes
Authors: Qiao Lu , Xu Le , Yu Lan , Wynn Julia , Hernan Rebecca , Zhou Xueya , Farkouh-Karoleski Christiana , Krishnan Usha S. , Khlevner Julie , De Aliva , Zygmunt Annette , Crombleholme Timothy , Lim Foong-Yen , Needelman Howard , Cusick Robert A. , Mychaliska George B. , Warner Brad W. , Wagner Amy J. , Danko Melissa E. , Chung Dai , Potoka Douglas , Kosiński Przemyslaw , McCulley David J. , Elfiky Mahmoud , Azarow Kenneth , Fialkowski Elizabeth , Schindel David , Soffer Samuel Z. , Lyon Jane B. , Zalieckas Jill M. , Vardarajan Badri N. , Aspelund Gudrun , Duron Vincent P. , High Frances A. , Sun Xin , Donahoe Patricia K. , Shen Yufeng , Chung Wendy K. 
Published: June 2021

AbstractCongenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.
Minimum manufacturing costs, national prices and estimated global availability of new repurposed therapies for COVID-19
Authors: Wang Junzheng , Levi Jacob , Ellis Leah , Hill Andrew 
Published: June 2021

AbstractBackgroundCurrently, only dexamethasone, tocilizumab and sarilumab have conclusively been shown to reduce mortality of COVID-19. Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programmes. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices.MethodsWe searched for repurposed drugs that have been approved by at least one of the WHO, FDA or NICE, or at least given emergency use authorisation or recommended for off-label prescription. Drug prices were searched for, for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab and imdevimab, and sarilumab using active pharmaceutical ingredients (API) data extracted from global shipping records. This was compared with national pricing data from a range of low, medium, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug.ResultsRepurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from $2.58 for IV dexamethasone (or $0.19 orally) and $4.34 for inhaled budesonide. No export price data was available for baricitinib, tocilizumab, casirivimab and imdevimab or sarilumab, but courses of these treatments are priced highly, ranging from $6.67 for baricitinib to $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries.ConclusionsSuccessful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whilst monoclonal antibodies and IV treatment courses are more expensive.Key PointsRe-purposed drugs must be affordable worldwide to compliment COVID-19 vaccine programmes.Estimated costs/course were: dexamethasone (Oral $0.22, IV $2.58), budesonide ($4.34), baricitnib ($6.67), tocilizumab ($410.59), sarilumab ($875.70). Casirivimab and imdevimab = no data available.High drug prices will limit access.
Insecticide resistance outpaces behavioural adaptation, as a response to Long-Lasting Insecticidal Net distribution, in malaria vectors in Burkina Faso
Authors: Sanou Antoine , Nelli Luca , Guelbéogo W. Moussa , Cissé Fatoumata , Tapsoba Michel M. , Ouédraogo Pierre , Sagnon N’falé , Ranson Hilary , Matthiopoulos Jason , Ferguson Heather M. 
Published: June 2021

AbstractThe decline in malaria across Africa has been largely attributed to vector control using Long-Lasting Insecticidal Nets (LLINs). However, this intervention has prompted widespread insecticide resistance (IR) and been associated with changes in mosquito behaviour that reduce their contact with LLINs. The relative importance and rate at which IR and behavioural adaptations emerge are poorly understood. We conducted surveillance of mosquito behaviour and IR at 12 sites in Burkina Faso to assess the magnitude and temporal dynamics of insecticide and behavioural resistance in vectors in the 2-year following mass LLIN distribution. Insecticide resistance was present in all vector populations and increased rapidly over the study. In contrast, no longitudinal shifts in LLIN-avoidance behaviours (earlier or outdoor biting and resting) were detected. There was a moderate shift in vector species composition fromAnopheles coluzziitoAnopheles gambiaewhich coincided with a reduction in the proportion of bites preventable by LLINs; possibly driven by between-species variation in behaviour. These findings indicate that adaptations based on insecticide resistance arise and intensify more rapidly than behavioural shifts within mosquito vectors. However, longitudinal shifts in mosquito vector species composition were evident within 2 years following a mass LLIN distribution. This ecological shift was characterized by a relative increase in the moderately more exophagic species (An. gambiae) and coincided with a predicted decline in the degree of protection expected from LLINs. Although human exposure fell through the study period due to reducing vector densities and infection rates, such ecological shifts in vector species along with insecticide resistance were likely to have eroded the efficacy of LLINs. While both adaptations impact malaria control, the rapid increase of the former indicates it is the most rapid strategy but interventions targeting both will be needed.
Why is non-suicidal self-injury more prevalent among women? Mediation and moderation analyses of psychological distress, emotion dysregulation, and impulsivity
Authors: Lutz Nina M. , Neufeld Sharon A.S. , Hook Roxanne W. , Jones Peter B. , Bullmore Ed T. , Goodyer Ian M. , Chamberlain Samuel R. , Wilkinson Paul O. 
Published: June 2021

AbstractObjectiveNon-suicidal self-injury (NSSI) appears to be more common among women than men, though the underlying reasons for this remain unclear. In a community sample of young adults (n=996, aged 18-30) assessed during the COVID-19 pandemic, we investigated gendered patterns in NSSI etiology.MethodsMediation and moderation analyses considered associations between past-year NSSI prevalence, gender, and putative mechanistic variables: self-reported psychological distress (K10), emotion dysregulation (DERS), and impulsivity (UPPS-P).ResultsNearly twice as many women as men reported past-year NSSI (14.47% versus 7.78%). Women reported significantly higher psychological distress and significantly lower sensation seeking and positive urgency than men. Psychological distress partially statistically mediated the relationship between gender and past-year NSSI. Gender did not significantly moderate associations between self-reported distress, emotion dysregulation, or impulsivity and past-year NSSI. Past-year NSSI prevalence did not significantly decrease with age and we found no significant age by gender interaction.ConclusionsGreater levels of NSSI in young women are explained by their greater levels of emotional distress. Women do not appear to be more likely than men to report NSSI due to differences in how they manage emotional distress: gender did not moderate the association between psychological distress and past-year NSSI, and there were no gender differences in emotion dysregulation or negative urgency. Furthermore, we show that NSSI remains prevalent beyond adolescence. Early interventions which reduce distress or improve distress tolerance, strengthen emotion regulation skills, and provide alternative coping strategies merit investigation for NSSI.HighlightsYoung women were significantly more likely to report past-year NSSI than young menPsychological distress partially mediated the relationship between gender and NSSIGender did not moderate associations between putative mechanistic variables and NSSI
ctDNA detection by personalised assays in early-stage NSCLC
Authors: Heider Katrin , Wan Jonathan C. M. , Gale Davina , Ruiz-Valdepenas Andrea , Mouliere Florent , Morris James , Qureshi Nagmi R. , Qian Wendi , Knock Helena , Wulff Jerome , Howarth Karen , Green Emma , Castedo Jenny , Rundell Viona , Cooper Wendy N. , Eisen Tim , Smith Christopher G. , Massie Charles , Gilligan David , Harden Susan V. , Rassl Doris M. , Rintoul Robert C. , Rosenfeld Nitzan 
Published: June 2021

AbstractBlood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent enrolled in the LUCID study (NCT04153526). Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1×10−6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-Lung™) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios >11 for selected patient subsets. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.
Causal and Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency
Authors: Gorsi B , Hernandez EJ , Moore B , Moriwaki M , Chow CY , Coelho E , Taylor E , Lu C , Walker A , Touraine P , Nelson LM , Cooper AR , Mardis ER , Rajkovic A , Yandell M , Welt CK 
Published: June 2021

AbstractA genetic etiology accounts for unexplained primary ovarian insufficiency (POI; amenorrhea with an elevated FSH level). Subjects with POI (n=291) and controls recruited for health in old age or 1000 Genomes (n=233) underwent whole exome or whole genome sequencing. Data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1 and BOD1L1). Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.
Relation of vaccination with severity, oxygen requirement and outcome of COVID-19 infection in Chattogram, Bangladesh
Authors: Das Shuva , Tumpa Nadia Islam , Khan Ayesha Ahmed , Hoque Md. Minhazul , Hoque Md. Ehsanul , Safatujjahan  , Ahmed Kazi Farhad , Biswas Rajat Sanker Roy 
Published: June 2021

AbstractIntroductionPeoples all around the world are waiting for vaccination against COVID -19 infection. In Bangladesh, Astra-Zeneca (AZ) vaccine was provided, but patients had infections of SARS-COV-2 even after vaccination. We focused on observing the severity, oxygen requirement and outcome of the COVID-19 infected patients who took the first dose or completed the immunization regimen.MethodsThis is an observational study done among 174 COVID-19 patients from three COVID-19 dedicated hospitals of Chattogram, Bangladesh, who took AZ vaccines 1st dose or completed the schedule. All patients were Real-Time Reverse Transcription Polymerase Chain Reaction (rRT-PCR) positive for COVID-19. Patients were enrolled after receiving written informed consent. Suspected cases or unwilling patients were excluded from the study. Ethical approval was granted by the CMOSH–ERB. SPSS-20 was used to analyze the information gathered.ResultsAmong 174 vaccinated patients, 55(31.61%) completed the vaccination schedule, and 119(68.39%) took their 1st dose of the COVID-19 vaccine. Gender distributions revealed 67(38.5%) female and 107(61.5%) male got the vaccine, and 55 patients completed the full two doses, and 119 patients took the 1st dose. Most of the patients were 40 years and above. In the completed vaccination group, 33(60.0%) out of 55 in and in the first dose vaccinated group, 75(63.0%) out of 119 had a mild COVID-19, and severe and critical cases were found very minimum. Among the patients who have completed the vaccination, 32(58.2%) needed no oxygen, and who was given the first dose, 78(65%) needed no oxygen. No death occurred who completed the vaccine, and 3(2.5%) patients died who took 1st dose of the vaccine.ConclusionVaccine provided in Bangladesh to the people so far seems safe and effective. Severe and critical COVID-19 is low, and the need for oxygen to admitted patients is less, and the death rate is minimal.
Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection
Authors: Karim F , Moosa MYS , Gosnell BI , Cele S , Giandhari J , Pillay S , Tegally H , Wilkinson E , San JE , Msomi N , Mlisana K , Khan K , Bernstein M , Manickchund N , Singh L , Ramphal U ,   COMMIT-KZN Team, Hanekom W , Lessells RJ , Sigal A , de Oliveira T 
Published: June 2021

SummaryWhile most people effectively clear SARS-CoV-2, there are several reports of prolonged infection in immunosuppressed individuals. Here we present a case of prolonged infection of greater than 6 months with shedding of high titter SARS-CoV-2 in an individual with advanced HIV and antiretroviral treatment failure. Through whole genome sequencing at multiple time-points, we demonstrate the early emergence of the E484K substitution associated with escape from neutralizing antibodies, followed by other escape mutations and the N501Y substitution found in most variants of concern. This provides support to the hypothesis of intra-host evolution as one mechanism for the emergence of SARS-CoV-2 variants with immune evasion properties.
Comparative Household Secondary Attack Rates associated with B.1.1.7, B.1.351, and P.1 SARS-CoV-2 Variants
Authors: Brown Kevin A. , Tibebu Semra , Daneman Nick , Schwartz Kevin , Whelan Michael , Buchan Sarah 
Published: June 2021

AbstractBackgroundThe emergence of SARS-CoV-2 variants associated with increased transmissibility are driving a 3rd global surge in COVID-19 incidence. There are currently few reliable estimates for the P.1 and B.1.351 lineages. We sought to compare the secondary attack rates of SARS-COV-2 mutations and variants in Canada’s largest province of Ontario, using a previously validated household-based approach.MethodsWe identified individuals with confirmed SARS-CoV-2 infection in Ontario’s provincial reportable disease surveillance system. Cases were grouped into households based on reported residential address. Index cases had the earliest of symptom onset in the household. Household secondary attack rate was defined as the percentage of household contacts identified as secondary cases within 1-14 days after the index case.ResultsWe identified 26,888 index household cases during the study period. Among these, 7,555 (28%) were wild-type, 17,058 (63%) were B.1.1.7, 1674 (6%) were B.1.351 or P.1, and 601 (2%) were non-VOC mutants (Table 1). The secondary attack rates, according to index case variant were as follows: 20.2% (wild-type), 25.1% (B.1.1.7), 27.2% (B.1.351 or P.1), and 23.3% (non-VOC mutants). In adjusted analyses, we found that B.1.1.7, B.1.351, and P.1 index cases had the highest transmissibility (presumptive B.1.1.7 ORadjusted=1.49, 95%CI 1.36, 1.64; presumptive B.1.351 or P.1 ORadjusted=1.60, 95%CI 1.37, 1.87).DiscussionSubstantially higher transmissibility associated with variants will make control of SARS-CoV-2 more difficult, reinforcing the urgent need to increase vaccination rates globally.
The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins
Authors: Petkau Georg , Mitchell Twm J. , Chakraborty Krishnendu , Bell Sarah E. , D’Angeli Vanessa , Matheson Louise , Turner David J. , Saveliev Alexander , Gizlenci Ozge , Salerno Fiamma , Katsikis Peter D. , Turner Martin 
Published: June 2021

AbstractCD8+ T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that determine the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8+ T cells and the potency of the resulting cytotoxic lymphocytes. The RBP act in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-ĸB, IRF8 and NOTCH1 transcription factors and cytokines, including IL2. Their absence in T cells, or the adoptive transfer of a small numbers of CD8+ T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals determining the speed and quality of the CD8 response.
A representative reference for MRI-based human axon radius assessment using light microscopy
Authors: Mordhorst Laurin , Morozova Maria , Papazoglou Sebastian , Fricke Björn , Oeschger Jan Malte , Tabarin Thibault , Rusch Henriette , Jäger Carsten , Geyer Stefan , Weiskopf Nikolaus , Morawski Markus , Mohammadi Siawoosh 
Published: June 2021

AbstractNon-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data on the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the frequency-weighted arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the potential error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (normalized-root-mean-square-error of reff: 7.2 %; rarith: 21.5 %) and lower bias (normalized-mean-bias-error of reff: −1.7 %; rarith: 16 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.9 % and 3 % to reff. In conclusion, the proposed method accurately estimates reff at MRI voxel resolution across a human corpus callosum sample. Further investigations are required to assess generalization to brain areas with different axon radii ensembles.
Indexable signal amplification for multiparametric imaging
Authors: Simonson Paul D. , Valencia Itzel , Patel Sanjay S. 
Published: June 2021

AbstractMultiparametric imaging allows researchers to measure the expression of many biomarkers simultaneously, allowing detailed characterization of cell microenvironments. One such technique, CODEX, allows fluorescence imaging of >30 proteins in a single tissue section. In the commercial CODEX system, primary antibodies are conjugated to DNA barcodes. This modification can result in antibody dysfunction, and development of a custom antibody panel can be very costly and time consuming as trial and error of modified antibodies proceeds. To address these challenges, we developed novel tyramide-conjugated DNA barcodes that can be used with primary antibodies via peroxidase-conjugated secondary antibodies. This approach results in signal amplification and imaging without the need to conjugate primary antibodies. When combined with commercially available barcode-conjugated primary antibodies, we can very quickly develop working antibody panels. We also present methods to perform antibody staining using a commercially available automated tissue stainer and in situ hybridization imaging on a CODEX platform.