bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-coverage genome sequencing for the detection of clinically relevant copy-number and mtDNA variants
Authors: Pajusalu Sander , Tooming Mikk , Oja Kaisa Teele , Šamarina Ustina , Kahre Tiina , Õunap Katrin
Published: September 2022

Background

Compared to exome sequencing, genome sequencing is widely appreciated for its superior ability to detect a wide range of genetic variations including copy-number variants (CNVs) and mitochondrial (mtDNA) variants. We assessed whether low-coverage genome sequencing, a considerably cheaper approach, would detect clinically relevant CNVs and mtDNA variants and would thus be a cost-efficient supplement to exome sequencing in rare disease diagnostics.

Methods

To assess the level of sequencing depth needed for variant detection, first, 30x mean coverage genome sequencing data were subsampled to 0.5x, 1x, 2x, and 4x coverage files in silico followed by CNV and mtDNA detection. Based on the analysis, 2x short-read sequencing was selected to be performed in 16 patients with putatively pathogenic CNVs or mtDNA variants to assess the empirical sensitivity.

Results

For CNV calling, 2x coverage was sufficient to detect all heterozygous CNVs greater than 10kb in size from in silico subsampled data. In experimental data, the results were similar, although a 16kb heterozygous deletion was once not detected. Regarding mtDNA variants, 2x coverage sufficed for variant confident variant calling and heteroplasmy assessment for all samples.

Conclusions

Low-coverage genome sequencing may be used to complement exome sequencing for simultaneous mtDNA variant and CNV detection.
Spliceosome Inhibition in SF3B1-Mutated Uveal Melanoma
Authors: Nguyen Josephine Q.N. , Drabarek Wojtek , Leeflang Aïsha M.C.H.J. , Brands Tom , van den Bosch Thierry P.P. , Verdijk Robert M. , van de Werken Harmen J.G. , van Riet Job , Paridaens Dion , de Klein Annelies , Brosens Erwin , Kiliç Emine
Published: September 2022

Treatment of uveal melanoma (UM) patients with metastatic disease is unfortunately limited. Twenty percent of UM harbor a mutation in splicing factor gene SF3B1, suggesting that aberrant spliceosome functioning plays a vital role in tumorigenesis. Splicing inhibitors exploit the preferential sensitivity of spliceosome compromised leukemic cells to these compounds. We have studied the effect of splicing inhibitor E7107 using two UM cell lines and ex vivo cultured SF3B1 and BAP1 mutated primary UM tumor slices. These UM cell lines and ex vivo tumor slices were exposed for 24h to different concentrations of E7107. Tumor slices were stained with H&E and incubated with BAP1, MelanA, MIB-1 and caspase-3 antisera. E7107 exposed UM cell lines showed decreased cell viability and increased apoptosis with the largest effect sizes in SF3B1-mutated UM. A similar effect was observed upon exposure of E7107 on UM tumor slices. Additionally, RNA was isolated for transcriptome analysis and the type and number of alternative and aberrant transcripts was evaluated. Ninety-seven transcripts had a decrease in aberrant transcripts in all samples after E7107 exposure, and this effect was mostly in intron retention. This study indicates / suggests that mutated SF3B1 UM cells are more sensitive to splicing inhibitor E7107 compared to wild-type SF3B1 UM cells.

Simple Summary

Uveal melanoma (UM) is an aggressive malignancy of the eye. UM prognosis varies and depends on mutational status. Mutations in spliceosome gene Splicing Factor 3b subunit 1 (SF3B1) are in UM associated with late onset metastasis. Also in other malignancies, such as breast cancer or leukemia, SF3B1 mutations have been implied as drivers for tumor formation. Targeting the spliceosome with inhibitors is possible and would make SF3B1-mutated UM amenable for treatment. We investigated and demonstrated using two cell lines and ex-vivo culturing of 3 SF3B1-mutated tumors and 17 SF3B1-wildtype tumors that spliceosome inhibitor E7107 decreased the cell viability of both SF3B1-mutated and SF3B1-wildtype UM cell line, but significantly more in SF3B1-mutated UM cell line. Therefore, inhibiting the spliceosome has the highest therapeutic potential in SF3B1-mutated UM, but further research is recommended to determine the best suited strategy to minimize risk and maximize efficacy in a therapeutic setting.
A Process-Mining Model to Detect Adverse Postoperative Blood Transfusions
Authors: Sumer Ahmet Murat , Ceylan Cemil
Published: September 2022

Importance

Errors that threaten patient safety can cause patient harm, death, and rising health care costs. Manual process to expose adverse events (AE) increase time spend to detect them and increase costs of detection.

Objective

This study aims to make it easier and faster to expose AEs related with postoperative blood usages by process mining.

Design

These errors can be reported voluntarily by healthcare givers or exposed by Global Trigger Tool (GTT) determined by the Institute for Healthcare Improvement (IHI). With process mining ‘Transfusion of Blood or Use of Blood Products’ (C1) cases were exposed in a data set. Actual life process was discovered and GTT C1 was searched as a process pattern in the discovered process. Instead of reviewing all cases manually, only detected cases were reviewed by patient safety subject matter experts.

Setting and Participants

Anadolu Medical Center, Turkey was selected as the reference site for this quality improvement study. The data set includes 42,086 records, 2,870 cases and 20 activities for the period between October and December 2018.

Main Outcomes and Measures

With the new process mining model, data was reduced to 2,704 records, 57 cases and 16 activities. 57 cases detected by the model were analyzed by the expert group and 10 of them are defined as AEs. Rate of C1 AEs per medical record is 1.0%. The rate of C1 AEs per medical record was between 1.3% and 8.3% in other research papers.

Conclusions and Relevance

Instead of running the classic GTT model manually, only detected 57 patient files were analyzed. The new model 95% decreases time of experts who will review medical records to expose AEs.
Higher risk of SARS-CoV-2 Omicron BA.4/5 infection than of BA.2 infection after previous BA.1 infection, the Netherlands, 2 May to 24 July 2022
Authors: Andeweg Stijn P. , de Gier Brechje , Vennema Harry , van Walle Ivo , van Maarseveen Noortje , Kusters Nina E. , de Melker Hester E. , Hahné Susan J.M. , van den Hof Susan , Eggink Dirk , Knol Mirjam J.
Published: September 2022

We investigate differences in protection from previous infection and/or vaccination against infection with Omicron BA.4/5 or BA.2. We observed a higher percentage of registered previous SARS-CoV-2 infections among 19836 persons infected with Omicron BA.4/5 compared to 7052 persons infected with BA.2 (31.3% vs. 20.0%) between 2 May and 24 July 2022 (adjusted odds ratio (aOR) for testing week, age group and sex: 1.4 (95%CI: 1.3-1.5)). No difference was observed in the distribution of vaccination status between BA.2 and BA.4/5 cases (aOR: 1.1 for primary and booster vaccination). Among reinfections, those newly infected with BA4/5 had a shorter interval between infections and the previous infection was more often caused by BA.1, compared to those newly infected with BA.2 (aOR: 1.9 (1.5-2.6). This suggests immunity induced by BA.1 is less effective against a BA.4/5 infection than against a BA.2 infection.
Brain and systemic inflammation in de novo Parkinson’s disease
Authors: Yacoubian Talene A. , Fang Yu-Hua Dean , Gerstenecker Adam , Amara Amy , Stover Natividad , Ruffrage Lauren , Collette Christopher , Kennedy Richard , Zhang Yue , Hong Huixian , Qin Hongwei , McConathy Jonathan , Benveniste Etty N. , Standaert David G.
Published: September 2022

Objective

To assess the presence of brain and systemic inflammation in subjects newly diagnosed with Parkinson’s disease (PD).

Background

Evidence for a pathophysiologic role of inflammation in PD is growing. However, several key gaps remain as to the role of inflammation in PD, including the extent of immune activation at early stages, potential effects of PD treatments on inflammation, and whether pro-inflammatory signals are associated with clinical features and/or predict more rapid progression.

Methods

We enrolled subjects with de novo PD (n=58) and age-matched controls (n=62). Subjects underwent clinical assessments, including the Movement Disorder Society-United Parkinson’s Disease rating scale (MDS-UPDRS). Comprehensive cognitive assessment meeting MDS Level II criteria for mild cognitive impairment (MCI) testing was performed. Blood was obtained for flow cytometry and cytokine/chemokine analyses. Subjects underwent imaging with 18F-DPA-714, a translocator protein 18kd (TSPO) ligand, and lumbar puncture if eligible and consented.

Results

Baseline demographics and medical history were comparable between groups. PD subjects showed significant differences in University of Pennsylvania Smell Identification Test, Schwab and England Activities of Daily Living, Scales for Outcomes in PD autonomic dysfunction, and MDS-UPDRS scores. Cognitive testing demonstrated significant differences in cognitive composite, executive function, and visuospatial domain scores at baseline. PET imaging showed increased 18F-DPA-714 signal in PD subjects. 18F-DPA-714 signal correlated with several cognitive measures and some chemokines.

Conclusions

18F-DPA-714 imaging demonstrated increased central inflammation in de novo PD subjects compared to controls. Longitudinal follow-up will be important to determine whether the presence of inflammation predicts cognitive decline.
Efficacy and safety of convalescent plasma versus standard care in hospitalized patients with COVID-19 from the Peruvian Social Security Health System: open-label, randomized, controlled clinical trial
Authors: Villanueva Cristian , Neyra Ibeth , Sagastegui Arturo , Chunga Ausberto , Oyanguren Martin , Guillermo-Roman Martina , Soto-Ordoñez Suly , Maguiña Jorge L. , Hurtado-Roca Yamilee , Soto-Becerra Percy , Araujo-Castillo Roger V.
Published: September 2022

OBJECTIVES

To assess the efficacy and safety of convalescent plasma plus standard of care (CP + SoC) compared with standard of care (SoC) alone in patients hospitalized for moderate to severe COVID-19 who do not yet require mechanical ventilation.

METHODS

Phase 2 randomized, parallel-group, randomized, open-label, controlled, superiority, single-center clinical trial. This clinical trial has been registered in REPEC with the following ID: 013-20. Hospitalized adult patients with moderate to severe COVID-19 were enrolled. The allocation ratio was 1:1 in a variable-size permuted block randomization scheme. The primary outcome was death 28 days after the intervention. Secondary outcomes were mortality at 14 and 56 days, time to death at 56 days, time in the ICU at 28 days, time on a mechanical ventilator at 28 days, frequency of adverse events, and frequency of serious adverse events.

RESULTS

A total of 64 participants were enrolled, 32 were assigned to CP + SoC, and 32 to SoC. One participant assigned to CP + SoC withdrew his informed consent before applying the treatment. At day 28, there were no statistically significant differences for the primary outcome between the CP + SoC and SoC groups (relative risk: 2.06; 95%CI 0.73 to 7.11; p = 0.190). No differences were found in the incidences of mortality at 56 days (hazard ratio: 2.21; 95%CI 0.66 to 7.33; p = 0.182), admission to the ICU at 28 days (sub-hazard ratio: 2.06; 95%CI 0.57 to 8.55; p = 0.250), admission to mechanical ventilation at 28 days (sub-hazard ratio: 2.19; 95%CI 0.57 to 8.51; p = 0.260). Estimates for days 14 were similar. No infusion-related adverse events were reported during the study. There were no statistically significant differences in the frequency of any adverse events (odds ratio: 2.74; 95%CI 0.90 to 9.10; p = 0.085) or the frequency of serious adverse events (odds ratio: 3.60; 95%CI 0.75 to 26.1; p = 0.75).

CONCLUSIONS

No evidence was found that CP had a significant effect in reducing 28-day mortality. There was also no evidence that the frequency of adverse events was higher in those who received CP + SoC than those who received only SoC.
The impact of 22q11.2 copy number variants on human traits in the general population
Authors: Zamariolli Malú , Auwerx Chiara , Sadler Marie C , van der Graaf Adriaan , Lepik Kaido , Moysés-Oliveira Mariana , Dantas Anelisa G , Melaragno Maria Isabel , Kutalik Zoltán
Published: September 2022

While extensively studied in clinical cohorts, the phenotypic consequences of 22q11.2 copy number variants (CNVs) in the general population remain understudied. To address this gap, we performed a phenome-wide association scan in 405’324 unrelated UK Biobank (UKBB) participants using CNV calls from genotyping array. We mapped 236 Human Phenotype Ontology terms linked to any of the 90 genes encompassed by the region to 170 UKBB traits and assessed the association between these traits and the copy-number state of 504 SNP-array probes in the region. We found significant associations for eight continuous and nine binary traits associated under different models (duplication-only, deletion-only, U-shape and mirror model). The causal effect of the expression level of 22q11.2 genes on associated traits was assessed through transcriptome-wide mendelian randomization (TWMR), revealing that increased expression of ARVCF increased BMI. Similarly, increased DGCR6 expression causally reduced mean platelet volume, in line with the corresponding CNV effect. Furthermore, cross-trait multivariable mendelian randomization (MVMR) suggested a predominant role of genuine (horizontal) pleiotropy in the CNV region. Our findings show that within the general population, 22q11.2 CNVs are associated with traits previously linked to genes in the region, with duplications and deletions acting upon traits in different fashion. We also showed that gain or loss of distinct segments within 22q11.2 may impact a trait under different association models. Our results have provided new insights to help further the understanding of the complex 22q11.2 region.
Less invasive SARS-CoV-2 testing for children: A comparison of saliva and a novel Anterior Nasal Swab
Authors: Tosif Shidan , Lee Lai-yang , Nguyen Jill , Selman Chris , Grobler Anneke C , McMinn Alissa , Steer Andrew , Daley Andrew , Crawford Nigel
Published: September 2022

Reducing procedural discomfort for children requiring respiratory testing for SARS-CoV-2 is important in supporting testing strategies for case identification. Alternative sampling methods to nose and throat swabs, which can be self-collected, may reduce laboratory-based testing requirements and provide rapid results for clearance to attend school or hospital settings. The aim of this study was to compare preference and diagnostic sensitivity of a novel anterior nasal swab (ANS), and saliva, with a standard combined nose and throat (CTN) swab. The three samples were self-collected by children aged 5-18 years who had COVID-19 or were a household close contact. Samples were analysed by reverse transcription polymerase chain reaction (RT-PCR) on the Allplex SARS-CoV-2 Assay. Most children and parents preferred the ANS and saliva swab over the CTN swab for future testing. The ANS was highly sensitive (sensitivity 1.000 (95% Confidence Interval (CI) 0.920, 1.000)) for SARS-CoV-2 detection, compared to saliva (sensitivity 0.886, 95% CI 0.754, 0.962). We conclude the novel ANS is a highly sensitive and more comfortable method for SARS-CoV-2 detection when compared to CTN swab.
Differential WMH progression trajectories in progressive and stable mild cognitive impairment
Authors: Kamal Farooq , Morrison Cassandra , Maranzano Josefina , Zeighami Yashar , Dadar Mahsa ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2022

Background

Pathological brain changes such as white matter hyperintensities (WMHs) occur with increased age and contribute to cognitive decline. Current research is still unclear regarding the association of amyloid positivity with WMH burden and progression to dementia in people with mild cognitive impairment (MCI).

Methods

This study examined whether WMH burden increases differently in both amyloid-negative (Aβ-) and amyloid-positive (Aβ+) people with MCI who either remain stable or progress to dementia. We also examined regional WMHs differences in all groups: amyloid positive (Aβ+) progressor, amyloid negative (Aβ–) progressor, amyloid positive (Aβ+) stable, and amyloid negative (Aβ–) stable. MCI participants from the Alzheimer’s Disease Neuroimaging Initiative were included if they had APOE ɛ4 status and if they had amyloid measures to determine amyloid status (i.e., positive, or negative). A total of 820 MCI participants that had APOE ɛ4 status and amyloid measures were included in the study with 5054 follow-up time points over a maximum period of 13 years with an average of 5.7 follow-up timepoints per participant. Linear mixed-effects models were used to examine group differences in global and regional WMHs.

Results

People who were Aß– stable had lower baseline WMHs compared to both Aß+ progressors and Aß+ stable across all regions. When examining change over time, compared to Aß– stable, all groups had steeper change in WMH burden with Aß+ progressors having the largest change (largest increase in WMH burden over time).

Conclusion

These findings suggest that WMH progression is a contributing factor to conversion to dementia both in amyloid-positive and negative people with MCI.
Metabolomic fingerprinting for biomarker discovery in renal amyloidosis
Authors: Ghosh Shreya , Singh Praveen , Govil Samir , Kala Chayanika , Chitkara Shivani , Sengupta Shantanu , Thakur Ashwani Kumar
Published: September 2022

Nephrotic syndrome (NS) manifested by proteinuria is the primary clinical hallmark of amyloid deposition in the kidney. However, proteinuria is observed in other kidney disorders misleading clinicians and limiting the scope of early diagnosis. We presumed that amyloid-driven pathophysiology could result in the perturbation of downstream cellular and metabolic pathways in these patients with NS. Herein, we have diagnosed one hundred patients with clinical evidence of nephrotic syndrome. Further, the histopathological evaluation identified the presence of amyloid in eleven patients. To decipher the downstream effects underlying amyloid formation, we performed plasma metabolomic profiling of these patients. Fifteen metabolites, including different lipids, carnitines and amino acids, were found altered in the renal amyloidosis patients compared to controls. It is the first study depicting the potential of metabolomics to identify biomarkers for early diagnosis of renal amyloidosis patients.
Sensitivity and Uncertainty Analysis for Two-Stream Capture-Recapture Methods in Disease Surveillance
Authors: Zhang Yuzi , Chen Jiandong , Ge Lin , Williamson John M. , Waller Lance A. , Lyles Robert H.
Published: September 2022

Capture-recapture methods are widely applied in estimating the number (N) of prevalent or cumulatively incident cases in disease surveillance. Here, we focus the bulk of our attention on the common case in which there are two data streams. We propose a sensitivity and uncertainty analysis framework grounded in multinomial distribution-based maximum likelihood, hinging on a key dependence parameter that is typically non-identifiable but is epidemiologically interpretable. Focusing on the epidemiologically meaningful parameter unlocks appealing data visualizations for sensitivity analysis and provides an intuitively accessible framework for uncertainty analysis designed to leverage the practicing epidemiologist’s understanding of the implementation of the surveillance streams as the basis for assumptions driving estimation of N. By illustrating the proposed sensitivity analysis using publicly available HIV surveillance data, we emphasize both the need to admit the lack of information in the observed data and the appeal of incorporating expert opinion about the key dependence parameter. The proposed uncertainty analysis is an empirical Bayes-like approach designed to more realistically acknowledge variability in the estimated N associated with uncertainty in an expert’s opinion about the non-identifiable parameter, together with the statistical uncertainty. We demonstrate how such an approach can also facilitate an appealing general interval estimation procedure to accompany capture-recapture methods. Simulation studies illustrate the reliable performance of the proposed approach for quantifying uncertainties in estimating N in various contexts. Finally, we demonstrate how the recommended paradigm has the potential to be directly extended for application to data from more than two surveillance streams.
MicroRNA-146a polymorphisms are Associated with Psoriasis Vulgaris
Authors: Zhu Kunju , Li Shijie , Liang Lifan
Published: September 2022

MicroRNA-146a acts as a critical physiological brake role to prevent the overactivation of inflammatory response pathways and was a key negative regulator of autoimmunity. Ets-1 could bind to the MicroRNA-146a promoter region as a regulator of MicroRNA-146a expression in vitro. IRAK1 is a prominent target of MicroRNA-146a that help it to negatively regulate the release of IL8. This study aimed to investigate the association of MicroRNA-146a, Ets-1(negative regulator) and IRAK1(target) polymorphisms with Psoriasis Vulgaris(PsV), the most prevalent chronic inflammatory skin disease in adults, in a Southern Chinese cohort. Seven SNPs in microRNA-146a (rs2431697; rs2910164; rs57095329), Ets-1(rs10893872; rs1128334) and IRAK1(rs1059703; rs3027898) genes were genotyped in 673 subjects (360 PsV cases and 313 controls) by SNaPshot Multiplex Kit (Applied Biosystems Co., USA). We found significant difference in the genotype and allele frequencies of rs2431697 and rs2910164 in MicroRNA-146a gene between the PsV cases and the controls. The dominant model genotype (CC+CT) (p=0.019; OR=1.463) and allele (C) (p=0.027; OR=1.496) of rs2431697 and the GG genotype (p= 0.027; OR=1.582) and allele (G) of rs2910164 were associated with an increased risk of PsV. There was no association of the SNPs with the clinical traits of PsV. Our data provide preliminary evidence that the rs2431697 and rs2910164 polymorphism in the microRNA-146a gene may be involved in the genetic susceptibility to PsV in Southern Chinese. Although further function studies will be required to identify the details of the process, the findings could make a significant step forward in our understanding of the genetic contribution to psoriasis.

What’s already known about this topic?

MicroRNA-146a is one of the most highly associated MicroRNA to psoriasis.

MicroRNA-146a acts as a critical physiological brake role to prevent the overactivation of inflammatory response pathways and was a key negative regulator of autoimmunity.

What does this study add?

Our data provide preliminary evidence that the rs2431697 and rs2910164 polymorphism in the microRNA-146a gene are involved in the genetic susceptibility to PsV in Southern Chinese.
Assessment tools and incidence of hospital-associated disability: a rapid systematic review
Authors: Giacomino Katia , Hilfiker Roger , Beckwée David , Taeymans Jan , Sattelmayer Karl Martin
Published: September 2022

Background

During hospitalization older people have a high risk of developing functional impairments unrelated to the reasons for their admission. This is termed hospital-associated disability. This systematic review aimed to assess the incidence of hospital-associated disability among older patients admitted to acute care, to identify the tools used to assess activities of daily living in these patients, and evaluate which functional task is most sensitive for detecting changes in disability among older hospitalized patients.

Methods

A rapid systematic review was performed according to the recommendations of the Cochrane Rapid Reviews Methods Group and the PRISMA statement. A literature search was performed in Medline (via Ovid), EMBASE, and Cochrane Central Register of Controlled Trials databases on 26 August 2021. Inclusion criteria: older people, assessment of activities of daily living at baseline and discharge. Exclusion criterion: diseases affecting functional decline.

Results

Eleven studies were included in the final review. Incidence of hospital-associated disability (overall score) was 37% (95% CI 0.31–0.42). Insufficient data prevented meta-analysis of the individual items. The most sensitive measure for detecting changes in disability was the overall score of assessment of activities of daily living.

Conclusions

Incidence of hospital-associated disability in older patients might be overestimated, due to the combination of disease-related disability and hospital-associated disability. The tools used to assess these patients presented some limitations. These results should be interpreted with caution, as a limited number of studies reported adequate information to assess the incidence of hospital-associated disability. Risk of bias in the included studies raised some concerns.
Natural language processing and modeling of clinical disease trajectories across brain disorders
Authors: Mekkes Nienke , Groot Minke , Wehrens Sophie , Hoekstra Eric , Herbert Megan K , Brummer Maaike , Wever Dennis ,   Netherlands Neurogenetics Database Consortium, Eggen Bart J.L. , Rozemuller Annemieke , Huitinga Inge , Holtman Inge R.
Published: September 2022

Brain disorders, including neurodegenerative diseases and mental illnesses, are often difficult to diagnose and study due to clinical and pathological heterogeneity, overlap in clinical manifestations between disorders, and frequent comorbidities, hampering drug development and fundamental research. Hence, there is a clear need for data-driven approaches to disentangle these complex disorders. Here, we established a computational pipeline to process clinical summaries from donors with a wide range of brain disorders that were neuropathologically diagnosed by the Netherlands Brain Bank. First, we identified and defined 90 cross-disorder signs and symptoms within cognitive, motor, sensory, psychiatric, and general domains. Second, we trained and optimized natural language processing (NLP) models to identify these signs and symptoms in individual sentences of the extensive clinical summaries from donors of the NBB, resulting in temporal disease trajectories. Third, we studied the temporal manifestation and survival profiles across rare and complex dementias, alpha-synucleinopathies, frontotemporal dementia subtypes, and mental illnesses, giving new insight into how symptomatology differs in manifestation and temporal profiles across brain disorders. Lastly, we trained a recurrent neural network to predict the Neuropathological Diagnosis. Taken together, this integrated approach resulted in a highly unique resource that can facilitate research into cross-disorder symptomatology.
Data-driven identification of unusual prescribing behaviour: an analysis and interactive data tool using six months of primary care data from 6500 practices in England
Authors: Hopcroft Lisa EM , Massey Jon , Curtis Helen , MacKenna Brian , Croker Richard , Macdonald Orla , Evans David , Inglesby Peter , Bacon Seb , O’Dwyer Tom , Goldacre Ben , Walker Alex J
Published: September 2022

Background

Approaches to addressing unwarranted variation in healthcare service delivery have traditionally relied on the prospective identification of activities and outcomes, based on a hypothesis, with subsequent reporting against defined measures. Practice-level prescribing data in England are made publicly available by the NHS Business Services Authority for all general practices. There is an opportunity to adopt a more data-driven approach to capture variability and identify outliers by applying hypothesis free data driven algorithms to national datasets.

Objectives

To develop and apply a hypothesis free algorithm to identify unusual prescribing behaviour in primary care data at multiple administrative levels in the NHS in England, and to visualise these results using organisation-specific interactive dashboards.

Methods

Here we report a new data-driven approach to quantify how ‘unusual’ prescribing rates of a particular chemical within an organisation are as compared to peer organisations, over a period of six months (June-December 2021). This is followed by ranking to identify which chemicals are the most notable outliers in each organisation. These outlying chemicals are calculated for all practices, primary care networks, clinical commissioning groups and sustainability and transformation partnerships in England. Results are presented via organisation-specific interactive dashboards, the iterative development of which has been informed by user feedback.

Results

User feedback and internal review of case studies demonstrate that our methodology identifies chemicals that are in line with local policies and internal reporting.

Conclusions

Data-driven approaches overcome existing biases with regards to the planning and execution of audits, interventions and policy-making within NHS organisations, potentially revealing new targets for improved healthcare service delivery. We provide our dashboards as a candidate list for the consideration of expert users to prioritise for further interpretation and qualitative research in terms of potential targets for improved performance.
Intensity of sample processing methods impacts wastewater SARS-CoV-2 whole genome amplicon sequencing outcomes
Authors: Feng Shuchen , Owens Sarah M. , Shrestha Abhilasha , Poretsky Rachel , Hartmann Erica M. , Wells George
Published: September 2022

Wastewater SARS-CoV-2 surveillance has been deployed since the beginning of the COVID-19 pandemic to monitor dynamics in virus burden in local communities. Genomic surveillance of SARS-CoV-2 in wastewater, particularly the efforts for whole genome sequencing for variant tracking or identification, are comparatively challenging due to low target concentration, complex microbial and chemical background, and lack of robust nucleic acid recovery experimental procedures. The intrinsic sample limitations are inherent to wastewater. In this study, we evaluated impacts from sample types, certain sample intrinsic features, and processing and sequencing methods on sequencing outcomes with a specific focus on the breadth of genome coverage. We collected 184 composite and grab wastewater samples from the Chicago area between March to October 2021 for SARS-CoV-2 quantification and genomic surveillance. Samples were processed using a mixture of processing methods reflecting different homogenization intensities (HA+Zymo beads, HA+glass beads, and Nanotrap), and were sequenced using two sequencing library preparation kits (the Illumina COVIDseq kit and the QIAseq DIRECT kit). A synthetic SARS-CoV-2 RNA experiment was performed to validate the potential impacts of processing methods on sequencing outcomes. Our findings suggested that 1) wastewater SARS-CoV-2 whole genome sequencing outcomes were associated with sample types and processing methods 2) in less intensive method processed samples (HA+glass beads), higher genome breadth of coverage in sequencing (over 80%) was associated with N1 concentration > 105 cp/L, while in intensive method (HA+Zymo beads), qPCR results were inconsistent with sequencing outcomes, and 3) sample processing methods and sequencing kits, rather than the extraction methods or intrinsic features of wastewater samples, played important roles in wastewater SARS-CoV-2 amplicon sequencing. Overall, extra attention should be paid to wastewater sample processing (e.g., concentration and homogenization) for sufficient, good quality RNA yield for downstream sequencing.
Effects of SARS-CoV-2 Infection on Attention, Memory, and Sensorimotor Performance
Authors: O’Connor Erin E. , Rednam Nikita , O’Brien Rory , O’Brien Shea , Rock Peter , Levine Andrea , Zeffiro Thomas A.
Published: September 2022

Background

Recovery after SARS-CoV-2 infection is extremely variable, with some individuals recovering quickly, and others experiencing persistent long-term symptoms or developing new symptoms after the acute phase of infection, including fatigue, poor concentration, impaired attention, or memory deficits. Many existing studies reporting cognitive deficits associated with SARS-CoV-2 infection are limited by the exclusive use of self-reported measures or a lack of adequate comparison groups.

Methods

Forty-five participants, ages 18-70, (11 Long-COVID, 14 COVID, and 20 No-COVID) underwent behavioral testing with the NIH Toolbox Neuro-Quality of Life survey and selected psychometric tests, including a flanker interference task and the d2 Test of Attention.

Results

We found greater self-reported anxiety, apathy, fatigue, emotional dyscontrol, sleep disturbance and cognitive dysfunction in COVID compared No-COVID groups. After categorizing COVID patients according to self-reported concentration problems, we observed declining performance patterns in multiple attention measures across No-COVID controls, COVID and Long-COVID groups. COVID participants, compared to No-COVID controls, exhibited worse performance on NIH Toolbox assessments, including the Eriksen Flanker, Nine-Hole Pegboard and Auditory Verbal Learning tests.

Conclusion

This study provides convergent evidence that previous SARS-CoV-2 infection is associated with impairments in sustained attention, processing speed, self-reported fatigue and concentration. The finding that some patients have cognitive and visuomotor dysfunction in the absence of self-reported problems suggests that SARS-CoV-2 infection can have unexpected and persistent subclinical consequences.
Prevalence, clusters, and burden of complex tuberculosis multimorbidity in low- and middle-income countries: a systematic review and meta-analysis
Authors: Jarde Alexander , Ma Ruimin , Todowede Olamide O. , Latif Abdul , Yaqoob Aashifa , Afaq Saima , Ferdous Tarana , Tomeny Ewan M , Rosu Laura , Mrema Lucy Elauteri , Rakhshanda Shagoofa , Fazid Sheraz , Rahman Farah Naz , Egere Uzochukwu , Elsony Asma , Elsey Helen , Siddiqi Kamran , Stubbs Brendon , Siddiqi Najma
Published: September 2022

Objectives

The co-occurrence of tuberculosis (TB) and multiple chronic communicable and non-communicable diseases is a growing concern in low- and middle-income countries (LMICs). Understanding this ‘complex TB multimorbidity’ (cTBMM) can contribute to improved patient care. We aimed to synthesise the prevalence of clusters of cTBMM and their impact on patient outcomes.

Design

Systematic review and meta-analysis.

Setting

LMICs.

Papers

We searched major databases from inception to 01/10/2020 to identify observational studies reporting primary (prevalence or risk) or secondary (related to disease burden) outcome data for people in LMICs with cTBMM. Titles, abstracts and full text screening, data extraction, and quality assessment were done in duplicate by independent reviewers, and random-effects meta-analyses were performed.

Primary and secondary outcome measures

Prevalence or risk of cTBMM (primary); any measure of burden of disease (secondary).

Results

From 21,884 search results, 82 studies representing 773,828 TB patients were included, reporting data on 78 different clusters of cTBMM. In TB patients, the most prevalent co-occurring conditions where depression and anxiety (15.3%, 95% confidence interval [CI] 10.7%-20.5%, 3 studies, 1,473 participants, I2=64%), HIV and anxiety (15.2%, 95%CI 11.3%-19.7%, 4 studies, 1,413 participants, I2=77%), and HIV and post-traumatic stress disorder (14.8%, 95%CI 13.9%-15.8%, 2 studies, 5,400 participants). Sparse evidence indicated lower treatment success and higher risks of death in people with cTBMM.

Conclusions

Although limited by high heterogeneity, this first systematic review and meta-analysis on cTBMM highlights that multiple conditions co-occurring in TB patients are common and that mental disorders often cluster together or with HIV. Further research assessing the burden of cTBMM and identifying effective health systems responses is required.

Registration

Prospero CRD42020214021.

Strengths and limitations of this study

To our knowledge, this is the first systematic review summarising the prevalence of the different clusters of complex TB multimorbidity (cTBMM) in LMICs.

While our focus was on cTBMM in LMICs overall, subgroup analyses by type of TB, country, and socio-economic group allow for a more nuanced assessment on cTBMM.

We used a broad definition for the term ‘chronic condition’ to be as inclusive as possible, but which could lead to heterogeneity in the definition of some clusters of cTBMM.
Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19
Authors: O’Halloran Jane A. , Kedar Eyal , Anstrom Kevin J. , McCarthy Matthew W. , Ko Emily R. , Nunez Patricia Segura , Boucher Cynthia , Smith P. Brian , Panettieri Reynold A. , de Tai Sabina Mendivil Tuchia , Maillo Martin , Khan Akram , Mena Lora Alfredo J. , Salathe Matthias , Capo Gerardo , Gonzalez Daniel Rodríguez , Patterson Thomas F , Palma Christopher , Ariza Horacio , Lima Maria Patelli , Lachiewicz Anne M. , Blamoun John , Nannini Esteban C. , Sprinz Eduardo , Mykietiuk Analia , Alicic Radica , Rauseo Adriana M. , Wolfe Cameron R. , Witting Britta , Benjamin Daniel K. , McNulty Steven E. , Zakroysky Pearl , Halabi Susan , Butler Sandra , Atkinson Jane , Adam Stacey J. , Melsheimer Richard , Chang Soju , LaVange Lisa , Proschan Michael , Bozzette Samuel A. , Powderly William G. ,   ACTIV-1 IM study group members
Published: September 2022

Background

Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care.

Methods

We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality.

Results

A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99–1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05–1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39–0.90). No differences in risk of serious adverse events including secondary infections.

Conclusions

Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care.

Trial registration

ClinicalTrials.gov (NCT04593940).
Identification of Causal Pathways among Gut Microbiota, Food Intake and Telomere Length: A Mendelian Randomization Study
Authors: Hou Lei , Yu Yuanyuan , Jin Chuandi , Zhang Lei , Ge Yilei , Liu Xinhui , Wu Sijia , Qian Fengtong , Wu Yutong , Yu Yifan , Luo Qingxin , He Yina , Feng Yue , Wei Yun , Li Hongkai , Xue Fuzhong
Published: September 2022

Background

Dietary habit plays an important role in the composition and function of gut microbiota which possibly manipulates host eating behavior. Gut microflora and nutritional imbalance are associated with telomere length (TL). However, the causality among them remains unclear.

Methods

Firstly, we calculate the significance threshold based on genetic correlations. Then we perform bi-directional Mendelian Randomization (MR) analyses among 82 food intakes (FIs) (UK Biobank, N=455,146), 95 gut microbial traits (Flemish Gut Flora Project, N=2,223) and TL (genome-wide meta-analysis from 15 cohorts, N=37,684) using summary-level data from large genome-wide association studies. Fixed-effect inverse variance weighting is the main analysis method and the other eight two-sample MR methods and three sensitivity analyses are performed. Finally, GO enrichment analyses are used to investigate the bio-function.

Results

Several bi-directional causal relationships among gut microbiota, FIs and TL are obtained by two-sample MR. Overall, we find suggestive evidence of three main causal pathways among them. Drinking more glasses of water per day is able to affect the habit of eating dried fruit through the host gut microbiota (Barnesiella). The change of one gut microbiota taxon (Collinsella) in the host causally influences another gut microbiota taxon (Lactonccus) through the diet habits (intake of oil-based spread). Additionally, the TL alters the habits of drinking ground coffee and further affects the gut microbiota (Acidaminococcaceae). GO enrichment analysis further confirmed the MR results.

Conclusion

TL has an impact on diet habits and gut microbiota and there are bi-directional relationships between diet habits and gut microbiota.
A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer’s Disease
Authors: Bai Haimeng , Naj Adam C. , Benchek Penelope , Dumitrescu Logan , Hohman Timothy , Hamilton-Nelson Kara , Kallianpur Asha R. , Griswold Anthony J. , Vardarajan Badri , Martin Eden R. , Beecham Gary W. , Below Jennifer E. , Schellenberg Gerard , Mayeux Richard , Farrer Lindsay , Pericak-Vance Margaret A. , Haines Jonathan L. , Bush William S. ,   Alzheimer’s Disease Genetics Consortium
Published: September 2022

Background

Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid-β (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2.

Methods

HP genotypes were imputed in 29 cohorts from the Alzheimer’s Disease (AD) Genetics Consortium (N=22,651). Associations between the HP polymorphism and AD risk and age of onset through APOE interactions were investigated using regression models.

Results

The HP polymorphism significantly impacts AD risk and age at onset in European-descent individuals (and in meta-analysis with African Americans) by modifying both the protective effect of APOEε2 and the detrimental effect of APOEε4, especially for APOEε4 carriers.

Discussion

The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.
Patterning and growth are coordinated early in the cell cycle
Authors: Winter Cara M. , Szekely Pablo , Belcher Heather , Carter Raina , Jones Matthew , Fraser Scott E. , Truong Thai V. , Benfey Philip N.
Published: September 2022

Precise control of cell division is essential for proper patterning and growth during the development of multicellular organisms. Coordination of formative (asymmetric) divisions that generate new tissue patterns with proliferative (symmetric) divisions that promote growth is poorly understood. Here, we employed quantitative 4D light sheet and confocal microscopy to probe in vivo the dynamics of two transcription factors, SHORTROOT (SHR) and SCARECROW (SCR), which are required for asymmetric division in the stem cell niche of Arabidopsis roots [1,2]. Long-term (up to 48 hours), frequent (every 15 minutes) imaging of the two regulators in tandem in single cells, in conjunction with a SHR induction system, enabled us to challenge an existing bistable model[3] of the SHR/SCR gene regulatory network. By directly controlling SHR and SCR expression dynamics, we were able to identify key features that are essential for rescue of asymmetric division in shr mutants. We show that instead of high stable levels of nuclear SHR and SCR, only low transient levels of expression are required. Nuclear SHR kinetics do not follow predictions of the bistable model, and the regulatory relationship between SHR and SCR can be modeled by monostable alternatives. Furthermore, expression of these two regulators early in the cell cycle determines the orientation of the division plane, resulting in either formative or proliferative cell division. Our findings provide evidence for an uncharacterized mechanism by which developmental regulators directly coordinate patterning and growth.
Grazers affect the composition of dissolved storage glycans and thereby bacterioplankton composition during a biphasic North Sea spring algae bloom
Authors: Sidhu Chandni , Kirstein Inga V. , Meunier Cédric L. , Rick Johannes , Wiltshire Karen H. , Steinke Nicola , Vidal-Melgosa Silvia , Hehemann Jan-Hendrik , Huettel Bruno , Schweder Thomas , Fuchs Bernhard M. , Amann Rudolf I. , Teeling Hanno
Published: September 2022

Blooms of marine microalgae play a pivotal role in global carbon cycling. Such blooms entail successive blooms of specialized clades of planktonic bacteria that remineralize algal biomass. We investigated the bacterioplankton response to a bloom in the German Bight in spring 2020. Metagenome sequencing at 30 time-points allowed reconstruction of 251 metagenome-assembled genomes (MAGs), 245 representing as yet uncultured species, while corresponding metatranscriptome sequencing highlighted 50 particularly active MAGs. Together with algae, copepod, protist and bacteria diversity and abundance data in combination with physico-chemical data and antibody-based saccharide measurements, we demonstrate (i) how dissolved primary photoassimilated algal and secondary bacterial storage glycans shape the bacterioplankton community composition, and (ii) how grazing on higher trophic levels determines the release of these abundant glycans. We thus elucidate principles governing how bacterioplankton clades respond to algal blooms and collectively remineralize gigatons of carbon annually on a global scale.
SIMBSIG: Similarity search and clustering for biobank-scale data
Authors: Adamer Michael F. , Roellin Eljas , Bourguignon Lucie , Borgwardt Karsten
Published: September 2022

In many modern bioinformatics applications, such as statistical genetics, or single-cell analysis, one frequently encounters datasets which are orders of magnitude too large for conventional in-memory analysis. To tackle this challenge, we introduce SIMBSIG, a highly scalable Python package which provides a scikit-learn-like interface for out-of-core, GPU-enabled similarity searches, principal component analysis, and clustering. Due to the PyTorch backend it is highly modular and particularly tailored to many data types with a particular focus on biobank data analysis.

Availability

SIMBSIG is freely available from PyPI and its source code and documentation can be found on GitHub (https://github.com/BorgwardtLab/simbsig) under a BSD-3 license.

Contact

michael.adamer@bsse.ethz.ch