Category: Statistics

Science. 2021 Aug 12:eaba7408. doi: 10.1126/science.aba7408. Online ahead of print.

ABSTRACT

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of LINE repeats. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

PMID:34385354 | DOI:10.1126/science.aba7408

Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2108064118. doi: 10.1073/pnas.2108064118.

ABSTRACT

We study an analog of Serre’s modularity conjecture for projective representations [Formula: see text], where K is a totally real number field. We prove cases of this conjecture when [Formula: see text].

PMID:34385325 | DOI:10.1073/pnas.2108064118

J Nucl Med. 2021 Aug 12:jnumed.121.262471. doi: 10.2967/jnumed.121.262471. Online ahead of print.

ABSTRACT

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal organ and tumor uptake of the PSMA ligand, ¹⁸F-rhPSMA-7.3, in patients with prostate cancer. Methods: The biodistribution of ¹⁸F-rhPSMA-7.3 on PET/CT scans performed with a high specific activity (median = 178.9MBq/µg, n = 42) and a low specific activity (median = 19.3MBq/µg, n = 42) were compared. Results: Tracer uptake by the parotid gland, submandibular gland and spleen was moderately, but significantly lower in the “low specific activity” group than in the “high specific activity” group (median SUVmean 16.7 vs. 19.2; 18.1 vs. 22.3, and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. Conclusion: A 10-fold decrease in specific activity has only minor effects on the biodistribution of ¹⁸F-rhPSMA-7.3. These findings suggest that ¹⁸F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to ¹⁸F-fluorodeoxyglucose.

PMID:34385338 | DOI:10.2967/jnumed.121.262471

Eur Respir J. 2021 Aug 12:2101209. doi: 10.1183/13993003.01209-2021. Online ahead of print.

ABSTRACT

BACKGROUND: Individual case series and cohort studies have reported conflicting results on the vulnerability to and risk of mortality of people with asthma from COVID-19.

RESEARCH QUESTION: Are people with asthma at a higher risk of being infected, hospitalised or of poorer clinical outcomes from COVID-19?

METHODS: A systematic review and meta-analysis based on five main databases including the WHO COVID-19 database between December 1, 2019 to July 11, 2021 on studies with a control (non-asthma) group was conducted. Prevalence and risk ratios were pooled using Sidik-Jonkman random effects meta-analyses.

FINDINGS: Fifty-one studies with an 8.08% (95% CI 6.87-9.30) pooled prevalence of people with asthma among COVID-19 positive cases. The risk ratios were 0.83 (95% CI 0.73-0.95, p=0.01) for acquiring COVID-19; 1.18 (95% CI 0.98-1.42, p=0.08) for hospitalisation; 1.21 (95% CI 0.97-1.51, p=0.09) for ICU admission; 1.06 (95% CI 0.82-1.36, p=0.65) for ventilator use and 0.94 (95% CI 0.76-1.17; p=0.58) for mortality for people with asthma. Subgroup analyses by continent revealed a significant difference in risk of acquiring COVID-19, ICU admission, ventilator use and death between the continents.

INTERPRETATION: The risk of being infected with SARS-CoV-2 was reduced compared to the non-asthma group. No statistically significant differences in hospitalisation, ICU admission and ventilator use were found between groups. Subgroup analyses showed significant differences in outcomes from COVID-19 between America, Europe and Asia. Additional studies are required to confirm this risk profile, particularly in Africa and South America where few studies originate.

PMID:34385278 | DOI:10.1183/13993003.01209-2021

BMJ Health Care Inform. 2021 Aug;28(1):e100349. doi: 10.1136/bmjhci-2021-100349.

ABSTRACT

INTRODUCTION: The SARS-CoV-2 (COVID-19) pandemic has exposed the need to understand the risk drivers that contribute to uneven morbidity and mortality in US communities. Addressing the community-specific social determinants of health (SDOH) that correlate with spread of SARS-CoV-2 provides an opportunity for targeted public health intervention to promote greater resilience to viral respiratory infections.

METHODS: Our work combined publicly available COVID-19 statistics with county-level SDOH information. Machine learning models were trained to predict COVID-19 case growth and understand the social, physical and environmental risk factors associated with higher rates of SARS-CoV-2 infection in Tennessee and Georgia counties. Model accuracy was assessed comparing predicted case counts to actual positive case counts in each county.

RESULTS: The predictive models achieved a mean R² of 0.998 in both states with accuracy above 90% for all time points examined. Using these models, we tracked the importance of SDOH data features over time to uncover the specific racial demographic characteristics strongly associated with COVID-19 incidence in Tennessee and Georgia counties. Our results point to dynamic racial trends in both states over time and varying, localized patterns of risk among counties within the same state. For example, we find that African American and Asian racial demographics present comparable, and contrasting, patterns of risk depending on locality.

CONCLUSION: The dichotomy of demographic trends presented here emphasizes the importance of understanding the unique factors that influence COVID-19 incidence. Identifying these specific risk factors tied to COVID-19 case growth can help stakeholders target regional interventions to mitigate the burden of future outbreaks.

PMID:34385289 | DOI:10.1136/bmjhci-2021-100349

BMJ Open. 2021 Aug 12;11(8):e050108. doi: 10.1136/bmjopen-2021-050108.

ABSTRACT

OBJECTIVES: This systematic review summarises the evidence on the correlation between recurrent acute otitis media (rAOM) or chronic suppurative otitis media (CSOM) and sensorineural hearing loss (SNHL).

RESEARCH METHODS: PubMed, Embase and Cochrane Library databases were searched from inception to 15 January 2021. Two authors independently identified articles, extracted data and performed quality assessment for included studies. Studies comparing the sensorineural hearing levels of patients with a history of rAOM/CSOM for >3 months to a control group were included.

RESULTS: Screening of 4168 articles lead to inclusion of two case-control studies (control-group: patients non-OM) and seven cohort-studies (control group: contralateral ear). Quality assessment indicated considerable risk of bias in all studies. Reported populations varied (sample size 13-607, mean age 22-41.5 years, mean duration of disease 6.1-12.4 years). The OR for SNHL in the OM-group was 3.30-7.86 (95% CI 1.16 to 9.40, p<0.05) in cohort studies (n=2), and 0.05 (95% CI 0 to 0.78, p<0.05) in a case-control study. Mean/median bone conduction thresholds were respectively 1.19-32.21/0-10 dB higher on all frequencies (0.5-4 kHz) for the OM-group in four cohort studies (p<0.05). Two other studies reported no statistical test outcomes.

CONCLUSION: Due to the high risk of bias of included studies, effect estimates heterogeneity and suboptimal research designs, no conclusion on the correlation between OM and SNHL can be made. It emphasises the need for future prognostic studies.

PMID:34385254 | DOI:10.1136/bmjopen-2021-050108

Eur Respir J. 2021 Aug 12:2101597. doi: 10.1183/13993003.01597-2021. Online ahead of print.

NO ABSTRACT

PMID:34385276 | DOI:10.1183/13993003.01597-2021

BMJ Open. 2021 Aug 12;11(8):e047995. doi: 10.1136/bmjopen-2020-047995.

ABSTRACT

OBJECTIVES: To design, deliver and evaluate a programme of training workshops for biomedical researchers aimed at building confidence and skills in actively involving patients and the public (PPI) in research.

DESIGN: A bespoke programme of training workshops in PPI aimed at researchers.

SETTING: A large National Institute for Health Research Biomedical Research Centre in London and several partner organisations.

PARTICIPANTS: 721 scientists, clinicians and research managers attending dedicated training in PPI at a major London NHS (National Health Service)-university partnership.

INTERVENTIONS: A programme of 72 training workshops, designed to build practical skills and confidence for researchers working with patients and the public in research, was delivered at a major research-active NHS:university partnership. An iterative approach was taken to the programme, with the content of the workshops continually reviewed and refreshed to respond to the needs of researchers. Surveys before, immediately following and 6 months after training investigated the impact on researchers’ confidence and skills in PPI work, and the kind of PPI they subsequently carried out.

RESULTS: Training brought about immediate marked increases in researchers’ self-reported confidence to carry out PPI activities within their research, and in their knowledge of good practice. The evaluation indicates that workshop attendees were more likely to involve patients in their research following training. Researchers tended to involve patients and the public in a range of areas, including input to study design and patient information, in particular.

CONCLUSIONS: When positioned within a broader organisational strategy for PPI in research, such training has an important role to play in progressing PPI in a major research partnership. Training appeared to provide the confidence needed to carry out PPI which enabled further development of confidence and skills. Involving researchers who have attended the training in the ongoing development of the programme and bringing in patients to the training programme are key next steps.

PMID:34385250 | DOI:10.1136/bmjopen-2020-047995

BMJ Open. 2021 Aug 12;11(8):e049000. doi: 10.1136/bmjopen-2021-049000.

ABSTRACT

OBJECTIVE: Antimicrobial resistance is a global public health challenge. Dispensing of antibiotics without prescription (DAWP), a major contributor to antibiotic resistance, is extensive in Eritrea. This study was, therefore, aimed at deeply understanding, qualitatively, the pharmacy professionals’ perspective on the factors that trigger DAWP and how this practice could be mitigated.

DESIGN: A qualitative exploratory study design was employed.

SETTING: Drug retail outlets of Asmara, capital of Eritrea, and pharmaceutical services of Eritrea.

PARTICIPANTS: Thirty pharmacy professionals who were owners and employees of the drug retail outlets stationed in Asmara and six key informants from the pharmaceutical services of all administrative regions of Eritrea, selected purposively, were the study participants.

DATA COLLECTION AND ANALYSIS: The data were collected using focus group discussions and key informant interviews between March and September 2020. The collected data were transcribed verbatim, translated to English and finally thematically analysed using an inductive approach.

RESULTS: The main triggering factors were related to the drug retail outlet owners, dispensers, healthcare system and patients. Knowledge and attitude-based motivation, economic interest, inadequate services in health facilities, weak regulatory enforcement, inadequate training, trust and satisfaction of patients, previous successful experience, seriousness of a condition and saving time and money were reported among others as determinants of DAWP.

CONCLUSIONS: The triggering factors to DAWP were found to be very complex and some of them were important that might require immediate attention from policymakers. Ensuring readily available and accessible healthcare services, empowering medicines regulation and continuing sensitisation of dispensers are highly recommended to minimise DAWP.

PMID:34385252 | DOI:10.1136/bmjopen-2021-049000

BMJ Open. 2021 Aug 12;11(8):e046707. doi: 10.1136/bmjopen-2020-046707.

ABSTRACT

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy is a class of immunotherapy. An economic evaluation conducted at an early stage of development of CAR-T therapy for treatment of adult relapsed or refractory acute lymphoblastic leukaemia could provide insight into factors contributing to the cost of treatment, the potential clinical benefits, and what the health system can afford. Traditionally, stakeholders are engaged in certain parts of health technology assessment processes, such as in the identification and selection of technologies, formulation of recommendations, and implementation of recommendations; however, little is known about processes for stakeholder engagement during the conduct of the assessment. This is especially the case for economic evaluations. Stakeholders, such as clinicians, policy-makers, patients, and their support networks, have insight into factors that can enhance the validity of an economic evaluation model. This research outlines a specific methodology for stakeholder engagement and represents an avenue to enhance health economic evaluations and support the use of these models to inform decision making for resource allocation. This protocol may inform a tailored framework for stakeholder engagement processes in future economic evaluation model development.

METHODS AND ANALYSIS: We will involve clinicians, healthcare researchers, payers, and policy-makers, as well as patients and their support networks in the conduct and verification of an early economic evaluation of a novel health technology to incorporate stakeholder-generated knowledge. Three stakeholder-specific focus groups will be conducted using an online adaptation of the nominal group technique to elicit considerations from each. This study will use CAR-T therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia as a basis for investigating broader stakeholder engagement processes.

ETHICS AND DISSEMINATION: This study received ethics approval from the Ottawa Hospital Research Institute Research Ethics Board (REB 20200320-01HT) and the results will be shared via conference presentations, peer-reviewed publications, and ongoing stakeholder engagement.

PMID:34385243 | DOI:10.1136/bmjopen-2020-046707