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A pragmatic pipeline for drug resistance and lineage identification in Mycobacterium tuberculosis using whole genome sequencing
Get PDFDelays in accurate diagnosis of drug resistant tuberculosis (DR-TB) can hinder treatment. Whole genome sequencing (WGS) provides more information than standard molecular and phenotypic testing, but commonly used platforms are expensive to implement, and data interpretation requires significant expertise. We aimed to optimise a TB WGS diagnostic pipeline balancing user-friendliness, cost-effectiveness and time to results, whilst ensuring accuracy. Growth conditions, DNA extraction protocols and Oxford Nanopore Technologies (ONT) library preparation kits were compared. ONT was compared with Illumina protocols. Software for basecalling and analysis were evaluated to find the most accurate resistance SNP and lineage predictor. Optimally, a spin-column CTAB DNA extraction method was combined with the RBK110.96 library preparation kit, high accuracy (HAC) basecalling and data analysis using TB-Profiler. Compared with Illumina, the pipeline was concordant for 16/17 (94%) isolates (lineage) and for 17/17 (100%) isolates (resistance SNPs). Our pipeline was 71% (12/17) concordant with phenotypic drug susceptibility test (DST) results. Time-to-diagnosis was around four weeks. This optimised TB sequencing pipeline requires less time and expertise to run and analyse than Illumina, takes less time than phenotypic DSTs and the results are comparable with Illumina. The cost per sample is comparable with other methods. These features make it an important tool for incorporating into routine DR-TB diagnostic pipelines and larger scale drug resistance surveillance in all settings
Blood folate level needed for fully effective fortification in the prevention of neural tube defects.
Get PDFOBJECTIVE: Neural tube defects (NTDs) are a preventable folate deficiency disorder; increasing folic acid intake through food fortification increases serum and red blood cell folate and reduces the risk of an NTD pregnancy. There is controversy over the blood folate level needed to achieve the full preventive effect because of discrepant study conclusions. METHODS: Results from two published studies were used to determine the relationship between serum folate and NTD risk which was compared with the observed result in a randomised trial of folic acid that increased serum folate from 5 ng/mL to 44 ng/mL among women who took a 4 mg daily periconceptional folic acid supplement. RESULTS: Both studies showed a proportional (logarithmic) relationship between serum folate and NTD risk without evidence of a folate threshold above which there is no further NTD risk reduction. The suggestion of a threshold is due to the incorrect interpretation of the folate-NTD risk association when plotted on arithmetic scales, which conceals the proportional relationship between the two. Also, both studies accurately estimated the observed result from the randomised trial that achieved a median serum folate level of 44 ng/mL and an 83% preventive effect. This is much higher than has been achieved with current levels of folic acid fortification with serum folate between 10 and 16 ng/mL, resulting in an approximate 20% preventive effect. CONCLUSION: To achieve fully effective fortification, median population serum folate levels need to be about 44 ng/mL, which would globally prevent about 250 000 NTD cases every year
Misrepresented multiple endocrine neoplasia 2: Do the British Thyroid Association guidelines accurately predict thyroid cancer risk in high-risk groups with multiple endocrine neoplasia 2? A case series
Get PDFIntroduction:
The incidence of thyroid nodules in the general population is around 40%. The British Thyroid Association U-grading has high sensitivity for identifying the common thyroid cancer subtypes (papillary and follicular). However, ultrasound features of the rarer medullary thyroid cancer differ, with lower sensitivity for ultrasound detection.
Hereditary medullary thyroid cancer accounts for 25% of cases, forming part of the multiple endocrine neoplasia syndromes (multiple endocrine neoplasia 2) and is associated with RET proto-oncogene mutation, for which gene testing is increasingly available. This study aims to evaluate British Thyroid Association U-grading for thyroid cancer risk stratification in this high-risk population.
Case report:
This was a retrospective review of four multiple endocrine neoplasia 2 patients referred for thyroid ultrasound. A total of 10 thyroid nodules were graded as part of routine evaluation, taken from an endocrine and genetics tertiary referral centre. Patients with identifiable RET mutation from March 2017 to February 2023 were reviewed.
Discussion:
Six patients had 10 thyroid nodules, of which 8 were graded as U2, 2 graded U3–5 and 8 confirmed as medullary thyroid cancer. However, two patients had no pathology data at the time of writing. For this cohort, U-grading and genetics were discordant, with RET gene testing more effective than ultrasound in cancer detection. All nodules should be considered high risk for medullary thyroid cancer, regardless of U-grade.
Conclusion:
Our data demonstrate that British Thyroid Association U-score has limited value for medullary thyroid cancer detection in this high-risk group and cannot be used for risk stratification or surveillance. As a rarer thyroid cancer subtype, medullary thyroid cancer and the high-risk multiple endocrine neoplasia 2 population are under-represented in British Thyroid Association 2014 guidance and deserve consideration in future edition
Does Student and Staff Gender Affect Physician Associate Student Experience on Clinical Rotations?
Get PDFINTRODUCTION: Physician assistant/associate (PA) courses rely heavily on hands-on experience during clinical placement, and higher education institutes aim to provide students with an equitable experience. This article aims to understand how student gender and supervisor gender affect student experience on clinical placement at 2 PA courses in the United Kingdom, where PAs are known as physician associates. We found no evidence of pedagogical literature that focused on the gender differences in PA experience, so we aim to be the first to provide this research. METHODS: To assess student experience, student feedback was collected through online qualitative surveys and stratified by student and supervisor gender. 95% confidence intervals were calculated for scaled questions. RESULTS: Qualitative feedback from students shows a clear difference in their clinical placement experiences. Male students report fewer opportunities to observe and assess female patients, while female students report fewer opportunities observe and assess male patients. The most significant difference is seen when male students are seeing female patients. The discrepancy becomes more pronounced when male students are supervised by male supervisors and when female students are supervised by female supervisors. DISCUSSION: In planning clinical placements for students, programs must understand and recognize the potential for differences in experience based on student and supervisor gender and should take action to ensure a more equitable experience for all students
Knowledge, attitudes, motivations and expectations regarding antimicrobial use among community members seeking care at the primary healthcare level: a scoping review protocol.
Get PDFINTRODUCTION: Inappropriate antibiotic use in (primary healthcare, PHC) settings fuels antimicrobial resistance (AMR), threatens patient safety and burdens healthcare systems. Patients' knowledge, attitudes, motivations and expectations play a crucial role in antibiotic use behaviour, especially in low-income and middle-income countries including South Africa. There is a need to ensure measures of antibiotic use, interventions and future guidance reflect cultural, community and demographic issues associated with patient views to reduce inappropriate use of antibiotics and associated AMR. The objective of this scoping review is to identify key themes surrounding knowledge, attitudes, motivations and expectations among patients and community members regarding antimicrobial use in PHC settings especially in low-income and middle-income countries. METHODS AND ANALYSIS: This scoping review employs a comprehensive search strategy across multiple electronic databases, including OVID, Medline, PubMed and CINHAL, to identify studies addressing patients or community members seeking care at PHC facilities and exploring key drivers of antimicrobial use. The Covidence web-based platform will be used for literature screening and data extraction and the Critical Appraisal Skills Programme qualitative checklist will assess the quality of qualitative papers. Anticipated results will provide an overview of the current evidence base, enabling identification of knowledge gaps. A narrative synthesis of findings will summarise key themes and patterns in patients' knowledge, attitudes, motivations and expectations related to antibiotic use across studies while considering methodological diversity and limitations. ETHICS AND DISSEMINATION: Ethics approval is not required for this scoping review. The findings of this scoping review will be disseminated through publication in a peer-reviewed journal, presentation at relevant conferences and workshops, and collaboration with policy-makers and healthcare stakeholders
Quasi-Diffusion Imaging: Application to ultra-high b-value and time-dependent diffusion images of brain tissue
Get PDFWe demonstrate that quasi-diffusion imaging (QDI) is a signal representation that extends towards the negative power law regime. We evaluate QDI for in vivo human and ex vivo fixed rat brain tissue across b -value ranges from 0 to 25,000 s mm-2, determine whether accurate parameter estimates can be acquired from clinically feasible scan times and investigate their diffusion time-dependence. Several mathematical properties of the QDI representation are presented. QDI describes diffusion magnetic resonance imaging (dMRI) signal attenuation by two fitting parameters within a Mittag-Leffler function (MLF). We present its asymptotic properties at low and high b -values and define the inflection point (IP) above which the signal tends to a negative power law. To show that QDI provides an accurate representation of dMRI signal, we apply it to two human brain datasets (Dataset 1: 0≤b≤15,000 s mm-2; Dataset 2: 0≤b≤17,800 s mm-2) and an ex vivo fixed rat brain (Dataset 3: 0≤b≤25,000 s mm-2, diffusion times 17.5≤Δ≤200 ms). A clinically feasible 4 b -value subset of Dataset 1 ( 0≤b≤15,000 s mm-2) is also analysed (acquisition time 6 min and 16 s). QDI showed excellent fits to observed signal attenuation, identified signal IPs and provided an apparent negative power law. Stable parameter estimates were identified upon increasing the maximum b -value of the fitting range to near and above signal IPs, suggesting QDI is a valid signal representation within in vivo and ex vivo brain tissue across large b -value ranges with multiple diffusion times. QDI parameters were accurately estimated from clinically feasible shorter data acquisition, and time-dependence was observed with parameters approaching a Gaussian tortuosity limit with increasing diffusion time. In conclusion, QDI provides a parsimonious representation of dMRI signal attenuation in brain tissue that is sensitive to tissue microstructural heterogeneity and cell membrane permeability
COVER-ME: developing and evaluating community-based interventions to promote vaccine uptake for COVID-19 and influenza in East London minority ethnicity (ME) and underserved individuals - protocol for a pilot randomised controlled trial
Get PDFIntroduction
Under-vaccination among underserved groups remains low due to existing disparities. This is particularly the case with postpandemic COVID-19 vaccinations and other vaccine-preventable diseases, including measles, mumps, rubella or influenza. Therefore, we aim to (1) determine the feasibility and practicality of implementing a patient engagement tool (PET) and gain vital insights to plan a subsequent definitive randomised controlled trial (RCT) to evaluate the effectiveness of this tool for increasing uptake of COVID-19 and influenza vaccinations and (2) define the appropriate level of support needed for healthcare providers at site-level to ensure successful implementation of the PET and to identify supporting activities needed to implement interventions for COVID-19 and influenza vaccinations.
Methods and analysis
This is a randomised controlled feasibility study evaluating a co-designed PET, involving randomisation at individual and cluster levels. For individual randomisation, patients will be individually randomised 1:1 to receive the intervention (PET) or routine care; whereas for cluster randomisation, six GP (General Practitioner) practices will be randomised 1:1 and divided into two tranches at two separate time points. Both groups will receive training and software activation. Data will be analysed using statistical software R (V.4.0 or greater) or STATA (V.17 or greater). Baseline characteristics will be summarised and presented in groups based on an intention-to-treat basis with categorical data, including demographics, socioeconomic variables, comorbidities and vaccination status.
Ethics and dissemination
Ethical approval was granted by the Westminster Ethics Committee (ref: 316860). Our dissemination strategy targets three audiences: (1) policy makers, public and health service managers, and clinicians responsible for delivering vaccines and infection prevention services; (2) patients and public from underserved population groups and (3) academics.
Trial registration number
ClinicalTrials.gov (NCT05866237)
CVOT summit report 2024: new cardiovascular, kidney, and metabolic outcomes
Get PDFThe 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5–6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20–21, 2025 (http://www.cvot.org)
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