Estimation of country-specific tuberculosis resistance antibiograms using pathogen genomics and machine learning.

BACKGROUND: Global tuberculosis (TB) drug resistance (DR) surveillance focuses on rifampicin. We examined the potential of public and surveillance Mycobacterium tuberculosis (Mtb) whole-genome sequencing (WGS) data, to generate expanded country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction. METHODS: We curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to 12 drugs and bias-corrected for model performance, outbreak sampling and rifampicin resistance oversampling. Validation leveraged a national DR survey conducted in South Africa. RESULTS: Mtb isolates from 29 countries (n=19 149) met sequence quality criteria. Global marginal genotypic resistance among mono-resistant TB estimates overlapped with the South African DR survey, except for isoniazid, ethionamide and second-line injectables, which were underestimated (n=3134). Among multidrug resistant (MDR) TB (n=268), estimates overlapped for the fluoroquinolones but overestimated other drugs. Globally pooled mono-resistance to isoniazid was 10.9% (95% CI: 10.2-11.7%, n=14 012). Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% (0.1-11%), n=111 and India 2.8% (0.08-9.4%), n=114). Given the recent interest in drugs enhancing ethionamide activity and their expected activity against isolates with resistance discordance between isoniazid and ethionamide, we measured this rate and found it to be high at 74.4% (IQR: 64.5-79.7%) of isoniazid-resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3964). CONCLUSIONS: This is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics, but public WGS data demonstrates oversampling of isolates with higher resistance levels than MDR. Nevertheless, our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug-susceptible TB in South Asia and indicate underutilisation of ethionamide in MDR treatment.

Outcome analysis of brain-death referral to NOD-Lb: A retrospective chart review of a single hospital experience over 3 years.

BACKGROUND: Organ donation shortage and in particular organ procurement is an international concern as the gap between the number of donors and recipients is steadily growing. Organ procurement is a chain of steps with donor identification and referral (ID&R) as the very first link in this chain. Failure of this step hinders the progress in the organ transplantation program. OBJECTIVES: Our study was conducted to evaluate and highlight the gap between the national system and the practice at the identification and referral (ID&R) step of the organ procurement chain in a single tertiary-care academic health center in Beirut: the Lebanese American University Medical Center-Rizk Hospital (LAUMC-RH), and to appraise the literature for challenges at this step and for possible interventions for improvement based on the international experience. MATERIALS AND METHODS: This retrospective study was a descriptive case series of ICU and ED deceased patients at a single tertiary-care university hospital in Beirut. Patients' characteristics were collected from medical records for all patients who died between 2017 and 2019 while in the ICU or the ED and shared with the National Organization for Organ and Tissue Donation and Transplantation (NOD-Lb), for each subject separately, to decide on the donor status. All data collected from the patient cohort was analyzed using R version 3.6.1. Wilcoxon signed-rank test, chi-squared, and fisher-exact tests were used to compare differences in clinical characteristics in terms of donor status when appropriate. RESULTS: This study served as 3 years audit of a single hospital experience, and it demonstrates failure to make any referrals to NOD-Lb and zero actual organ and tissue donations over the study period. The review of 295 deceased subjects' charts demonstrates 295 missed alerts to NOD-Lb and the overall missing of 5 organ and tissue donors and 24 cornea donors assuming the organ procurement chain of steps will continue uninterrupted after ID&R. CONCLUSION: The data gathered suggests the presence of an inefficient identification and referral system that is translated into a complete failure of reporting to NOD-Lb from LAUMC-RH. A systematic evidence-based approach to evaluate for the most cost-effective intervention to increase identification and referral rates is needed with a serious effort to examine and account for any inefficient implantation.

A genetic basis for cancer sex differences revealed in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a female-predominant kidney cancer driven by translocations between the TFE3 gene on chromosome Xp11.2 and partner genes located on either chrX or on autosomes. The rearrangement processes that underlie TFE3 fusions, and whether they are linked to the female sex bias of this cancer, are largely unexplored. Moreover, whether oncogenic TFE3 fusions arise from both the active and inactive X chromosomes in females remains unknown. Here we address these questions by haplotype-specific analyses of whole-genome sequences of 29 tRCC samples from 15 patients and by re-analysis of 145 published tRCC whole-exome sequences. We show that TFE3 fusions universally arise as reciprocal translocations with minimal DNA loss or insertion at paired break ends. Strikingly, we observe a near exact 2:1 female:male ratio in TFE3 fusions arising via X:autosomal translocation (but not via X inversion), which accounts for the female predominance of tRCC. This 2:1 ratio is at least partially attributable to oncogenic fusions involving the inactive X chromosome and is accompanied by partial re-activation of silenced chrX genes on the rearranged chromosome. Our results highlight how somatic alterations involving the X chromosome place unique constraints on tumor initiation and exemplify how genetic rearrangements of the sex chromosomes can underlie cancer sex differences.

Single-Centre Retrospective Study on the Effects of Bariatric Surgery on Nocturia.

PURPOSE: The incidence of nocturia is increased in obesity, which causes significant negative impact on quality of life. Bariatric surgery is a reliable method in which to achieve major weight loss and this study aims to determine the effect of bariatric surgery on nocturia and other lower urinary tract symptoms (LUTS) in men and women. MATERIALS AND METHODS: Retrospective study of patients undergoing bariatric surgery had pre- and post-operative questionnaires using the validated International Prostate Symptoms Score (IPSS) to assess nocturia between 2018 and 2021. The primary outcome was effect of bariatric surgery on nocturia RESULTS: A total of 99 patients were included with median age of 52.9 (44.9-60.2) and 83.8% being female. The median weight was 129.9kg (110-151.9) and median BMI was 45.5 (41.4-53.4). Improvements were demonstrated in all criteria assessed in IPSS and nocturia significantly improved with a decrease in 1.14 points (p < 0.05). Linear regression analysis showed that, in the post operative period assessed, there were no significant effect on variables measured such as obstructive sleep apnoea, type 2 diabetes on the effect of IPSS post-bariatric surgery within the follow-up period of 4-6 months. CONCLUSION: Bariatric surgery can have significant improvements on nocturia symptoms in men and women with obesity. This is another means in how bariatric surgery can reduce morbidity and improve quality of life.

The Impact of Bariatric Surgery on Nocturia Symptoms: a Systematic Review and Meta-Analysis.

There is a significant association between obesity and nocturia, which can cause a significant negative impact on quality of life. This meta-analysis aims to determine the effects of bariatric surgery on nocturia in both men and women. Studies searched via MEDLINE and Embase databases. The primary outcome was difference in nocturia scores before and after bariatric surgery. A total of 522 patients were included in the analysis of this paper. Statistically significant decreases in nocturia scores were observed post-bariatric surgery. Bariatric surgery also resulted in statistically significant reduction of BMI. Bariatric surgery can have significant improvements on nocturia symptoms in men and women with obesity. This would thereby reduce morbidity and improve quality of life following bariatric surgery.

Improving detection of undiagnosed HIV through routine screening in a central London emergency department.

HIV is a global public health issue. Routine testing for HIV should be performed on all 16-59 years old attending emergency departments (EDs) in high-prevalence areas in the UK.In August 2020, Charing Cross Hospital ED, situated in an 'extremely high-prevalence' area, had no formal guidelines on HIV testing. We aimed to increase HIV testing in 16-59 years old attending our ED to 25% by August 2021 through a quality improvement project, based on the Methodology for Improvement Model, performing six Plan-Do-Study-Act cycles over a 12-month period.An initial ED staff survey revealed 55% (n=22/40) of respondents were unsure of national HIV testing guidelines. Barriers to good testing practice included: lack of clarity on protocols for consent and indication, cost and perceived stigmatisation of patient groups. Interventions were employed at regular intervals, including employment of an HIV nurse advocate, inclusion of HIV tests in a blood test careset during ED triage, and updated trust guidelines that reflect national guidelines.Overall, we did achieve our original 12 month aim, with an average testing rate of 28% of our target group between September 2020 and August 2021. Extending the project to January 2022 has resulted in continued improvements in monthly testing rates, reaching 44% in December 2021. Further analysis revealed interventions led to a statistically significant and sustained increase in monthly testing rates on seven occasions.Valuable lessons were learnt in sustaining improvements in a busy department, changing long-held beliefs regarding consent for testing, and education around HIV care in the UK. Project write-up was formatted using the Revised Standards for Quality Improvement Reporting Excellence (SQUIRE) template.

Axillary staging in ductal carcinoma in situ with microinvasion: A meta-analysis.

INTRODUCTION: Ductal carcinoma in situ with microinvasion (DCISM); arguably a more aggressive subtype of DCIS, currently has variable recommendations governing its staging and management in the UK. As a result, there is ongoing controversy surrounding the most appropriate management of DCISM, in particular the need of axillary staging. METHOD: A search was conducted on the databases MEDLINE and Embase using the keywords: breast, DCISM, microinvasion, "ductal carcinoma in situ with microinvasion", sentinel lymph node biopsy, SLNB, axillary staging was performed. 23 studies were selected for analysis. Primary outcome was the positivity of metastasis of lymph node; secondary outcome looked at characteristics of DCISM that may affect node positivity. RESULTS: A total of 2959 patients were included. Significant heterogeneity was observed amongst the studies with regards to metastases (I2 = 61%; P < 0.01). Lymph node macrometastases was estimated to be 2%. Significant subgroup difference was not observed between SLNB technique and lymph node macrometastases (Q = 0.74; p = 0.69). Statistical significance was observed between the focality of the DCISM and lymph node macrometastases (Q = 8.71; p = 0.033). CONCLUSION: Although histologically more advanced than DCIS, DCISM is not linked with higher rates of clinically significant metastasis to axillary lymph nodes. Survival rates are very similar to those seen in cases of DCIS. Current evidence suggests that axillary staging in cases of DCISM will not change their overall management, thus may only be an unnecessary and inconvenient additional intervention considering the majority of DCISM diagnoses are made from post-operative pathology samples. A multidisciplinary team approach evaluating pre-operative clinical and histological information to tailor the management specific to individual cases of DCISM would be a preferred approach than routine axillary staging.

The impact of the COVID-19 pandemic on final year medical students in the United Kingdom: a national survey.

BACKGROUND: The coronavirus disease (COVID-19) global pandemic has resulted in unprecedented public health measures. This has impacted the UK education sector with many universities halting campus-based teaching and examinations. The aim of this study is to identify the impact of COVID-19 on final year medical students' examinations and placements in the United Kingdom (UK) and how it might impact their confidence and preparedness going into their first year of foundation training. METHODS: A 10-item online survey was distributed to final year medical students across 33 UK medical schools. The survey was designed by combining dichotomous, multiple choice and likert response scale questions. Participants were asked about the effect that the COVID-19 global pandemic had on final year medical written exams, electives, assistantships and objective structured clinical examinations (OSCEs). The survey also explored the student's confidence and preparedness going into their first year of training under these new unprecedented circumstances. RESULTS: Four hundred forty students from 32 UK medical schools responded. 38.4% (n = 169) of respondents had their final OSCEs cancelled while 43.0% (n = 189) had already completed their final OSCEs before restrictions. 43.0% (n = 189) of assistantship placements were postponed while 77.3% (n = 340) had electives cancelled. The impact of COVID-19 on OSCEs, written examinations and student assistantships significantly affected students' preparedness (respectively p = 0.025, 0.008, 0.0005). In contrast, when measuring confidence, only changes to student assistantships had a significant effect (p = 0.0005). The majority of students feel that measures taken during this pandemic to amend their curricula was necessary. Respondents also agree that assisting in hospitals during the outbreak would be a valuable learning opportunity. CONCLUSIONS: The impact on medical student education has been significant, particularly affecting the transition from student to doctor. This study showed the disruptions to student assistantships had the biggest effect on students' confidence and preparedness. For those willing to assist in hospitals to join the front-line workforce, it is crucial to maintain their wellbeing with safeguards such as proper inductions, support and supervision.

Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid.

BACKGROUND: Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics. METHODS: Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype-phenotype associations. RESULTS: Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192-198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192-198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance. CONCLUSIONS: This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.