The Genome of Mycobacterium Africanum West African 2 Reveals a Lineage-Specific Locus and Genome Erosion Common to the M. tuberculosis Complex

Mycobacterium africanum, a close relative of M. tuberculosis, is studied for the following reasons: M. africanum is commonly isolated from West African patients with tuberculosis yet has not spread beyond this region, it is more common in HIV infected patients, and it is less likely to lead to tuberculosis after one is exposed to an infectious case. Understanding this organism's unique biology gets a boost from the decoding of its genome, reported in this issue. For example, genome analysis reveals that M. africanum contains a region shared with “ancient” lineages in the M. tuberculosis complex and other mycobacterial species, which was lost independently from both M. tuberculosis and M. bovis. This region encodes a protein involved in transmembrane transport. Furthermore, M. africanum has lost genes, including a known virulence gene and genes for vitamin synthesis, in addition to an intact copy of a gene that may increase its susceptibility to antibiotics that are insufficiently active against M. tuberculosis. Finally, the genome sequence and analysis reported here will aid in the development of new diagnostics and vaccines against tuberculosis, which need to take into account the differences between M. africanum and other species in order to be effective worldwide

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bifidobacteria grown on human milk oligosaccharides downregulate the expression of inflammation-related genes in Caco-2 cells

BACKGROUND: Breastfed human infants are predominantly colonized by bifidobacteria that thrive on human milk oligosaccharides (HMO). Two predominant species of bifidobacteria in infant feces are Bifidobacterium breve (B. breve) and Bifidobacterium longum subsp. infantis (B. infantis), both of which include avid HMO-consumer strains. Our laboratory has previously shown that B. infantis, when grown on HMO, increases adhesion to intestinal cells and increases the expression of the anti-inflammatory cytokine interleukin-10. The purpose of the current study was to investigate the effects of carbon source—glucose, lactose, or HMO—on the ability of B. breve and B. infantis to adhere to and affect the transcription of intestinal epithelial cells on a genome-wide basis. RESULTS: HMO-grown B. infantis had higher percent binding to Caco-2 cell monolayers compared to B. infantis grown on glucose or lactose. B. breve had low adhesive ability regardless of carbon source. Despite differential binding ability, both HMO-grown strains significantly differentially affected the Caco-2 transcriptome compared to their glucose or lactose grown controls. HMO-grown B. breve and B. infantis both downregulated genes in Caco-2 cells associated with chemokine activity. CONCLUSION: The choice of carbon source affects the interaction of bifidobacteria with intestinal epithelial cells. HMO-grown bifidobacteria reduce markers of inflammation, compared to glucose or lactose-grown bifidobacteria. In the future, the design of preventative or therapeutic probiotic supplements may need to include appropriately chosen prebiotics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12866-015-0508-3) contains supplementary material, which is available to authorized users

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Inquiry Guided Learning Projects for the Development of Critical Thinking in the College Classroom: a pilot study

This paper describes the inaugural success of implementing Inquiry Guided Learning projects in a college-level human anatomy and physiology course. In this context, scientific inquiry was used as a means of developing skills required for critical thinking amoung students. The projects were designed using the Information Search Process (Kuhlthau, 1991) as a framework with emphasis placed on three of the six stages: question selection, scientific research, and presentation of results. The projects were quantitatively assessed using self-reported confidence ratings from a 10-point Likert scale. The projects were also qualitatively assessed using informal student feedback focusing on student suggestions for project improvement. Moving forward, the Inquiry Guided Learning projects will continue to be a formal course component, with the next stage of implementation to include a thorough assessment of student learning outcomes

Resting blood pressure reductions following handgrip exercise training and the impact of age and sex: a systematic review and narrative synthesis

Abstract Background The risk of developing cardiovascular disease can be directly correlated to one’s resting blood pressure (BP), age, and biological sex. Resting BP may be successfully reduced using handgrip exercise training, although the impact of age and sex on training effectiveness has yet to be systematically evaluated. The objective of this systematic review is to determine this impact of age and sex on handgrip-induced changes to resting BP. Methods Data sources included MEDLINE, Embase, Cochrane Reviews, CINAHL, SPORTDiscus, Web of Science, AMED, PubMed, and Scopus through May 2018. Eligibility criteria were those with prospective handgrip exercise training of ≥ 4 weeks with reported impact on resting systolic BP (SBP). Screening of articles, data extraction, and quality appraisal were completed in duplicate. When necessary, the corresponding authors were contacted to provide segregated data based on age (younger, 18–54 years; aged, > 55 years) and sex (men, women) categories. SBP was primarily explored with numerous secondary outcomes of interest summarized as a narrative synthesis. Results After screening 1789 articles, 26 full texts were reviewed. Eight studies reported data in a way that facilitated age and sex comparisons of primary outcomes, while 7 of 18 studies reporting pooled data (men and women) provided segregated results. Research spans 1992–2018 and represents 466 participants; at least 43.1% of whom are women. Although weighted mean differences reveal that handgrip training-induced SBP reductions are similar when merely comparing sexes (women; − 5.6 mmHg, men; − 4.4 mmHg) or ages (younger; − 5.7 mmHg, aged; − 4.4 mmHg), when the impact of sex and age is simultaneously evaluated, aged women experience the largest reduction in SBP (− 6.5 mmHg). Many factors were explored for their impact on resting BP reductions and have been summarized in the corresponding narrative synthesis. Conclusions Handgrip exercise is an effective modality for resting BP reduction resulting in clinically significant reductions for men and women of all ages. Systematic review registration PROSPERO CRD4201501979

Resting blood pressure reductions following isometric handgrip exercise training and the impact of age and sex: protocol for a systematic review

Abstract Background The risk of developing cardiovascular disease is directly correlated to one’s resting blood pressure (BP), age, and biological sex. Resting BP can be reduced using handgrip exercise training, but the impact of age and sex on the effectiveness of training is not well documented. Methods/design A systematic search of the literature will be conducted for all experimental studies (including randomized controlled trials and prospective experiments) that report the influence of isometric handgrip exercise training on resting systolic blood pressure. The databases Medline, Embase, Cochrane Reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTDiscus, Web of Science, Allied and Complementary Medicine (AMED), PubMed, and Scopus will be searched until 1 December 2015. Screening of potential articles, data abstraction, and quality appraisal will be completed in duplicate independently. When necessary, corresponding authors will be contacted in order to facilitate the separation of pooled data into age and sex categories. Methodological quality will be determined using the Quality Assessment Framework developed by the Cochrane Collaboration and the Newcastle-Ottawa Quality Assessment Scale as appropriate. Any discrepancies will be resolved by a third author. Findings will be presented in accordance with the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Discussion This systematic review will determine the overall effectiveness of handgrip exercise training in improving resting blood pressure. A novel, focused assessment will contrast effectiveness of handgrip training based on the age (younger 18–54 years, older >55 years) and the sex (men, women) of study participants. This information is essential to consolidate before moving forward with the development and implementation of handgrip exercise training programmes which are designed to best meet the needs of particular cohorts. Systematic review registration PROSPERO CRD4201501979