Solving genomic puzzles: computational methods for metagenomic binning.

Metagenomics involves the study of genetic material obtained directly from communities of microorganisms living in natural environments. The field of metagenomics has provided valuable insights into the structure, diversity and ecology of microbial communities. Once an environmental sample is sequenced and processed, metagenomic binning clusters the sequences into bins representing different taxonomic groups such as species, genera, or higher levels. Several computational tools have been developed to automate the process of metagenomic binning. These tools have enabled the recovery of novel draft genomes of microorganisms allowing us to study their behaviors and functions within microbial communities. This review classifies and analyzes different approaches of metagenomic binning and different refinement, visualization, and evaluation techniques used by these methods. Furthermore, the review highlights the current challenges and areas of improvement present within the field of research.

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe COVID-19, and sexual dimorphism in clinical outcomes has been reported. Neurological symptoms are widely observed in COVID-19 patients, with many survivors exhibiting persistent neurological and cognitive impairment. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6J mice were intranasally inoculated with SARS-CoV-2 lineage B.1.351, a variant known to infect mice. Older male mice exhibited a significantly greater weight loss and higher viral loads in the lung at 3 days post infection. Notably, no viral RNA was detected in the brains of infected mice. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain increased with viral infection. RNA-seq transcriptomic analysis of brains showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, implicating innate immunity, defense response to virus, and cerebrovascular and neuronal functions. These findings demonstrate that SARS-CoV-2 infection triggers a neuroinflammatory response, despite the lack of detectable virus in the brain. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and suppression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Outcomes of the MAMA Training: A Simulation and Experiential Learning Intervention for Labor and Delivery Providers to Improve Respectful Maternity Care for Women Living with HIV in Tanzania.

Respectful maternity care (RMC) for women living with HIV (WLHIV) improves birth outcomes and may influence women's long-term commitment to HIV care. In this study, we evaluated the MAMA training, a team-based simulation training for labor and delivery (L&D) providers to improve RMC and reduce stigma in caring for WLHIV. The study was conducted in six clinical sites in the Kilimanjaro Region of Tanzania. 60 L&D providers participated in the MAMA training, which included a two-and-a-half-day workshop followed by a half-day on-site refresher. We assessed the impact of the MAMA training using a pre-post quasi-experimental design. To assess provider impacts, participants completed assessments at baseline and post-intervention periods, measuring RMC practices, HIV stigma, and self-efficacy to provide care. To evaluate patient impacts, we enrolled birthing women at the study facilities in the pre- (n = 229) and post- (n = 214) intervention periods and assessed self-reported RMC and perceptions of provider HIV stigma. We also collected facility-level data on the proportion of patients who gave birth by cesarean section, disaggregated by HIV status. The intervention had a positive impact on all provider outcomes; providers reported using more RMC practices, lower levels of HIV stigma, and greater self-efficacy to provide care for WLHIV. We did not observe differences in self-reported patient outcomes. In facility-level data, we observed a trend in reduction in cesarean section rates for WLHIV (33.0% vs. 24.1%, p = 0.14). The findings suggest that the MAMA training may improve providers' attitudes and practices in caring for WLHIV giving birth and should be considered for scale-up.

HIV-related Shame among Women Giving Birth in Tanzania: A Mixed Methods Study.

Women living with HIV (WLHIV) commonly experience HIV-related shame which can interfere with HIV care-seeking behavior and lead to poor clinical outcomes. HIV-related shame may be particularly heightened during the pregnancy and postpartum periods. This study aimed to describe HIV-related shame among WLHIV giving birth, identify associated factors, and qualitatively examine the impacts of HIV-related shame on the childbirth experience. Postpartum WLHIV (n = 103) were enrolled in the study between March and July 2022 at six clinics in the Kilimanjaro Region, Tanzania. Participants completed a survey within 48 h after birth, prior to being discharged. The survey included a 13-item measure of HIV-related shame, which assessed levels of HIV-related shame (Range: 0-52). Univariable and multivariable regression models examined factors associated with HIV-related shame. Qualitative in-depth interviews were conducted with pregnant WLHIV (n = 12) and postpartum WLHIV (n = 12). Thematic analysis, including memo writing, coding, and synthesis, was employed to analyze the qualitative data. The survey sample had a mean age of 29.1 (SD = 5.7), and 52% were diagnosed with HIV during the current pregnancy. Nearly all participants (98%) endorsed at least one item reflecting HIV-related shame, with an average endorsement of 9 items (IQR = 6). In the final multivariable model, HIV-related shame was significantly associated with being Muslim vs. Christian (ß = 6.80; 95%CI: 1.51, 12.09), attending less than four antenatal care appointments (ß = 5.30; 95%CI: 0.04, 10.55), and reporting experiences of HIV stigma in the health system (ß = 0.69; 95%CI: 0.27, 1.12). Qualitative discussions revealed three key themes regarding the impact of HIV-related shame on the childbirth experience: reluctance to disclose HIV status, suboptimal adherence to care, and the influence on social support networks. WLHIV giving birth experience high rates of HIV-related shame, and social determinants may contribute to feelings of shame. HIV-related shame impacts the childbirth experience for WLHIV, making the labor and delivery setting an important site for intervention and support.The study is funded by the National Institutes of Health (R21 TW012001) and is registered on clinicaltrials.gov (NCT05271903).

CHronic hypERtension and L-citRulline studY (CHERRY): an Early-Phase Randomised Controlled Trial in Pregnancy.

Oral supplementation with L-citrulline, which is sequentially converted to L-arginine then nitric oxide, improves vascular biomarkers and reduces blood pressure in non-pregnant, hypertensive human cohorts and pregnant mice with a pre-eclampsia-like syndrome. This early-phase randomised feasibility trial assessed the acceptability of L-citrulline supplementation to pregnant women with chronic hypertension and its effects on maternal BP and other vascular outcomes. Pregnant women with chronic hypertension were randomised at 12-16 weeks to receive 3-g L-citrulline twice daily (n = 24) or placebo (n = 12) for 8 weeks. Pregnant women reported high acceptability of oral L-citrulline. Treatment increased maternal plasma levels of citrulline, arginine and the arginine:asymmetric dimethylarginine ratio, particularly in women reporting good compliance. L-citrulline had no effect on diastolic BP (L-citrulline: - 1.82 95% CI (- 5.86, 2.22) vs placebo: - 5.00 95% CI (- 12.76, 2.76)), uterine artery Doppler or angiogenic biomarkers. Although there was no effect on BP, retrospectively, this study was underpowered to detect BP changes < 9 mmHg, limiting the conclusions about biological effects. The increase in arginine:asymmetric dimethylarginine ratio was less than in non-pregnant populations, which likely reflects altered pharmacokinetics of pregnancy, and further pharmacokinetic assessment of L-citrulline in pregnancy is advised.Trial Registration EudraCT 2015-005792-25 (2017-12-22) and ISRCTN12695929 (2018-09-20).

Knowing and Naming: Phage Annotation and Nomenclature for Phage Therapy.

Bacteriophages, or phages, are viruses that infect bacteria shaping microbial communities and ecosystems. They have gained attention as potential agents against antibiotic resistance. In phage therapy, lytic phages are preferred for their bacteria killing ability, while temperate phages, which can transfer antibiotic resistance or toxin genes, are avoided. Selection relies on plaque morphology and genome sequencing. This review outlines annotating genomes, identifying critical genomic features, and assigning functional labels to protein-coding sequences. These annotations prevent the transfer of unwanted genes, such as antimicrobial resistance or toxin genes, during phage therapy. Additionally, it covers International Committee on Taxonomy of Viruses (ICTV)-an established phage nomenclature system for simplified classification and communication. Accurate phage genome annotation and nomenclature provide insights into phage-host interactions, replication strategies, and evolution, accelerating our understanding of the diversity and evolution of phages and facilitating the development of phage-based therapies.

Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study.

Post-COVID-19 condition (also known as long COVID) is a new, complex, and poorly understood disorder. A core outcome set (COS) for post-COVID-19 condition in adults has been developed and agreement is now required on the most appropriate measurement instruments for these core outcomes. We conducted an international consensus study involving multidisciplinary experts and people with lived experience of long COVID. The study comprised a literature review to identify measurement instruments for the core outcomes, a three-round online modified Delphi process, and an online consensus meeting to generate a core outcome measurement set (COMS). 594 individuals from 58 countries participated. The number of potential instruments for the 12 core outcomes was reduced from 319 to 19. Consensus was reached for inclusion of the modified Medical Research Council Dyspnoea Scale for respiratory outcomes. Measures for two relevant outcomes from a previously published COS for acute COVID-19 were also included: time until death, for survival, and the Recovery Scale for COVID-19, for recovery. Instruments were suggested for consideration for the remaining nine core outcomes: fatigue or exhaustion, pain, post-exertion symptoms, work or occupational and study changes, and cardiovascular, nervous system, cognitive, mental health, and physical outcomes; however, consensus was not achieved for instruments for these outcomes. The recommended COMS and instruments for consideration provide a foundation for the evaluation of post-COVID-19 condition in adults, which should help to optimise clinical care and accelerate research worldwide. Further assessment of this COMS is warranted as new data emerge on existing and novel measurement instruments.

Factors associated with respectful maternity care and influence of HIV status among women giving birth in Kilimanjaro, Tanzania.

BACKGROUND: Respectful maternity care (RMC) is a rights-based approach to childbirth that centers the dignity, autonomy, and well-being of birthing women. This study aimed to examine factors associated with RMC among women giving birth in Tanzania and to examine whether HIV status was associated with self-reported RMC. METHODS: We enrolled 229 postpartum women in six clinics in the Kilimanjaro Region; of them, 103 were living with HIV. Participants completed a survey within 48 h after birth before being discharged. RMC was measured using a 30-item scale with three subscales (dignity and respect; supportive care; communication and autonomy), each standardized from 0 to 100. Univariable and multivariable regression models examined factors associated with RMC. RESULTS: The median score of the full RMC score was 74, differing slightly by subscale: 83 for dignity and respect, 76 for supportive care, and 67 for communication and autonomy. RMC did not differ by HIV status (median 67.0 vs. 67.0, p = 0.89). In multivariable linear regression, women who would not recommend the birth facility to their friends and who did not receive breastfeeding education had significantly lower RMC scores on the full RMC scale. In the dignity and respect subscale, variables associated with significantly lower RMC scores were not being able to read and write, delivering in a public facility, and delivering vaginally. CONCLUSIONS: Although self-reported RMC was generally high, we identified areas for improvement. Practitioners need ongoing training on RMC principles and the delivery of equitable care.

Phables: from fragmented assemblies to high-quality bacteriophage genomes.

MOTIVATION: Microbial communities have a profound impact on both human health and various environments. Viruses infecting bacteria, known as bacteriophages or phages, play a key role in modulating bacterial communities within environments. High-quality phage genome sequences are essential for advancing our understanding of phage biology, enabling comparative genomics studies and developing phage-based diagnostic tools. Most available viral identification tools consider individual sequences to determine whether they are of viral origin. As a result of challenges in viral assembly, fragmentation of genomes can occur, and existing tools may recover incomplete genome fragments. Therefore, the identification and characterization of novel phage genomes remain a challenge, leading to the need of improved approaches for phage genome recovery. RESULTS: We introduce Phables, a new computational method to resolve phage genomes from fragmented viral metagenome assemblies. Phables identifies phage-like components in the assembly graph, models each component as a flow network, and uses graph algorithms and flow decomposition techniques to identify genomic paths. Experimental results of viral metagenomic samples obtained from different environments show that Phables recovers on average over 49% more high-quality phage genomes compared to existing viral identification tools. Furthermore, Phables can resolve variant phage genomes with over 99% average nucleotide identity, a distinction that existing tools are unable to make. AVAILABILITY AND IMPLEMENTATION: Phables is available on GitHub at https://github.com/Vini2/phables.

Host interactions of novel Crassvirales species belonging to multiple families infecting bacterial host, Bacteroides cellulosilyticus WH2.

Bacteroides, the prominent bacteria in the human gut, play a crucial role in degrading complex polysaccharides. Their abundance is influenced by phages belonging to the Crassvirales order. Despite identifying over 600 Crassvirales genomes computationally, only few have been successfully isolated. Continued efforts in isolation of more Crassvirales genomes can provide insights into phage-host-evolution and infection mechanisms. We focused on wastewater samples, as potential sources of phages infecting various Bacteroides hosts. Sequencing, assembly, and characterization of isolated phages revealed 14 complete genomes belonging to three novel Crassvirales species infecting Bacteroides cellulosilyticus WH2. These species, Kehishuvirus sp. 'tikkala' strain Bc01, Kolpuevirus sp. 'frurule' strain Bc03, and 'Rudgehvirus jaberico' strain Bc11, spanned two families, and three genera, displaying a broad range of virion productions. Upon testing all successfully cultured Crassvirales species and their respective bacterial hosts, we discovered that they do not exhibit co-evolutionary patterns with their bacterial hosts. Furthermore, we observed variations in gene similarity, with greater shared similarity observed within genera. However, despite belonging to different genera, the three novel species shared a unique structural gene that encodes the tail spike protein. When investigating the relationship between this gene and host interaction, we discovered evidence of purifying selection, indicating its functional importance. Moreover, our analysis demonstrated that this tail spike protein binds to the TonB-dependent receptors present on the bacterial host surface. Combining these observations, our findings provide insights into phage-host interactions and present three Crassvirales species as an ideal system for controlled infectivity experiments on one of the most dominant members of the human enteric virome.

Impact of age and sex on neuroinflammation following SARS-CoV-2 infection in a murine model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent for the worldwide COVID-19 pandemic, is known to infect people of all ages and both sexes. Senior populations have the greatest risk of severe disease, and sexual dimorphism in clinical outcomes has been reported in COVID-19. SARS-CoV-2 infection in humans can cause damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with COVID-19, with many survivors suffering from persistent neurological and cognitive impairment, potentially accelerating Alzheimer's disease. The present study aims to investigate the impact of age and sex on the neuroinflammatory response to SARS-CoV-2 infection using a mouse model. Wild-type C57BL/6 mice were inoculated, by intranasal route, with SARS-CoV-2 lineage B.1.351 variant known to infect mice. Older animals and in particular males exhibited a significantly greater weight loss starting at 4 dpi. In addition, male animals exhibited higher viral RNA loads and higher titers of infectious virus in the lung, which was particularly evident in males at 16 months of age. Notably, no viral RNA was detected in the brains of infected mice, regardless of age or sex. Nevertheless, expression of IL-6, TNF-α, and CCL-2 in the lung and brain was increased with viral infection. An unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles in the brain, with innate immunity, defense response to virus, cerebravascular and neuronal functions, as the major molecular networks affected. The data presented in this study show that SARS-CoV-2 infection triggers a neuroinflammatory response despite the lack of detectable virus in the brain. Age and sex have a modifying effect on this pathogenic process. Aberrant activation of innate immune response, disruption of blood-brain barrier and endothelial cell integrity, and supression of neuronal activity and axonogenesis underlie the impact of SARS-CoV-2 infection on the brain. Understanding the role of these affected pathways in SARS-CoV-2 pathogenesis helps identify appropriate points of therapeutic interventions to alleviate neurological dysfunction observed during COVID-19.

Burnout among labor and birth providers in northern Tanzania: A mixed-method study.

Burnout, characterized by emotional exhaustion, depersonalization, and a diminished sense of accomplishment, is a serious problem among healthcare workers. Burnout negatively impacts provider well-being, patient outcomes, and healthcare systems globally, and is especially worrisome in settings with a shortage of healthcare workers and resources. The goal of this study is to explore the experience of burnout in a population of labor and delivery (L&D) providers in Tanzania. We examined burnout using three data sources. A structured assessment of burnout was collected at four time points from a sample of 60 L&D providers in six clinics. The same providers participated in an interactive group activity from which we drew observational data on burnout prevalence. Finally, we conducted in-depth interviews (IDIs) with a subset of 15 providers to further explore their experience of burnout. At baseline, prior to any introduction to the concept, 18% of respondents met criteria for burnout. Immediately after a discussion and activity on burnout, 62% of providers met criteria. One- and three- months later, 29% and 33% of providers met criteria, respectively. In IDIs, participants saw the lack of understanding of burnout as the cause for low baseline rates and attributed the subsequent decrease in burnout to newly acquired coping strategies. The activity helped providers realize they were not alone in their experience of burnout. High patient load, low staffing, limited resources, and low pay emerged as contributing factors. Burnout was prevalent among a sample of L&D providers in northern Tanzania. However, a lack of exposure to the concept of burnout leads to providers being unaware of the issue as a collective burden. Therefore, burnout remains rarely discussed and not addressed, thus continuing to impact provider and patient health. Previously validated burnout measures cannot adequately assess burnout without a discussion of the context.

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

The human gut virome: composition, colonization, interactions, and impacts on human health.

The gut virome is an incredibly complex part of the gut ecosystem. Gut viruses play a role in many disease states, but it is unknown to what extent the gut virome impacts everyday human health. New experimental and bioinformatic approaches are required to address this knowledge gap. Gut virome colonization begins at birth and is considered unique and stable in adulthood. The stable virome is highly specific to each individual and is modulated by varying factors such as age, diet, disease state, and use of antibiotics. The gut virome primarily comprises bacteriophages, predominantly order Crassvirales, also referred to as crAss-like phages, in industrialized populations and other Caudoviricetes (formerly Caudovirales). The stability of the virome's regular constituents is disrupted by disease. Transferring the fecal microbiome, including its viruses, from a healthy individual can restore the functionality of the gut. It can alleviate symptoms of chronic illnesses such as colitis caused by Clostridiodes difficile. Investigation of the virome is a relatively novel field, with new genetic sequences being published at an increasing rate. A large percentage of unknown sequences, termed 'viral dark matter', is one of the significant challenges facing virologists and bioinformaticians. To address this challenge, strategies include mining publicly available viral datasets, untargeted metagenomic approaches, and utilizing cutting-edge bioinformatic tools to quantify and classify viral species. Here, we review the literature surrounding the gut virome, its establishment, its impact on human health, the methods used to investigate it, and the viral dark matter veiling our understanding of the gut virome.

Transplanting Microglia for Treating CNS Injuries and Neurological Diseases and Disorders, and Prospects for Generating Exogenic Microglia.

Microglia are associated with a wide range of both neuroprotective and neuroinflammatory functions in the central nervous system (CNS) during development and throughout lifespan. Chronically activated and dysfunctional microglia are found in many diseases and disorders, such as Alzheimer's disease, Parkinson's disease, and CNS-related injuries, and can accelerate or worsen the condition. Transplantation studies designed to replace and supplement dysfunctional microglia with healthy microglia offer a promising strategy for addressing microglia-mediated neuroinflammation and pathologies. This review will cover microglial involvement in neurological diseases and disorders and CNS-related injuries, current microglial transplantation strategies, and different approaches and considerations for generating exogenic microglia.

Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts.

Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[18F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[18F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.

Health status and clinical outcomes in older adults with chronic coronary disease: the ISCHEMIA trial

BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

Phables: from fragmented assemblies to high-quality bacteriophage genomes.

Microbial communities influence both human health and different environments. Viruses infecting bacteria, known as bacteriophages or phages, play a key role in modulating bacterial communities within environments. High-quality phage genome sequences are essential for advancing our understanding of phage biology, enabling comparative genomics studies, and developing phage-based diagnostic tools. Most available viral identification tools consider individual sequences to determine whether they are of viral origin. As a result of the challenges in viral assembly, fragmentation of genomes can occur, leading to the need for new approaches in viral identification. Therefore, the identification and characterisation of novel phages remain a challenge. We introduce Phables, a new computational method to resolve phage genomes from fragmented viral metagenome assemblies. Phables identifies phage-like components in the assembly graph, models each component as a flow network, and uses graph algorithms and flow decomposition techniques to identify genomic paths. Experimental results of viral metagenomic samples obtained from different environments show that Phables recovers on average over 49% more high-quality phage genomes compared to existing viral identification tools. Furthermore, Phables can resolve variant phage genomes with over 99% average nucleotide identity, a distinction that existing tools are unable to make. Phables is available on GitHub at https://github.com/Vini2/phables.

Health Status and Clinical Outcomes in Older Adults With Chronic Coronary Disease: The ISCHEMIA Trial.

BACKGROUND: Whether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown. OBJECTIVES: The goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. METHODS: One-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure. RESULTS: Among 4,617 participants, 2,239 (48.5%) were aged <65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged <65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (Pinteraction = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (Pinteraction = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (Pinteraction = 0.29). CONCLUSIONS: Older patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).