Effects of Alcohol Use on Patient Retention in HIV Care in East Africa.

We sought to investigate the association between hazardous alcohol use and gaps in care for people living with HIV over a long-term follow-up period. Adults who had participated in our previously published Phase I study of hazardous alcohol use at HIV programs in Kenya and Uganda were eligible at their 42 to 48 month follow-up visit. Those who re-enrolled were followed for an additional ~ 12 months. Hazardous alcohol use behavior was measured using the Alcohol Use Disorders Identification Test (AUDIT) tool. Deidentified clinical data were used to assess gaps in care (defined as failure to return to clinic within 60 days after a missed visit). The proportion of patients experiencing a gap in care at a specific time point was based on a nonparametric moment-based estimator. A semiparametric Cox proportional hazard model was used to determine the association between hazardous alcohol use at enrollment in Phase I (AUDIT score ≥ 8) and gaps in care. Of the 731 study-eligible participants from Phase I, 5.5% had died, 10.1% were lost to follow-up, 39.5% transferred, 7.5% declined/not approached, and 37.3% were enrolled. Phase II participants were older, had less hazardous drinking and had a lower WHO clinical stage than those not re-enrolled. Hazardous drinking in the re-enrolled was associated with a Hazard Ratio (HR) of 1.88 [p-value = 0.016] for a gap in care. Thus, hazardous alcohol use at baseline was associated with an increased risk of experiencing a gap in care and presents an early target for intervention.

RESUMEN: Buscamos investigar la asociación entre el uso riesgoso de alcohol y retención en programas de VIH a largo plazo. Todo adulto que participó en nuestro estudio previamente publicado sobre el uso riesgoso de alcohol en programas de VIH en Kenia y Uganda era elegible a los 42 a 48 meses de seguimiento. Los adultos reinscritos en la fueron seguidos por ~ 12 meses adicionales. Usamos el "Alcohol Use Disorders Identification Test" (AUDIT) para medir uso de alcohol. Usamos datos clínicos anonimizados para evaluar interrupciones en cuidado (definido como falta de regresar a clínica 60 días después de faltar a una cita). Basamos la proporción de pacientes con una interrupción en cuidado clínico en un estimador momentáneo y no-paramétrico. Determinamos la asociación entre el uso riesgoso de alcohol al inicio de la primera fase (puntuación AUDIT ≥8) con retención en servicios clínicos usando un modelo de riesgo Cox semiparamétrico. De los 731 participantes elegibles, 5.5% habían muerto, 10.1% fueron perdidos a seguimiento clínico, 39.5% se transfirieron a otro programa, 7.5% declinaron participación o no fueron reclutados y 37.3% fueron reinscritos en la segunda fase. Los participantes reinscritos eran mayores, tenían menos uso riesgoso de alcohol y tenían VIH menos avanzado. El uso peligroso del alcohol se vio asociado con el riesgo de tener una interrupción en cuidado clínico [Proporción de Riesgo (Hazard Ratio, HR) PR=1.88, valor-p = 0.016]. Por lo tanto, el uso peligroso del alcohol incrementa el riesgo de perder seguimiento clínico y presenta una oportunidad para intervención.

The roles and responsibilities of general practice nurses in China: a qualitative study.

BACKGROUND: General hospitals in China have been establishing General Practice Departments (GPD). Although General Practice Nurses (GPNs) are an important part of this medical system, their training has not been synchronised. This study explored the working status of nurses in GPDs in general hospitals in Beijing to provide a theoretical basis for the training and development of GPNs in China. METHODS: We conducted in-depth, individual interviews with outpatient nurses at 19 hospitals in Beijing between March and April 2021. We employed a qualitative analysis to interpret participant narratives and used a codebook thematic analysis to analyse the interview data and extract themes. RESULTS: The analysis revealed four themes: (i) a lack of full-time GPNs in GPDs of most tertiary hospitals, (ii) the inability of GPNs to fully express their potential and skills owing to their limited roles, (iii) insufficient standardised patient education provided by nurses in GPDs, and (iv) a lack of systematic and relevant training for nurses working in general practice settings. CONCLUSIONS: To promote the development of GPNs, GPDs in general hospitals in China should hire full-time GPNs, define their job duties in alignment with their values, and provide standardised training to strengthen their core competencies.

Clostridium autoethanogenum alters cofactor synthesis, redox metabolism, and lysine-acetylation in response to elevated H2:CO feedstock ratios for enhancing carbon capture efficiency.

BACKGROUND: Clostridium autoethanogenum is an acetogenic bacterium that autotrophically converts carbon monoxide (CO) and carbon dioxide (CO2) gases into bioproducts and fuels via the Wood-Ljungdahl pathway (WLP). To facilitate overall carbon capture efficiency, the reaction stoichiometry requires supplementation of hydrogen at an increased ratio of H2:CO to maximize CO2 utilization; however, the molecular details and thus the ability to understand the mechanism of this supplementation are largely unknown. RESULTS: In order to elucidate the microbial physiology and fermentation where at least 75% of the carbon in ethanol comes from CO2, we established controlled chemostats that facilitated a novel and high (11:1) H2:CO uptake ratio. We compared and contrasted proteomic and metabolomics profiles to replicate continuous stirred tank reactors (CSTRs) at the same growth rate from a lower (5:1) H2:CO condition where ~ 50% of the carbon in ethanol is derived from CO2. Our hypothesis was that major changes would be observed in the hydrogenases and/or redox-related proteins and the WLP to compensate for the elevated hydrogen feed gas. Our analyses did reveal protein abundance differences between the two conditions largely related to reduction-oxidation (redox) pathways and cofactor biosynthesis, but the changes were more minor than we would have expected. While the Wood-Ljungdahl pathway proteins remained consistent across the conditions, other post-translational regulatory processes, such as lysine-acetylation, were observed and appeared to be more important for fine-tuning this carbon metabolism pathway. Metabolomic analyses showed that the increase in H2:CO ratio drives the organism to higher carbon dioxide utilization resulting in lower carbon storages and accumulated fatty acid metabolite levels. CONCLUSIONS: This research delves into the intricate dynamics of carbon fixation in C. autoethanogenum, examining the influence of highly elevated H2:CO ratios on metabolic processes and product outcomes. The study underscores the significance of optimizing gas feed composition for enhanced industrial efficiency, shedding light on potential mechanisms, such as post-translational modifications (PTMs), to fine-tune enzymatic activities and improve desired product yields.

Departure Decisions: Exit Survey of Family Medicine Residency Directors.

Background and Objectives: Program director (PD) tenure, continuity, and stability may enhance residency program quality, yet many PDs do not stay long in their positions. No prior study has taken a comprehensive census of departing PDs to determine reasons for leaving the role. This study aimed to survey all exiting family medicine (FM) PDs to identify decision factors contributing to their departure. Methods: From October 2021 to October 2022, we sent a web-based exit survey to all departing FM PDs. The survey asked departing PDs to rate the strength of 36 factors in the decision to exit the PD role in terms of job satisfaction, accomplishments, career choices, workload, preparation, expectations, and support. We used the Fisher exact test to assess all 36 decision factors and PD characteristics for significant associations with shorter or longer PD tenures. Results: PDs submitted 73 surveys out of 109 invitations (67.0% response). We analyzed 68 with complete data. The median PD tenure was 5.6 years (mean 6.9 years). Most respondents (66/68, 97.1%) identified three or more strong factors in their decision to leave. The strongest factors reflected stable residency programs, an established succession plan, a desire for more personal/family time, and a sense that the time was right. PDs with tenures longer than 3 years were more likely to have completed the National Institute for Program Director Development (P=.001). Conclusions: PDs leave the position for multiple reasons, often positive, and not necessarily due to lack of support and preparation. Further exploration of decision factors may inform strategies to support PDs in their positions.

Perspectives From Patients Using a Food Pantry in a Family Medicine Residency Clinic: A Qualitative Study.

BACKGROUND AND OBJECTIVES: Food insecurity is common in patients receiving care in primary care offices. Some health systems and primary care offices provide food directly to food insecure patients. Our family medicine residency clinic started a food pantry to directly address this social determinant of health. We aimed to understand the reasons patients in primary care visited our food pantry and their impressions of food available directly in a primary care office. METHODS: We conducted semistructured interviews with 21 patients obtaining food from our food pantry. We recorded and transcribed the interviews, and analyzed them with an editing organizing style to highlight noteworthy segments, recognize patterns, and understand important themes. RESULTS: Patients reported numerous barriers to obtaining healthy food, including cost, transportation, and time. Life-changing events often led a patient to a food pantry, and patients often prioritized family members when addressing food insecurity. Food pantry users appreciated the convenience of obtaining food at a medical visit and felt supported by healthy food that aligned with a message received from their physician. CONCLUSIONS: Food insecure patients face many barriers to obtaining healthy food. A colocated food pantry in a primary care office helps address barriers, is convenient, and is appreciated by patients using the service.

Multi-omics correlates of insulin resistance and circadian parameters mapped directly from human serum.

While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells.

Maternal immune activation exerts long-term effects on activity and sleep in male offspring mice.

Exposure to infectious or non-infectious immune activation during early development is a serious risk factor for long-term behavioural dysfunctions. Mouse models of maternal immune activation (MIA) have increasingly been used to address neuronal and behavioural dysfunctions in response to prenatal infections. One commonly employed MIA model involves administering poly(I:C) (polyriboinosinic-polyribocytdilic acid), a synthetic analogue of double-stranded RNA, during gestation, which robustly induces an acute viral-like inflammatory response. Using electroencephalography (EEG) and infrared (IR) activity recordings, we explored alterations in sleep/wake, circadian and locomotor activity patterns on the adult male offspring of poly(I:C)-treated mothers. Our findings demonstrate that these offspring displayed reduced home cage activity during the (subjective) night under both light/dark or constant darkness conditions. In line with this finding, these mice exhibited an increase in non-rapid eye movement (NREM) sleep duration as well as an increase in sleep spindles density. Following sleep deprivation, poly(I:C)-exposed offspring extended NREM sleep duration and prolonged NREM sleep bouts during the dark phase as compared with non-exposed mice. Additionally, these mice exhibited a significant alteration in NREM sleep EEG spectral power under heightened sleep pressure. Together, our study highlights the lasting effects of infection and/or immune activation during pregnancy on circadian activity and sleep/wake patterns in the offspring.

BDNF-TrkB signaling orchestrates the buildup process of local sleep.

Sleep debt accumulates during wakefulness, leading to increased slow wave activity (SWA) during sleep, an encephalographic marker for sleep need. The use-dependent demands of prior wakefulness increase sleep SWA locally. However, the circuitry and molecular identity of this "local sleep" remain unclear. Using pharmacology and optogenetic perturbations together with transcriptomics, we find that cortical brain-derived neurotrophic factor (BDNF) regulates SWA via the activation of tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We map BDNF/TrkB-induced sleep SWA to layer 5 (L5) pyramidal neurons of the cortex, independent of neuronal firing per se. Using mathematical modeling, we here propose a model of how BDNF's effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Proteomic analysis further reveals that TrkB activation enriches ubiquitin and proteasome subunits. Together, our study reveals that local SWA control is mediated by BDNF-TrkB-CREB signaling in L5 excitatory cortical neurons.

Modulation of sleep/wake patterns by gephyrin phosphorylation status.

Sleep/wake cycles intricately shape physiological activities including cognitive brain functions, yet the precise molecular orchestrators of sleep remain elusive. Notably, the clinical impact of benzodiazepine drugs underscores the pivotal role of GABAergic neurotransmission in sleep regulation. However, the specific contributions of distinct GABAA receptor subtypes and their principal scaffolding protein, gephyrin, in sleep dynamics remain unclear. The evolving role of synaptic phospho-proteome alterations at excitatory and inhibitory synapses suggests a potential avenue for modulating gephyrin and, consequently, GABAARs for sleep through on-demand kinase recruitment. Our study unveils the distinctive roles of two prevalent GABAA receptor subtypes, α1- and α2-GABAARs, in influencing sleep duration and electrical sleep activity. Notably, the absence of α1-GABAARs emerges as central in sleep regulation, manifesting significant alterations in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during dark or active phases, accompanied by altered electroencephalogram (EEG) patterns across various frequencies. Gephyrin proteomics analysis reveals sleep/wake-dependent interactions with a repertoire of known and novel kinases. Crucially, we identify the regulation of gephyrin interaction with ERK1/2, and phosphorylations at serines 268 and 270 are dictated by sleep/wake cycles. Employing AAV-eGFP-gephyrin or its phospho-null variant (S268A/S270A), we disrupt sleep either globally or locally to demonstrate gephyrin phosphorylation as a sleep regulator. In summary, our findings support the local cortical sleep hypothesis and we unveil a molecular mechanism operating at GABAergic synapses, providing critical insights into the intricate regulation of sleep.

Association Between ERAS Application Changes and Unfilled Positions in the 2024 Family Medicine Match.

BACKGROUND AND OBJECTIVES: The number of family medicine positions unfilled in the Main Match has increased from 2019 to 2023. In the 2023-2024 family medicine application season, the specialty adopted the changes in the Electronic Residency Application Service (ERAS or MyERAS), which included geographic preferences and offered applicants five program signals. We compared the number of unfilled positions from prior years to results of the 2024 family medicine Match after the adoption of these changes. METHODS: We analyzed publicly available data from the National Resident Matching Program to compare the number of positions filled in the Main Match from 2019 to 2024. We estimated the number of expected positions filled using multiple linear regression and application data from ERAS and the number of available positions in the Match. RESULTS: A total of 636 positions were unfilled in the 2024 family medicine Main Match. Our statistical analysis, based only on the number of applicants and the number of available positions, predicted 630.65 unfilled slots with a 95% confidence interval from 605.53 to 655.77. The 2024 family medicine position fill rate decreased slightly at 87.8% compared to 88.7% in the 2023 Match. The number of family medicine programs that did not fill in the Main Match increased in 2024 to 241 (30.3% of programs) compared to 217 (28.1%) in 2023. CONCLUSIONS: MyERAS changes in the 2023-2024 family medicine application season, including geographic preferences and program signaling, were not associated with a change in the number of programs or positions filled in the family medicine Main Match.

Treatment options for patients with pilonidal sinus disease: PITSTOP, a mixed-methods evaluation.

Background: There is no consensus on optimal management of pilonidal disease. Surgical practice is varied, and existing literature is mainly single-centre cohort studies of varied disease severity, interventions and outcome assessments. Objectives: A prospective cohort study to determine: • disease severity and intervention relationship • most valued outcomes and treatment preference by patients • recommendations for policy and future research. Design: Observational cohort study with nested mixed-methods case study. Discrete choice experiment. Clinician survey. Three-stage Delphi survey for patients and clinicians. Inter-rater reliability of classification system. Setting: Thirty-one National Health Service trusts. Participants: Patients aged > 16 years referred for elective surgical treatment of pilonidal disease. Interventions: Surgery. Main outcome measures: Pain postoperative days 1 and 7, time to healing and return to normal activities, complications, recurrence. Outcomes compared between major and minor procedures using regression modelling, propensity score-based approaches and augmented inverse probability weighting to account for measured potential confounding features. Results: Clinician survey: There was significant heterogeneity in surgeon practice preference. Limited training opportunities may impede efforts to improve practice. Cohort study: Over half of patients (60%; N = 667) had a major procedure. For these procedures, pain was greater on day 1 and day 7 (mean difference day 1 pain 1.58 points, 95% confidence interval 1.14 to 2.01 points, n = 536; mean difference day 7 pain 1.53 points, 95% confidence interval 1.12 to 1.95 points, n = 512). There were higher complication rates (adjusted risk difference 17.5%, 95% confidence interval 9.1 to 25.9%, n = 579), lower recurrence (adjusted risk difference -10.1%, 95% confidence interval -18.1 to -2.1%, n = 575), and longer time to healing (>34 days estimated difference) and time to return to normal activities (difference 25.9 days, 95% confidence interval 18.4 to 33.4 days). Mixed-methods analysis: Patient decision-making was influenced by prior experience of disease and anticipated recovery time. The burden involved in wound care and the gap between expected and actual time for recovery were the principal reasons given for decision regret. Discrete choice experiment: The strongest predictors of patient treatment choice were risk of infection/persistence (attribute importance 70%), and shorter recovery time (attribute importance 30%). Patients were willing to trade off these attributes. Those aged over 30 years had a higher risk tolerance (22.35-34.67%) for treatment failure if they could experience rapid recovery. There was no strong evidence that younger patients were willing to accept higher risk of treatment failure in exchange for a faster recovery. Patients were uniform in rejecting excision-and-leave-open because of the protracted nursing care it entailed. Wysocki classification analysis: There was acceptable inter-rater agreement (κ = 0.52, 95% confidence interval 0.42 to 0.61). Consensus exercise: Five research and practice priorities were identified. The top research priority was that a comparative trial should broadly group interventions. The top practice priority was that any interventions should be less disruptive than the disease itself. Limitations: Incomplete recruitment and follow-up data were an issue, particularly given the multiple interventions. Assumptions were made regarding risk adjustment. Conclusions and future work: Results suggest the burden of pilonidal surgery is greater than reported previously. This can be mitigated with better selection of intervention according to disease type and patient desired goals. Results indicate a framework for future higher-quality trials that stratify disease and utilise broad groupings of common interventions with development of a patient-centred core outcome set. Trial registration: This trial is registered as ISRCTN95551898. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/17/02) and is published in full in Health Technology Assessment; Vol. 28, No. 33. See the NIHR Funding and Awards website for further award information.

Pilonidal disease is caused by ingrowing hairs between the buttocks. It can cause pain and infection and may need surgery. We do not know which operation gives the best results, or who operations help. PITSTOP aimed to find out which operation is the best and what is important to patients when deciding on surgery, and to suggest ideas for better treatment and future research. We looked at what operations were done and their outcomes. We interviewed patients about their experiences. Some completed a survey to help us understand what operations they might prefer based on risks and outcomes. Surgeons completed a survey about their experiences, and we explored whether a new tool could help us tell the difference between 'mild' and 'bad' disease. We used findings from these studies to help patients and surgeons give priorities for future practice and research. Six hundred and sixty-seven patients joined PITSTOP. People who had a major operation had more pain and took longer to return to normal activities. Some were still affected 6 months after surgery. However, disease recurrence was lower than after a minor procedure. Patients based decisions about treatment on the likelihood of success and the time to recover. The study and the surgeons' survey both showed marked differences in practice. Surgeons tended to offer one or two operations learned during training. A classification tool put cases in similar groups, but this did not influence treatment choices. The consensus exercise identified five research priorities, the top one being to put types of surgery into two groups. Of the five practice priorities, the top one was that surgery should not make the patient worse than the disease. There is variation in the treatment of pilonidal disease. Wound issues and impact on daily living should be avoided. The highlighted research questions should be addressed to improve care.

On the connection between creativity and aesthetics.

Within cognitive psychology, there are separate experimental fields devoted to the study of creativity, on the one hand, and aesthetics, on the other, with virtually no cross-talk between them. In this article, I propose a means of uniting creativity and aesthetics via a consideration of the mechanisms of cultural evolution. I call this the creativity/aesthetics cycle. The basic tenet of the model is that creativity and aesthetics mediate, respectively, the processes of variation (production) and selection (perception or consumption) in evolutionary models of culture. By means of this cycle, creators produce works that they hope will be evaluated positively by consumers, where such appraisals ultimately feed back to influence the subsequent decision-making processes of creators. I discuss the implications of this model for the fields of creativity and aesthetics.

Diagnosis of Cervical Spinal Cord Multiple Sclerosis by a Chiropractic Physician: A Case Report.

We present a case report of diagnosis of cervical spine multiple sclerosis by a chiropractic physician. This unique case contributes an account of a challenging differential diagnosis to the literature. A 30-year-old male presented with a three-year history of diffuse left upper extremity motor strength deficits and paresthesia (numbness and tingling). The patient had seen multiple physicians for these symptoms with no diagnosis of multiple sclerosis and no advanced imaging. The differential diagnosis included lower cervical spine nerve root compression or neurological disorders such as amyotrophic lateral sclerosis, cerebral lesion, motor neuropathy, multiple sclerosis, or spinal cord lesion. MRI of the cervical spine with and without IV contrast revealed evidence of spinal cord multiple sclerosis. The patient was referred to a neurologist where the diagnosis of multiple sclerosis was confirmed. A 10-year follow-up showed the patient was controlling his condition with medications and had no disability. This case underscores the importance for physicians to consider neurological conditions and advanced imaging in the presence of diffuse motor strength deficits and paresthesia in the absence of injury, pain, or any other symptoms.

Attitudes toward and training in medications for opioid use disorders: a descriptive analysis among employees in the youth legal system and community mental health centers.

BACKGROUND: Research demonstrates gaps in medications for opioid use disorder uptake (MOUDs; methadone, buprenorphine, and naltrexone) especially among adolescents. These gaps may be partly attributable to attitudes about and training in MOUDs among youth-serving professionals. We extended prior research by conducting descriptive analyses of attitudes regarding effectiveness and acceptability of MOUDs, as well as training in MOUDs, among youth legal system (YLS) employees and community mental health center (CMHC) personnel who interface professionally with youth. METHODS: Using survey data from participants (n = 181) recruited from eight Midwest counties, we examined: (1) differences in MOUD attitudes/training by MOUD type and (2) by respondent demographics, and (3) prediction of MOUD attitudes/training by participant-reported initiatives to implement evidence-based practices (EBPs), workplace culture around EBPs, and workplace stress. Attitudes and training were measured in reference to five MOUD types (methadone, oral buprenorphine, injectable buprenorphine, oral naltrexone, injectable naltrexone) on three subscales (effectiveness, acceptability, training). RESULTS: Wilcoxon signed-rank tests demonstrated that most outcomes differed significantly by MOUD type (differences observed among 22 of 30 tests). Kruskal-Wallis tests suggested MOUD differences based on demographics. For methadone, CMHC providers endorsed greater perceived effectiveness than YLS providers and age explained significant differences in perceived effectiveness. For buprenorphine, CHMC providers viewed oral or injectable buprenorphine as more effective than YLS employees, respondents from more rural counties viewed oral buprenorphine as more effective than those from less rural counties, and age explained differences in perceived effectiveness. For naltrexone, perceived gender differed by gender. Hierarchical ordinal logistic regression analysis did not find an association between personal initiatives to implement EBPs, workplace culture supporting EBPs, or workplace stress and effectiveness or acceptability of MOUDs. However, personal initiatives to implement EBPs was associated with training in each MOUD. CONCLUSIONS: These results highlight a few key findings: effectiveness/acceptability of and training in MOUDs largely differ by MOUD type; setting, rurality, age, gender, and education explain group differences in perceived effectiveness of and training in MOUDs; and implementing EBPs is associated with training in MOUDs. Future research would benefit from examining what predicts change in MOUD attitudes longitudinally.

Modeling the HIV Cascade of Care Using Routinely Collected Clinical Data to Guide Programmatic Interventions and Policy Decisions.

BACKGROUND: The HIV care cascade is a framework to examine effectiveness of HIV programs and progress toward global targets to end the epidemic but has been conceptualized as a unidirectional process that ignores cyclical care patterns. We present a dynamic cascade that accounts for patient "churn" and apply novel analytic techniques to readily available clinical data to robustly estimate program outcomes and efficiently assess progress toward global targets. METHODS: Data were assessed for 35,649 people living with HIV and receiving care at 78 clinics in East Africa between 2014 and 2020. Patients were aged ≥15 years and had ≥1 viral load measurements. We used multi-state models to estimate the probability of being in 1 of 5 states of a dynamic HIV cascade: (1) in HIV care but not on antiretroviral therapy (ART), (2) on ART, (3) virally suppressed, (4) in a gap-in-care, and (5) deceased and compared these among subgroups. To assess progress toward global targets, we summed those probabilities across patients and generated population-level proportions of patients on ART and virally suppressed in mid-2020. RESULTS: One year after enrollment, 2.8% of patients had not initiated ART, 86.7% were receiving ART, 57.4% were virally suppressed, 10.2% were disengaged from care, and 0.3% had died. At 5 years, the proportion on ART remained steady but viral suppression increased to 77.2%. Of those aged 15-25, >20% had disengaged from care and <60% were virally suppressed. In mid-2020, 90.1% of the cohort was on ART, 90.7% of whom had suppressed virus. CONCLUSIONS: Novel analytic approaches can characterize patient movement through a dynamic HIV cascade and, importantly, by capitalizing on readily available data from clinical cohorts, offer an efficient approach to estimate population-level proportions of patients on ART and virally suppressed. Significant progress toward global targets was observed in our cohort but challenges remain among younger patients.

ECCO Guidelines on Therapeutics in Crohn's Disease: Surgical Treatment.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO guidelines.

Autotrophic adaptive laboratory evolution of the acetogen Clostridium autoethanogenum delivers the gas-fermenting strain LAbrini with superior growth, products, and robustness.

Microbes able to convert gaseous one-carbon (C1) waste feedstocks are increasingly important to transition to the sustainable production of renewable chemicals and fuels. Acetogens are interesting biocatalysts since gas fermentation using Clostridium autoethanogenum has been commercialised. However, most acetogen strains need complex nutrients, display slow growth, and are not robust for bioreactor fermentations. In this work, we used three different and independent adaptive laboratory evolution (ALE) strategies to evolve the wild-type C. autoethanogenum to grow faster, without yeast extract and to be robust in operating continuous bioreactor cultures. Multiple evolved strains with improved phenotypes were isolated on minimal media with one strain, named "LAbrini", exhibiting superior performance regarding the maximum specific growth rate, product profile, and robustness in continuous cultures. Whole-genome sequencing of the evolved strains identified 25 mutations. Of particular interest are two genes that acquired seven different mutations across the three ALE strategies, potentially as a result of convergent evolution. Reverse genetic engineering of mutations in potentially sporulation-related genes CLAU_3129 (spo0A) and CLAU_1957 recovered all three superior features of our ALE strains through triggering significant proteomic rearrangements. This work provides a robust C. autoethanogenum strain "LAbrini" to accelerate phenotyping and genetic engineering and to better understand acetogen metabolism.