Malaria: an update on treatment of adults in non-endemic countries.

Every year people die from malaria in Britain and other industrialised countries. Most of these deaths are avoidable: they occur because a patient or doctor has underestimated the severity of the disease or has not considered the diagnosis early enough. This article provides the essential facts on treating malaria in adults in a non-endemic setting and is based on the best available evidenc

Use of the wellness thermometer to improve consultations for patients with human immunodeficiency virus

Aim To evaluate the effectiveness of using the wellness thermometer in healthcare consultations with patients with HIV. Method This was a service evaluation that was undertaken in three UK HIV clinics in 2014. After using the wellness thermometer, patients and healthcare professionals completed a survey to indicate whether they felt the tool improved their consultations. Results A total of 231 patients completed the survey. It was found that 80% (n = 185) of patients felt the wellness thermometer helped to identify their concerns, while 79% (n = 182) of patients felt the wellness thermometer improved their conversation with the healthcare professional. Of the 12 healthcare professionals who completed the survey, most felt that the tool helped patients to identify their concerns (n = 10) and that it was easy to use (n = 11). Conclusion There are several benefits associated with using the wellness thermometer in healthcare consultations, and it may support patients with HIV to report any concerns they have in relation to their treatment and quality of life. The authors hope envisage that the tool will become a routine part of the care of these patients

EPICE-HIV: An Epidemiologic Cost-Effectiveness Model for HIV Treatment.

The goal of this research was to establish a new and innovative framework for cost-effectiveness modeling of HIV-1 treatment, simultaneously considering both clinical and epidemiological outcomes. EPICE-HIV is a multi-paradigm model based on a within-host micro-simulation model for the disease progression of HIV-1 infected individuals and an agent-based sexual contact network (SCN) model for the transmission of HIV-1 infection. It includes HIV-1 viral dynamics, CD4+ T cell infection rates, and pharmacokinetics/pharmacodynamics modeling. Disease progression of HIV-1 infected individuals is driven by the interdependent changes in CD4+ T cell count, changes in plasma HIV-1 RNA, accumulation of resistance mutations and adherence to treatment. The two parts of the model are joined through a per-sexual-act and viral load dependent probability of disease transmission in HIV-discordant couples. Internal validity of the disease progression part of the model is assessed and external validity is demonstrated in comparison to the outcomes observed in the STaR randomized controlled clinical trial. We found that overall adherence to treatment and the resulting pattern of treatment interruptions are key drivers of HIV-1 treatment outcomes. Our model, though largely independent of efficacy data from RCT, was accurate in producing 96-week outcomes, qualitatively and quantitatively comparable to the ones observed in the STaR trial. We demonstrate that multi-paradigm micro-simulation modeling is a promising tool to generate evidence about optimal policy strategies in HIV-1 treatment, including treatment efficacy, HIV-1 transmission, and cost-effectiveness analysis

Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly

Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages

Новое в развитии пластической хирургии носа

Рассмотрены проблемы, возникающие при реконструктивных вмешательствах на структурах наружного носа и его внутренних полостях, характеристики трансплантатов и условия, способствующие возникновению осложнений. На основании собственных наблюдений сделан вывод о практической целесообразности использования гомо− и гетеротрансплантатов с учетом конкретных медико−социальных показаний.The problems arising at reconstructive surgery on the external structures of the nose and its inner cavities as well as characteristics of the implants and the conditions promoting complication development are featured. Basing on the original research the authors conclude about practical expediency of application of homo− and heterotransplants with the account of definite medical−social parameters

First-line HIV treatment outcomes following the introduction of integrase inhibitors in UK guidelines.

OBJECTIVE: To investigate the characteristics and outcomes of people who initiated different antiretroviral therapy (ART) regimens during the era of integrase strand transfer inhibitors (INSTIs). DESIGN: UK-based observational cohort study. METHODS: UK Collaborative HIV Cohort study participants were included if they had started ART between 1 January 2012 and 30 June 2017. Virological failure was defined as the first of two consecutive plasma HIV RNA more than 50 copies/ml, at least 6 months after starting ART. Follow-up was censored at ART discontinuation, class switch or death. The risk of virological failure among those on INSTI, protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens was compared using Kaplan-Meier and Cox regression methods. RESULTS: Of 12?585 participants, 45.6% started a NNRTI, 29.0% a protease inhibitor and 25.4% an INSTI regimen. Over a median follow-up of 20.3 months (interquartile range 7.9-38.9), 7.5% of participants experienced virological failure. Compared with those starting an NNRTI regimen, people receiving INSTIs or protease inhibitors were more likely to experience virological failure: INSTI group adjusted hazard ratio 1.52, 95% confidence interval 1.19-1.95, P?=?0.0009; protease inhibitor group adjusted hazard ratio 2.70, 95% confidence interval 2.27-3.21, P less than 0.0001, likelihood ratio test P less than 0.0001. CONCLUSION: First-line INSTI regimens were associated with a lower risk of virological failure than protease inhibitor regimens but both groups were more likely to experience virological failure than those initiating treatment with a NNRTI. There is likely to be residual channelling bias resulting from selected use of INSTIs and protease inhibitors in specific clinical contexts, including in those with a perceived risk of poor adherence

Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19.

COVID-19 pathogenesis is associated with an exaggerated immune response. However, the specific cellular mediators and inflammatory components driving diverse clinical disease outcomes remain poorly understood. We undertook longitudinal immune profiling on both whole blood and peripheral blood mononuclear cells (PBMCs) of hospitalized patients during the peak of the COVID-19 pandemic in the UK. Here, we report key immune signatures present shortly after hospital admission that were associated with the severity of COVID-19. Immune signatures were related to shifts in neutrophil to T cell ratio, elevated serum IL-6, MCP-1 and IP-10, and most strikingly, modulation of CD14+ monocyte phenotype and function. Modified features of CD14+ monocytes included poor induction of the prostaglandin-producing enzyme, COX-2, as well as enhanced expression of the cell cycle marker Ki-67. Longitudinal analysis revealed reversion of some immune features back to the healthy median level in patients with a good eventual outcome. These findings identify previously unappreciated alterations in the innate immune compartment of COVID-19 patients and lend support to the idea that therapeutic strategies targeting release of myeloid cells from bone marrow should be considered in this disease. Moreover, they demonstrate that features of an exaggerated immune response are present early after hospital admission suggesting immune-modulating therapies would be most beneficial at early timepoints

Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with CYP2B6 c.516G→T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis.

Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin in vitro, inducing neuronal damage at concentrations of 3.3 ng/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published in vitro and in vivo data. The effect of the CYP2B6 c.516G→T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the in vitro toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the in vitro toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the CYP2B6 genotype, particularly in those with impaired blood-brain barrier integrity

Alterations in T and B cell function persist in convalescent COVID-19 patients

BackgroundEmerging studies indicate that some COVID-19 patients suffer from persistent symptoms including breathlessness and chronic fatigue; however the long-term immune response in these patients presently remains ill-defined.MethodsHere we describe the phenotypic and functional characteristics of B and T cells in hospitalised COVID-19 patients during acute disease and at 3-6 months of convalescence.FindingsWe report that the alterations in B cell subsets observed in acute COVID-19 patients were largely recovered in convalescent patients. In contrast, T cells from convalescent patients displayed continued alterations with persistence of a cytotoxic programme evident in CD8+ T cells as well as elevated production of type-1 cytokines and IL-17. Interestingly, B cells from patients with acute COVID-19 displayed an IL-6/IL-10 cytokine imbalance in response to toll-like receptor activation, skewed towards a pro-inflammatory phenotype. Whereas the frequency of IL-6+ B cells was restored in convalescent patients irrespective of clinical outcome, recovery of IL-10+ B cells was associated with resolution of lung pathology.ConclusionsOur data detail lymphocyte alterations in previously hospitalized COVID-19 patients up to 6 months following hospital discharge and identify 3 subgroups of convalescent patients based on distinct lymphocyte phenotypes, with one subgroup associated with poorer clinical outcome. We propose that alterations in B and T cell function following hospitalisation with COVID-19 could impact longer term immunity and contribute to some persistent symptoms observed in convalescent COVID-19 patients

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease

Introduction: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. // Methods and analysis: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). Eligibility criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18–49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. // Ethics and dissemination: Ethical approval granted by South Central–Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. // Trial registration number: ISRCTN30448031; EudraCT number: 2021-005748-31