Integration of genomic and pharmacokinetic data to predict clinical outcomes in HIV-associated cryptococcal meningitis.

Unlabelled: Cryptococcal meningitis causes an estimated 112,000 global deaths per annum. Genomic and phenotypic features of the infecting strain of spp. have been associated with outcomes from cryptococcal meningitis.

Remodelling of the translatome controls diet and its impact on tumorigenesis.

Fasting is associated with a range of health benefits. How fasting signals elicit changes in the proteome to establish metabolic programmes remains poorly understood. Here we show that hepatocytes selectively remodel the translatome while global translation is paradoxically downregulated during fasting.

Measuring cyber wisdom: preliminary validation of a new four-component measure.

Cyber-wisdom is the ability to know and do the right thing at the right time, when using digital technologies, and is a concept that is gaining attention from educators. Whilst the theory and practice of cyber-wisdom education is established, to date there has been no attempt to investigate how the virtue of cyber-wisdom might be measured. This is a lacuna as it limits future research in the area, including, in particular, proximal evaluations of cyber-wisdom interventions.

HIV and fungal priority pathogens.

The burden of invasive fungal infections associated with opportunistic fungal pathogens is a persistent challenge, particularly among people with advanced HIV disease. In October, 2022, WHO published the Fungal Priority Pathogens List (FPPL)-the first global effort to systematically prioritise fungal pathogens. Of the 19 pathogens in the WHO FPPL, four opportunistic pathogens in particular cause invasive diseases in people living with HIV: Cryptococcus neoformans, Histoplasma spp, Pneumocystis jirovecii, and Talaromyces marneffei.

Subfunctionalized expression drives evolutionary retention of ribosomal protein paralogs and in vertebrates.

The formation of paralogs through gene duplication is a core evolutionary process. For paralogs that encode components of protein complexes such as the ribosome, a central question is whether they encode functionally distinct proteins or whether they exist to maintain appropriate total expression of equivalent proteins. Here, we systematically tested evolutionary models of paralog function using the ribosomal protein paralogs () and () as a case study.

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

Background: There are limited data describing clinical flucytosine pharmacokinetics (PK). The variability of flucytosine partitioning into the CNS is not known. We described the interindividual variability in flucytosine PK in patients with HIV-associated cryptococcal meningoencephalitis.

Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3.

Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product ('A3') was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3-two out of 128 possible A3 epimers-and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3.

Wisdom in the digital age: a conceptual and practical framework for understanding and cultivating cyber-wisdom.

The internet presents not just opportunities but also risks that range, to name a few, from online abuse and misinformation to the polarisation of public debate. Given the increasingly digital nature of our societies, these risks make it essential for users to learn how to wisely use digital technologies as part of a more holistic approach to promoting human flourishing. However, insofar as they are exacerbated by both the affordances and the political economy of the internet, this article argues that a new understanding of wisdom that is germane to the digital age is needed.

Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases.

The Ser/Thr protein kinase Wee1 plays a regulatory role at the G/M checkpoint by phosphorylating CDK1 when DNA is damaged to allow time for DNA to repair, disruption of which is a key approach to sensitise cancer cells to DNA-damaging therapies. The main selective inhibitor for Wee1 undergoing development in clinical trials, AZD1775, however, has been shown to have off target effects towards other protein kinases with similar potency. Here we describe the synthesis and assessment of a series of Wee1-degrading PROTACs using AZD1775 linked to either the VHL ligand VH032 or to the CRBN ligand pomalidomide using different types and lengths of linkers.

The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity.

Obesity is a global epidemic leading to increased mortality and susceptibility to comorbidities, with few viable therapeutic interventions. A hallmark of disease progression is the ectopic deposition of lipids in the form of lipid droplets in vital organs such as the liver. However, the mechanisms underlying the dynamic storage and processing of lipids in peripheral organs remain an outstanding question.

Presentations and outcomes of central nervous system TB in a UK cohort: The high burden of neurological morbidity.

Objectives: Most data for Central Nervous System Tuberculosis (CNS-TB) derive from high-incidence, resource-limited countries. We sought to determine the presentation, management and outcomes of CNS-TB in a low-incidence setting with accessible healthcare.

Methods: We undertook a retrospective, observational study of CNS-TB in adults at a single tertiary-referral London hospital (2001-2017).

A cost comparison of amikacin therapy with bedaquiline, for drug-resistant tuberculosis in the UK.

Objectives: Prioritisation of oral bedaquiline over the injectable agents in the treatment of multidrug-resistant Tuberculosis (MDR-TB) in the World Health Organisations (WHO) 2019 guidelines prompted this UK analysis of cost implications. The objective was to estimate the costs of amikacin versus bedaquiline in MDR TB treatment regimens using a historical cohort where the injectable agents were the standard of care.

Methods: This was a retrospective study using a known cohort of UK patients treated with an injectable agent, with data available on resource use, costs for the use of amikacin were compared with those for bedaquiline, based on recommended monitoring for bedaquiline.

XDR-TB transmission in London: Case management and contact tracing investigation assisted by early whole genome sequencing.

Objectives: We describe the first published cluster of extensively drug resistant Tuberculosis (XDR-TB) in the UK and show how early whole genome sequencing (WGS) of Mtb can assist in case management and contact investigations.

Methods: We describe the contact tracing investigation undertaken after the presentation of an adult with XDR-TB. Active cases were treated with an XDR-TB drug regimen and contacts underwent a programme of follow-up for 2 years.

Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both.

Background: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained.

AIDS-related mycoses: the way forward.

The contribution of fungal infections to the morbidity and mortality of HIV-infected individuals is largely unrecognized. A recent meeting highlighted several priorities that need to be urgently addressed, including improved epidemiological surveillance, increased availability of existing diagnostics and drugs, more training in the field of medical mycology, and better funding for research and provision of treatment, particularly in developing countries.

A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi.

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data.

Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi.

Airway and parenchymal manifestations of pulmonary aspergillosis.

Pulmonary aspergillosis encompasses a heterogeneous group of mycoses that result from either colonisation or pathogenic damage of lung tissue by Aspergillus fungi. These clinical entities range from relatively benign saprophytic hypersensitivity associated with fungal inhabitation to life threatening invasive disease. The diagnosis of pulmonary disorders related to Aspergillus is on the increase and it is more important than ever those both general and respiratory physicians have a good understanding of these disorders.

A well-being programme in severe mental illness. Reducing risk for physical ill-health: a post-programme service evaluation at 2 years.

Introduction: Cardiovascular disease is more prevalent in patients with severe mental illness (SMI) than in the general population.

Method: Seven geographically diverse centres were assigned a nurse to monitor the physical health of SMI patients in secondary care over a 2-year period in the "Well-being Support Programme" (WSP). A physical health screen was performed and patients were given individual weight and lifestyle advice including smoking cessation to reduce cardiovascular risk.

John Rickman, Wilfred Ruprecht Bion, and the origins of the therapeutic community.

The history of psychiatric therapeutic communities is complex and obscure. Nevertheless, one can make a reasonable case for saying that the first true therapeutic community was created at Northfield Military Hospital, Birmingham, England, in 1945. That community had its origins in the thought and practice of two British psychoanalysts, John Rickman and Wilfred Ruprecht Bion.

Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all.

The concomitant treatment of HIV-tuberculosis co-infection is complicated by pharmacological interactions between drugs, resulting in unpredictable drug levels. We monitored efavirenz levels in all tuberculosis-HIV-treated patients over 2 years. Using 800 mg/day of efavirenz, high levels and toxicity were detected in seven out of nine patients, necessitating reduction or discontinuation.

The Nramp orthologue of Cryptococcus neoformans is a pH-dependent transporter of manganese, iron, cobalt and nickel.

Cryptococcus neoformans is an important human opportunistic pathogen and a facultative intracellular parasite, particularly in HIV-infected individuals. Little is known about metal ion transport in this organism. C.

Intrathecal production and secretion of vascular endothelial growth factor during Cryptococcal Meningitis.

Background: Patients with cryptococcal meningitis (CM) show elevated intracranial pressure (ICP) and blood-brain barrier (BBB) disruption in most cases. Elevated ICP is an important contributor to mortality. Vascular endothelial growth factor (VEGF) might be the mediator of BBB disruption during CM.

Immunity to hepatitis A in people born and raised in endemic areas.

Background: Hepatitis A is the most common vaccine-preventable disease in international travelers. Many individuals born and raised in hepatitis A endemic areas are likely to be immune to hepatitis A. Unnecessary hepatitis A immunization could be avoided by taking into account prior exposure to hepatitis A and judicious use of serotesting prior to immunization.

Leadership, complexity and the mental health professional. A report on some approaches to leadership training.

Background: Psychiatrists commonly take on a range of leadership roles. These responsibilities are complex because of an environment which is ever-changing, lack of training and competition between disciplines.

Aims: This article outlines some of the issues facing the psychiatrist within the multidisciplinary team and describes a leadership programme initiated in the West Midlands.