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. This article introduces a new four-component measure of cyber-wisdom, which is relevant to how the virtue may be cultivated in practice via formal education and the teaching of what is generally referred to as digital citizenship education. The measure was piloted with 1,331 13-16 year-olds. The findings provide initial evidence that cyber-wisdom literacy, reasoning, reflection, and motivation can be measured. This study provides preliminary validation of cyber-wisdom sub-measures that might be used in evaluations of educational interventions that seek to help children and adolescents live with wisdom in the digital age.

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. In addition, we quantified the extent and variability of CSF partitioning of flucytosine. METHODS: A PK study was conducted in 64 patients with confirmed HIV-associated cryptococcal meningoencephalitis in Blantyre, Malawi. A four-compartment PK model was developed, and Monte Carlo simulations were performed with flucytosine administered at different doses and in different schedules. RESULTS: The estimated mean apparent volume of the central compartment was 17.50 (SD 9.99) L; mean apparent clearance was 5.88 (SD 3.35) L/h; mean apparent volume of the CNS compartment was 41.73 (SD 13.66) L. From the Bayesian posterior estimates, AUC24 values at steady state (144-168 h) with doses of 25 mg/kg q6h were median (IQR) 890.38 (603.81-1213.70) mg.h/L in plasma and 595.66 (425.69-776.64) mg.h/L in CSF. The ratio of CSF:plasma AUC24 was 0.69 (IQR 0.58-0.82). CONCLUSIONS: This study revealed significant interindividual variability in flucytosine PK in plasma and CSF in patients with HIV-associated cryptococcal meningoencephalitis. The population PK model is a first critical step for revised flucytosine regimens that maximize fungal killing and minimize toxicity and the emergence of resistance.

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 G2/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 conversion of AZD1775 into a PROTAC induces selective Wee1 degradation for compounds of both series depending on the nature of the linker.

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. As a result, we propose a framework for conceptualising what we call cyber-wisdom, and how this can be cultivated via formal education, in ways that are grounded in neo-Aristotelian virtue ethics and that build on three prominent existing models of wisdom. The framework, according to which cyber-wisdom is crucial to navigating online risks and opportunities through the deployment of character virtues necessary for flourishing online, suggests that cyber-wisdom consists of four components: cyber-wisdom literacy, cyber-wisdom reasoning, cyber-wisdom self-reflection, cyber-wisdom motivation. Unlike the models on which it builds, the framework accounts for the specificity of the digital age and is both conceptual and practical. On the one hand, each component has conceptual implications for what it means to be wise in the digital age. On the other hand, informed by character education literature and practice, it has practical implications for how to cultivate cyber-wisdom in the classroom through teaching methods that match its different components.

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. OBJECTIVE: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. METHODS: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. RESULTS: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the 3 patients with Candida albicans-induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans-induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C albicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). CONCLUSION: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

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. These four fungal pathogens are major causes of illness and death in people with advanced HIV and overwhelmingly affect those in low-income and middle-income countries. Access to diagnostics, improved surveillance, targeted support for innovation, and an enhanced public health focus on these diseases are needed in the effort to reduce HIV-associated deaths.

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). Cases were categorised as either TB meningitis (TBM) or TB mass lesions without meningitis (TBML), applying novel criteria for definite, probable, and possible TBML. RESULTS: We identified sixty-two cases of TBM (37% definite; 31% probable; 32% possible) alongside 14 TBML cases (36% definite; 29% probable; and 36% possible). Clinical presentation was highly variable. Among CSF parameters, hypoglycorrhachia proved most discriminatory for "definite" TBM. Neurosurgical intervention was required for mass-effect or hydrocephalus in 16%. Mortality was higher in TBM versus TBML (16% vs. 0%) but overall morbidity was significant; 33% of TBM and 29% of TBML survivors suffered persisting neurological disability at 12-months. In TBM, hydrocephalus, infarct, basal enhancement and low CSF white cell count were independently associated with worse neurological outcomes. CONCLUSION: Although mortality was lower than previously reported in other settings, morbidity was significant, highlighting the need for improved CNS-TB diagnostics, therapeutics and interventions to mitigate neurological sequelae.

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. RESULTS: The estimated cost of treatment per patient had mean (sd) of £27,236 (4952) for the observed injectable group, £30,264 (3392) and 36,309 (3901) for the 6 and 8 month amikacin groups, and £31,760 (2092) for the bedaquiline group. The cost in the bedaquiline group was £30,772 (1855) with a 10% reduction and £27,079 (1234) with a 33% reduction in-patient stay. CONCLUSIONS: In most scenarios, bedaquiline is close to cost neutral compared with injectable therapy, especially if, as expected, some reduction in duration of admission is possible as a result of bedaquiline's more rapid culture conversion.

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. RESULTS: Nine hundred and sixty-six outpatients with SMI >2 years were enrolled. The completion rate at 2 years was 80%. Significant improvements were observed in levels of physical activity (p<0.0001), smoking (p<0.05) and diet (p<0.0001). There were no changes in mean BMI although 42% lost weight over 2 years. Self-esteem improved significantly. Low self-esteem decreased from 43% at baseline to 15% at 2 years (p<0.0001). At the end of the programme significant cardiovascular risk factors remained, 46% of subjects smoked, 26% had hypertension and 81% had BMI >25. CONCLUSION: Physical health problems are common in SMI subjects. Many patients completed 2 years follow up suggesting that this format of programme is an acceptable option for SMI patients. Cardiovascular risk factors were significantly improved. Interventions such as the Well-being Support Programme should be made widely available to people with SMI.

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. Accordingly, in the present article their careers and the social and intellectual influences bearing on them are discussed. The article then continues by describing Rickman's work as a military psychiatrist, Bion's prototype of a therapeutic community, and the therapeutic community that was eventually created at Northfield. It is hoped that the article will provide some of the groundwork for an adequate history of the therapeutic community.

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. neoformans encodes a single member of the Nramp (natural resistance-associated macrophage protein) family of bivalent cation transporters, known as Cramp, which we have cloned and expressed in Xenopus laevis oocytes and Spodoptera frugiperda Sf 21 insect cells. Cramp induces saturable transport of a broad range of bivalent transition series cations, including Mn2+, Fe2+, Co2+ and Ni2+. Maximal cation transport occurs at pH 5.5-6.0, consistent with the proton gradient-based energetics of other Nramp orthologues. Mn2+ transport is diminished in the presence of 140 mM Na+, compatible with a Na+ slippage mechanism proposed for the Saccharomyces cerevisiae Nramp orthologue Smf1p. Cramp resembles Smf1p with respect to predicted membrane topology, substrate specificity and pH dependence, but differs in terms of its apparent affinity for Mn2+ and negligible inhibition by Zn2+. Cramp is the first Nramp orthologue from a fungal pathogen to be functionally characterized. Insights afforded by these findings will allow the formulation of new hypotheses regarding the role of metal ions in the pathophysiology of cryptococcosis.

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. All isolates of Mycobacterium tuberculosis (Mtb) were assessed early using whole genome sequencing (WGS) as well as routine drug susceptibility testing (DST). RESULTS: Thirty-three contacts were screened. In the first year one confirmed and one probable case were identified through contact tracing. A further possible case was identified through epidemiological links. Two confirmed cases were identified through WGS 2 years later. Twenty-five (80%) contacts without evidence of tuberculosis were adherent to 1 year of follow-up and 14 (45%) were adherent to 2 years of follow-up. WGS of Mtb was used to guide drug choices, rapidly identify transmission events, and alter public health management. CONCLUSION: WGS of Mtb enabled rapid effective individualized treatment and facilitated public health interventions by early identification of transmission events.

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. Polymorphisms in cytochrome P450 2B6 may account for this. Therapeutic drug monitoring, dose reduction or a lower starting dose may be appropriate in some patients to abrogate toxicity.

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. METHODS: Patients born and raised in countries of high prevalence of hepatitis A who were seen for pretravel consultation and who had hepatitis antibody measured were eligible. Data were collected about country of birth and length of residence there before emigration, length of time till departure on current trip, current age, and hepatitis A antibody result. RESULTS: Patients ranged from 12 to 74 years of age and were from 27 countries. Their pretravel visit occurred from 4 to more than 90 days prior to departure. Ninety-five percent (122 of 129) of patients were immune to hepatitis A, including 100% (83 of 83) of those who resided in their country of origin until at least aged 20. Most patients were seen for pretravel consultation less than 28 days prior to departure. CONCLUSION: Individuals born and raised until aged 20 in hepatitis A endemic countries are likely to be immune to hepatitis A. Serotesting is most helpful in assessing immunity to hepatitis A in those under 20 years of age.

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.

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. This paper reviews the contemporary understanding of the clinical, radiographic and histopathological aspects of pulmonary aspergillosis.

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. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. RESULTS: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score <14 of 15), moderate/severe neurological disability (modified Rankin Score >3 of 5) and confusion (Abbreviated Mental Test Score <8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. CONCLUSIONS: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit.

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. METHOD: A programme of in-house leadership training and increased delegation of leadership roles within one NHS Trust. RESULTS: These initiatives have been favourably received; but it is recognised that the approach can be further developed. CONCLUSION: This basic strategy should be enhanced and delivered more widely.

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. METHODS: We measured VEGF levels in serum, plasma, and cerebrospinal fluid (CSF) of 95 patients and 63 control subjects, and we analyzed the required trigger and cellular source of VEGF secretion in vitro. RESULTS: Cryptococcus neoformans and its capsular antigens dose-dependently induced VEGF secretion by polymorphonuclear neutrophils, monocytes, and peripheral blood mononuclear cells (PBMCs). VEGF production by PBMCs induced by antigens strongly exceeded production by monocytes (P<.001). The addition of major histocompatibility complex class II antibody inhibited this production of VEGF (P=.005). Confirming the in vitro data, patients with CM showed significantly elevated VEGF levels in CSF (P<.001), plasma (P=.028), and serum (P<.001), compared with healthy control subjects. Calculated VEGF indices demonstrated that VEGF was produced intrathecally. CONCLUSIONS: Our findings suggest that VEGF plays a role in the pathophysiology of CM. We propose that CD4(+) T lymphocytes--stimulated by monocytes acting as antigen-presenting cells--are the cells that produce VEGF in response to cryptococcal antigens.