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Key Points Cryptococcosis is a widespread opportunistic fungal infection of humans and other animals. Cryptococcus species that infect humans likely evolved as accidental pathogens in response to environmental selective pressure. Recent genomic analyses have highlighted the evolutionary history of Cryptococcus spp. and narrowed down the geographical origin of an unusual, hypervirulent outbreak. Despite being accidental pathogens, cryptococci display a remarkable ability to manipulate the human immune response to facilitate disease establishment and spread. Detailed in vivo and in vitro characterization of Cryptococcus spp. has started to elucidate the details of multiple mechanisms of pathogenesis that probably have important roles in disease severity. These include changes in fungal morphology, interactions with host phagocytes and mechanisms that allow Cryptococcus spp. to disseminate from the lung to the central nervous system. Renewed efforts to develop improved therapeutic approaches have highlighted potential new drugs and new uses for old drugs in the fight against cryptococcal disease. Recent studies have elucidated multiple virulence mechanisms used by Cryptococcus spp. to infect, disseminate within and ultimately kill their human host. In this Review, May et al . describe these recent developments in understanding host–fungal interactions, discuss how they affect disease severity and debate current and future therapeutic interventions against cryptococcosis. Cryptococcosis is a globally distributed invasive fungal infection that is caused by species within the genus Cryptococcus which presents substantial therapeutic challenges. Although natural human-to-human transmission has never been observed, recent work has identified multiple virulence mechanisms that enable cryptococci to infect, disseminate within and ultimately kill their human host. In this Review, we describe these recent discoveries that illustrate the intricacy of host–pathogen interactions and reveal new details about the host immune responses that either help to protect against disease or increase host susceptibility. In addition, we discuss how this improved understanding of both the host and the pathogen informs potential new avenues for therapeutic development.

Liposomal amphotericin B (AmBisome ® ; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients.

Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship.

Online social media networks are an integral part of modern life. Microblogging sites such as Twitter have hundreds of millions of active users globally and have been enthusiastically adopted by many in the medical profession. For advancing a relatively neglected field such as fungal infection, this can be especially advantageous. Education, research networking, case discussions and public and patient engagement can all be greatly enhanced through the use of social media networks. This review highlights the ways in which this can work successfully in the case of aspergillosis and fungal infection in general, as well as highlighting the dangers and pitfalls of social media medicine.

Ethnic and religious minorities have been disproportionately affected by the SARS-CoV-2 pandemic and are less likely to accept coronavirus vaccinations. Orthodox (Haredi) Jewish neighbourhoods in England experienced high incidences of SARS-CoV-2 in 2020–21 and measles outbreaks (2018–19) due to suboptimal childhood vaccination coverage. The objective of our study was to explore how the coronavirus vaccination programme (CVP) was co-delivered between public health services and an Orthodox Jewish health organisation. Methods included 28 semi-structured interviews conducted virtually with public health professionals, community welfare and religious representatives, and household members. We examined CVP delivery from the perspectives of those involved in organising services and vaccine beneficiaries. Interview data was contextualised within debates of the CVP in Orthodox (Haredi) Jewish print and social media. Thematic analysis generated five considerations: i) Prior immunisation-related collaboration with public health services carved a role for Jewish health organisations to host and promote coronavirus vaccination sessions, distribute appointments, and administer vaccines ii) Public health services maintained responsibility for training, logistics, and maintaining vaccination records; iii) The localised approach to service delivery promoted vaccination in a minority with historically suboptimal levels of coverage; iv) Co-delivery promoted trust in the CVP, though a minority of participants maintained concerns around safety; v) Provision of CVP information and stakeholders’ response to situated (context-specific) challenges and concerns. Drawing on this example of CVP co-delivery, we propose that a localised approach to delivering immunisation programmes could address service provision gaps in ways that involve trusted community organisations. Localisation of vaccination services can include communication or implementation strategies, but both approaches involve consideration of investment, engagement and coordination, which are not cost-neutral. Localising vaccination services in collaboration with welfare groups raises opportunities for the on-going CVP and other immunisation programmes, and constitutes an opportunity for ethnic and religious minorities to collaborate in safeguarding community health.

Objective To report the identification and results of susceptibility testing for fungal isolates from the cornea or contact lens care systems. Materials and methods In this retrospective epidemiological study, we searched the results of fungal cultures from cornea or contact lens systems referred for identification and susceptibility testing to the United Kingdom National Mycology Reference Laboratory between October 2016 and March 2022. For each fungal isolate, we recorded the genus and species of the fungus and the minimum inhibitory concentration (MIC) to six antifungal agents available to treat corneal infection (amphotericin, econazole, itraconazole, natamycin, posaconazole, and voriconazole). Results There were 600 isolates from 585 patients, comprising 374 (62%) from corneal samples and 226 from contact lenses and care systems, of which 414 (69%) isolates were moulds (filamentous fungi) and 186 (31%) were yeasts. The most frequent moulds isolated were Fusarium spp (234 isolates, 39%) and Aspergillus spp (62, 10%). The most frequent yeasts isolated were Candida spp (112, 19%), predominantly Candida parapsilosis (65, 11%) and Candida albicans (33, 6%), with 35 isolates (6%) of Meyerozyma guilliermondii . In vitro susceptibility was greatest for natamycin (347 moulds tested, mode 4 mg/L, range 0.25–64 mg/L; 98 yeasts tested, mode 4 mg/L, range 0.5–32 mg/L), with susceptibility for 94% for moulds and 99% yeasts. Of the 16 isolates interpreted as highly resistant to natamycin (MIC ≥16 mg/L), 13 were Aspergillus flavus complex. Conclusions In vitro susceptibility supports the use of natamycin for the empiric treatment of fungal keratitis in the UK.

Although HIV/AIDS has been anything but neglected over the last decade, opportunistic infections (OIs) are increasingly overlooked as large-scale donors shift their focus from acute care to prevention and earlier antiretroviral treatment (ART) initiation. Of these OIs, cryptococcal meningitis, a deadly invasive fungal infection, continues to affect hundreds of thousands of HIV patients with advanced disease each year and is responsible for an estimated 15%–20% of all AIDS-related deaths [1, 2]. Yet cryptococcal meningitis ranks amongst the most poorly funded “neglected” diseases in the world, receiving 0.2% of available relevant research and development (R&D) funding, according to Policy Cures’ 2016 Global Funding of Innovation for Neglected Diseases (G-Finder) Report [3, 4].

[...]high levels of fitness do not protect absolutely against ASCVD, so regardless of fitness level, strong recommendations remain for statin therapy in those with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/100 ml (monogenic or polygenic forms of inherited hypercholesterolemia) and in those adults aged 40 to 75 years with DM and LDL-C ≥70−189 mg/100 ml.1 Traditional ASCVD risk factors, including smoking and hypertension, and risk enhancing factors, including LDL-C ≥160 mg/100 ml, non–high-density lipoprotein cholesterol ≥190 mg/100 ml, elevated lipoprotein(a), family history of premature ASCVD, inflammatory disorders, and South Asian ancestry, are recommended as part of the patient-clinician risk discussion that may be especially pertinent to statin decisions in the high-volume athlete.1 Althoughthe single best test to reclassify risk is the coronary artery calcium (CAC) score, interpretation of CAC scores in the high-volume, high-intensity athlete is not straightforward. A subset analysis of 9,501 women in the Cooper Longitudinal Study did not show a statistically significant risk of prevalent CAC (≥100 AU) with increasing physical activity levels.6 More studies are necessary to evaluate the prevalence and prognostic significance of CAC in female athletes. [...]in asymptomatic high-volume athletes, an elevated CAC score may not correlate with adverse outcomes typically associated with obstructive epicardial coronary disease. [...]clinicians need to understand the benefits of regular exercise and the potential for estimation of CRF to improve the assessment of cardiac risk.

Clinical evaluation of REFs allows an opportunity to quantitatively refine ASCVD risk in a patient-specific fashion that is beyond the purview of the PCE.6 In particular, REFs aid in refining ASCVD risk across the expanse of subjects who fall within the breadth of borderline-to-intermediate risk as determined by the PCE. [...]REFs are an advantageous tool in young patients in whom the PCE underperforms in predicting cardiovascular events. Evaluation of data from 3 large population cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis) showed that individual REFs may predict ASCVD risk independently of the PCE; however, the relative increment in risk of an individual enhancer is limited.6 In contrast, an aggregate of ≥3 REFs conferred sufficient power to predict increases in 10-year ASCVD and exceeded threshold risk levels for initiation of statin therapy.6 Specifically, subjects with ≥3 REFs, irrespective of PCE risk classification, carried a 10-year ASCVD risk of >8%.6 By comparison, subjects identified as having intermediate risk according to the PCE who simultaneously possessed ≥3 REFs carried a 10-year ASCVD risk of close to 13%.7 In this study, aggregate risk-assessment analysis was performed drawing from the 6 REFs independently associated with ASCVD after adjusting for PCE (Family History, Chronic Kidney Disease, ABI, hsCRP >2, ApoB >130 mg/100 ml, Lp(a) >50 mg/100 ml). [...]this tool may be most apt in circumstances of intermediate risk associated with minimal REFs and/or patient reluctance to initiate risk-mitigating strategies.

The log linear association between on-treatment LDL-C levels and ASCVD events is amplified in higher risk patient subgroups of statin versus placebo trials. Update previous systematic review to evaluate how the log linear association influences the magnitude of cardiovascular risk reduction from intensifying LDL-C lowering therapy. MEDLINE/PubMED, Clinical trials.gov, and author files were searched from 1/1/2005 through 10/30/2019 for subgroup analyses of cardiovascular outcomes trials of moderate versus high intensity statin, ezetimibe, and PCSK9 mAbs with an ASCVD endpoint (nonfatal myocardial infarction or stroke, cardiovascular death). Annualized ASCVD event rates were used to extrapolate 5-year ASCVD risk for each treatment group reported in subgroup analyses, which were grouped into a priori risk groups according to annualized placebo/control rates of ≥4%, 3-3.9%, or <3% ASCVD risk. Data were pooled using a random-effects model. Weighted least-squares regression was used to fit linear and log-linear models. Systematic review identified 96 treatment subgroups from 2 trials of moderate versus high intensity statin, 2 trials of a PCSK9 mAb versus placebo, and 1 trial of ezetimibe versus placebo. A log linear association between on-treatment LDL-C and ASCVD risk represents the association between on-treatment LDL-C levels and ASCVD event rates, especially in higher risk subgroups. Greater relative and absolute cardiovascular risk reductions from LDL-C lowering were observed when baseline LDL-C was >100 mg/dl and in extremely high risk ASCVD patient groups. Greater cardiovascular and mortality risk reduction benefits from intensifying LDL-C lowering therapy may be expected in those with LDL-C ≥100 mg/dl, or in extremely high risk patient groups. When baseline LDL-C <100 mg/dl, the log linear association between LDL-C and event rates suggests that treatment options other than further LDL-C lowering should also be considered for optimal risk reduction.