Síle F Molloy

St George's, University of London | SGUL · Centre for Global Health, Institute for Infection and Immunity

Background Cryptococcal meningitis is a leading cause of adult community-acquired meningitis in sub-Saharan Africa with high mortality rates in the first 10 weeks post diagnosis. Practical tools to stratify mortality risk may help to tailor effective treatment strategies. Methods We pooled individual-level data from two randomised-controlled trial...

Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we...

Background Invasive pulmonary aspergillosis is a complication of severe COVID-19, with regional variation in reported incidence and mortality. We describe the incidence, risk factors and mortality associated with COVID-19-associated pulmonary aspergillosis (CAPA) in a prospective, multicentre UK cohort. Methods From March 2020 to March 2021, 266 m...

Background HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and wa...

Infection outcomes for cryptococcosis, most commonly caused by C. neoformans , are influenced by host immune responses as well as by host and pathogen genetics. Infecting yeast isolates are genetically diverse; however, we lack a deep understanding of how this diversity impacts patient outcomes.

S7.1 Update in management of fungal infection in adult hematology, September 23, 2022, 10:30 AM - 12:00 PM Background: Bedside point-of-care (POC) testing, with parallel laboratory testing, represents a unique opportunity to improve and speed up the diagnostic workup of people living with HIV with suspected CNS infection in resource-limited setting...

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM Background: Cryptococcal meningitis (CM) remains a leading cause of HIV-related meningoencephalitis in African low- and middle-income countries (LMICs), causing 15%-20% of HIV-related deaths. Rapid Diagnostic Tests (RDTs) are powerful tools and key to speeding-up the diagnosis at the bedside,...

Cryptococcal antigen (CrAg) is detectable in blood prior to the onset of symptomatic cryptococcal meningitis, a leading cause of death among people living with advanced HIV disease globally. Highly sensitive assays can detect CrAg in blood, and screening people living with HIV with low CD4 counts, followed by pre-emptive antifungal treatment, is re...

Background The commonest causes of mortality in people living with HIV (PLHIV) are preventable and the majority can be attributed to undiagnosed tuberculosis (TB). National HIV/AIDS control programs are encouraged to implement the WHO package of interventions to improve survival among PLHIV. We assessed the implementation of the WHO TB-related pack...

Background Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa. Based on phase-II data, we performed a phase-III randomized controlled non-inferiority trial to determine the efficacy of a single high-dose liposomal amphotericin B based treatment regimen. Methods HIV-positive adults with cryptococcal meningitis...

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using...

Multi-arm, parallel-group clinical trials are an efficient way of testing several new treatments, treatment regimens or doses. However, guidance on the requirement for statistical adjustment to control for multiple comparisons (type I error) using a shared control group is unclear. We argue, based on current evidence, that adjustment is not always...

Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes, accounting for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate; however, our current understanding of how genetic diversity contributes to clinical outcomes is limited....

Background An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) prior to presentation. There is some evidence suggesting an increased two-week mortality in those receiving ART for less than 14 days compared with those on ART for more than 14 days. However, presentation and outco...

Amongst 472 patients with HIV-associated cryptococcal meningitis, 16% had severe visual loss at presentation, of whom 46% of 4-week survivors remained severely impaired. Baseline CSF opening pressure ≥40 cmH20 (aOR 2.56, 95% CI 1.36-4.83, p=0.02) and fungal burden >6.0 log10Colonies/ml (aOR 3.01, 95%CI 1.58-5.7, p= 0.003) were independently associa...

Background: HIV-associated cryptococcal meningitis accounts for 15% of AIDS related deaths globally. In sub-Saharan Africa, acute mortality ranges from 24% to 100%. In addition to the mortality directly associated with cryptococcosis, patients with HIV-associated cryptococcal meningitis are at risk of a range of opportunistic infections (OIs) and h...

Background: HIV-associated cryptococcal meningitis accounts for 15% of AIDS related deaths globally. In sub-Saharan Africa, acute mortality ranges from 24% to 100%. In addition to the mortality directly associated with cryptococcosis, patients with HIV-associated cryptococcal meningitis are at risk of a range of opportunistic infections (OIs) and h...

Background: High cryptococcal antigen (CrAg) titers in blood are associated with subclinical meningitis and mortality in CrAg-positive individuals with advanced HIV-disease (AHD). We evaluated a novel semi-quantitative lateral flow assay (LFA), CryptoPS, that may be able to identify individuals with high CrAg titers in a cohort of AHD patients unde...

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 ter...

Background: Higher cryptococcal antigen (CrAg) titers are strongly associated with mortality risk in individuals with HIV-associated cryptococcal disease. Rapid tests to quantify CrAg level may provide important prognostic information and enable treatment stratification. Methods: We performed a laboratory-based validation of the semi-quantitative I...

Background: Cryptococcal meningitis (CM) is the commonest neurological complication in patients with advanced HIV. Visual disturbance is a frequent presenting symptom. Papilloedema is commonly reported but other ophthalmic findings are not well described. Methods: We performed an observational study comparing severely immunocompromised HIV-infected...

Background. Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different...

In Malawi, 236 participants from the ACTA cryptococcal meningitis treatment trial were followed-up for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericinB plus flucytosine was associated with the lowest 1 year mortality (27.5% [95%CI: 16.3 to 44.1]).

Background: Cryptococcal meningitis (CM) is the commonest neurological complication in patients with advanced HIV. Visual disturbance is a frequent presenting symptom. Papilloedema is commonly reported but other ophthalmic findings are not well described. Methods: We performed an observational study comparing severely immunocompromised HIV-infected...

BACKGROUND: Cryptococcal meningitis (CM) is the commonest neurological complication in patients with advanced HIV. Visual disturbance is a frequent presenting symptom. Papilloedema is commonly reported but other ophthalmic findings are not well described. METHODS: We performed an observational study comparing severely immunocompromised HIV-infected...

Introduction Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to s...

Background DREAMM is an implementation study aiming to reduce meningo-encephalitis related mortality. Delays in diagnosis and treatment through poor access to diagnostics and treatments are significant contributing factors to the ongoing high mortality of HIV-associated central nervous system (CNS) infections, causing up to 25% of all HIV-related d...

Mortality from cryptococcal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment c...

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the ACTA trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2-week amphotericin-based regimens. However, many African settings treat with FLU monotherapy and the cost effectiveness of adding 5FC to FLU is uncertain. METH...

Background: 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 unde...

Background Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dos...

In comparison of 2-weeks amphotericin B (AmB) + flucystosine (5FC), both 1-week AmB+5FC and 2-weeks oral fluconazole (FLU)+5FC are cost-saving; 1-week AmB+5FC is more effective in reducing mortality and somewhat more costly than 2-weeks oral FLU+5FC Abstract Background Mortality from cryptococcal meningitis remains high. The ACTA trial demonstrated...

Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposo...

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and crypto...

: We assessed the effect of fluconazole 1200 mg/day on the QT interval in cryptococcal meningitis patients. Mean corrected QT (QTc) change from baseline to day 7 was 10.1 ms (IQR: -28 to 46 ms) in the fluconazole treatment group and -12.6 ms (IQR: -39 to 13.5 ms) in those not taking fluconazole (P = 0.04). No significant increase in QTc measurement...

Background: Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms-many related to the structure or function of red blood cells-and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respi...

Background: Cryptococcal meningitis (CM) causes 10-20% of HIV-related deaths in Africa. We performed a phase-II non-inferiority trial examining the Early Fungicidal Activity (EFA) of three short-course, high-dose liposomal amphotericin B (L-AmB) regimens for CM in Tanzania and Botswana. Method: HIV-infected adults with CM were randomized to: (i)...

Background Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. Methods We randoml...

Background: Cryptococcal meningitis (CM) is a major cause of AIDS-related mortality in Africa. Detection of serum cryptococcal antigen (CrAg) predicts development of CM in antiretroviral (ART) naïve HIV-infected patients with severe immune depression. Systematic pre-ART CrAg screening and pre-emptive oral fluconazole is thus recommended. We postula...

Cryptococcal meningitis (CM) is the primary cause of meningitis in HIV-infected adults and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3 months) impact of CM (C. neoformans and C. gattii) on mortality and disability in HIV-infe...

Appendix S1 Results. Table S1 Relative contribution of Bioclim layers to the maxent model. Table S2 List of sample used in ITS2 metabarcoding – The two ecoregions investigated were the Zambezi Mopane Woodlands (ZM) and the Miombo Woodlands (MW). Table S3 ANOSIM and permutation manova of microbial diversity patterns across Zambian ecoregions. T...

Single SNP association test results with adjustment for additive effect of G6PD+202.DOI: http://dx.doi.org/10.7554/eLife.15085.007

G6PDd score association test results.DOI: http://dx.doi.org/10.7554/eLife.15085.015

(A) Summary of study designs of contributing partner studies to MalariaGEN Consortial Project 1 (CP1). (B) Genotyped sample distribution. (C) Summary of 65 SNPs selected for analysis and successfully genotyped. (D) G6PD+202 female association test results. (E) G6PD+202 male association test results. (F) G6PD+202 all individuals association test res...

(A) SNP selection across G6PD region for genotyping. (B) SpectroDESIGNER assay design file for 135 G6PD locus SNPs in four multiplexes. (C) SpectroDESIGNER assay design file for 107 G6PD locus SNPs in four multiplexes. (D) SpectroDESIGNER assay design file for 68 G6PD locus SNPs in three multiplexes. DOI: http://dx.doi.org/10.7554/eLife.15085.020

Single SNP association test results.DOI: http://dx.doi.org/10.7554/eLife.15085.006

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outco...

HIV-associated cryptococcal meningitis is by far the most common cause of adult meningitis in many areas of the world that have high HIV seroprevalence. In most areas in Sub-Saharan Africa, the incidence of cryptococcal meningitis is not decreasing despite availability of antiretroviral therapy, because of issues of adherence and retention in HIV c...

Emerging infections caused by fungi have become a widely recognised global phenomenon and are causing an increasing burden of disease. Genomic techniques are providing into new insights into the structure of fungal populations, revealing hitherto undescribed fine-scale adaptations to environments and hosts that govern their emergence as infections....

This paper describes the processes and procedures involved in planning, conducting and reporting monitoring activities for large clinical trials of investigational medicinal products, focusing on those conducted in resource-limited settings. This article is protected by copyright. All rights reserved.

The high prevalence of sickle haemoglobin in Africa shows that malaria has been a major force for human evolutionary selection, but surprisingly few other polymorphisms have been proven to confer resistance to malaria in large epidemiological studies. To address this problem, we conducted a multi-centre genome-wide association study (GWAS) of life-...

Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites a...

Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-...

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. T...

HIV-associated cryptococcal meningoencephalitis (CM) is a leading cause of adult meningitis in sub-Saharan Africa. Neuroradiological data is however limited to case reports and small case series from developed countries and/or immunocompetent patients. Eighty seven patients aged ≥18 hospitalized with a first episode of CM had magnetic resonance (MR...

Background Malaria is a major cause of morbidity and mortality worldwide with over one million deaths annually, particularly in children under five years. This study was the first to examine plasma cytokines, chemokines and cellular immune responses in pre-school Nigerian children infected with Plasmodium falciparum from four semi-urban villages ne...

Sample of gating strategy for T Cells. Shown is a PBMC sample stimulated with 50 ng/ml PMA and 1 mg/ml ionomycin for 4 h in the presence of BFA (10 mg/ml). Cell subsets were identified as CD3 cells and then analysed for expression of cytokines and markers γδcells.

The average age, cytokine, nitric oxide (NO), RANTES, metalloproteinase (MMP) type 8 and tissue inhibitor of metalloproteinase (TIMP) type 1 plasma concentrations from the study cohort classified according to P falciparum parasitaemia.

The average age, parasitemia, cytokine, nitric oxide (NO), RANTES, metalloproteinase (MMP) type 8 and tissue inhibitor of metalloproteinase (TIMP) type 1 plasma concentrations from the study cohort classified according in infection status (uninfected, Ascaris only, malaria only, Ascaris and malaria.

Background Co-infection with malaria and intestinal parasites such as Ascaris lumbricoides is common. Malaria parasites induce a pro-inflammatory immune response that contributes to the pathogenic sequelae, such as malarial anaemia, that occur in malaria infection. Ascaris is known to create an anti-inflammatory immune environment which could, in t...

A cross-sectional study was conducted to investigate risk factors for sporadic Cryptosporidium infection in a paediatric population in Nigeria. Of 692 children, 134 (19·4%) were infected with Cryptosporidium oocysts. Cryptosporidium spp. were identified in 49 positive samples using PCR-restriction fragment length polymorphism and direct sequencing...

Dendritic cells (DCs) matured with helminth-derived molecules that promote Th2 immune responses do not follow conventional definitions of DC maturation processes. While a number of models of DC maturation by Th2 stimuli are postulated, further studies are required if we are to clearly define DC maturation processes that lead to Th2 immune responses...

Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on Plasmodium infections in preschool children. A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on Plasmodium infection in children aged 12-59 months. Ch...

A longitudinal study was conducted to determine the epidemiology of Cryptosporidium in 1,636 children in Nigeria. Oocyst prevalence ranged from 15.6% to 19.6% over one year. Cryptosporidium hominis (34), C. parvum (25), C. parvum/C. hominis (4), C. meleagridis (5), Cryptosporidium rabbit genotype (5), Cryptosporidium cervine genotype (3), and C. ca...

Chemical cues can assist intraspecific communication associated with sexual behavior, territoriality, and home-site philopatry. We tested experimentally the influence of chemical cues on the behavior of male Common Musk Turtles (Sternotherus odoratus). In laboratory-controlled choice boxes, we video recorded the location of turtles moving between t...

Children aged between one and five years are particularly vulnerable to disease caused by soil-transmitted helminths (STH). Periodic deworming has been shown to improve growth, micronutrient status (iron and vitamin A), and motor and language development in preschool children and justifies the inclusion of this age group in deworming programmes. Ou...