Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomised, placebo-controlled trial.

BACKGROUND: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use. METHODS AND FINDINGS: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507. INTERPRETATION: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947.

Development and implementation of a core genome multilocus sequence typing scheme for Haemophilus influenzae.

Haemophilus influenzae is part of the human nasopharyngeal microbiota and a pathogen causing invasive disease. The extensive genetic diversity observed in H. influenzae necessitates discriminatory analytical approaches to evaluate its population structure. This study developed a core genome multilocus sequence typing (cgMLST) scheme for H. influenzae using pangenome analysis tools and validated the cgMLST scheme using datasets consisting of complete reference genomes (N = 14) and high-quality draft H. influenzae genomes (N = 2297). The draft genome dataset was divided into a development dataset (N = 921) and a validation dataset (N = 1376). The development dataset was used to identify potential core genes, and the validation dataset was used to refine the final core gene list to ensure the reliability of the proposed cgMLST scheme. Functional classifications were made for all the resulting core genes. Phylogenetic analyses were performed using both allelic profiles and nucleotide sequence alignments of the core genome to test congruence, as assessed by Spearman's correlation and ordinary least square linear regression tests. Preliminary analyses using the development dataset identified 1067 core genes, which were refined to 1037 with the validation dataset. More than 70% of core genes were predicted to encode proteins essential for metabolism or genetic information processing. Phylogenetic and statistical analyses indicated that the core genome allelic profile accurately represented phylogenetic relatedness among the isolates (R 2 = 0.945). We used this cgMLST scheme to define a high-resolution population structure for H. influenzae, which enhances the genomic analysis of this clinically relevant human pathogen.

WHO global research priorities for antimicrobial resistance in human health.

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR.

Immunogenicity of Abdala COVID-19 vaccine in Vietnamese people after primary and booster vaccinations: A prospective observational study in Vietnam.

OBJECTIVES: We studied the immunogenicity after primary and booster vaccinations of the Abdala COVID-19 vaccine, a receptor-binding domain protein subunit vaccine, in Vietnamese people by determining the level of neutralization and cross-neutralization activities against the ancestral SARS-CoV-2 and its variants and SARS-CoV-1. METHODS: We performed a prospective observational study, enrolling adults aged 19-59 years in Dong Thap province, southern Vietnam, and collected blood samples from baseline until 4 weeks after the booster dose. We measured anti-nucleocapsid, anti-spike, and neutralizing antibodies against SARS-CoV-2 and assessed the cross-neutralization against 14 SARS-CoV-2 variants and SARS-CoV-1. Complementary antibody data came from Vietnamese health care workers fully vaccinated with ChAdOx1-S. RESULTS: After primary vaccination, anti-spike antibody and neutralizing antibodies were detectable in 98.4% and 87% of 251 study participants, respectively, with neutralizing antibody titers similar to that induced by ChAdOx1-S vaccine. Antibody responses after a homologous (Abdala COVID-19) or heterologous (messenger RNA BNT162b2) booster could neutralize 14 SARS-CoV-2 variants (including Omicron) and SARS-CoV-1. CONCLUSIONS: Abdala COVID-19 vaccine is immunogenic in Vietnamese people. Enhanced antibody response after a booster dose could cross-neutralize 14 SARS-CoV-2 variants and SARS-CoV-1. Our results have added to the growing body of knowledge about the contribution of protein subunit vaccine platforms to pandemic control.

Anti-SARS-CoV-2 antibody dynamics after primary vaccination with two-dose inactivated whole-virus vaccine, heterologous mRNA-1273 vaccine booster, and Omicron breakthrough infection in Indonesian health care workers.

BACKGROUND: Data on the dynamics and persistence of humoral immunity against SARS-CoV-2 after primary vaccination with two-dose inactivated vaccine (CoronaVac) are limited. This study evaluated the sequential effects of prior infection, heterologous boosting with mRNA-1273 (Moderna), and the occurrence of Omicron vaccine-breakthrough infection (VBI) thereafter. METHODS: We evaluated anti-spike IgG (Abbott) and neutralising (cPASS/GenScript) antibody (nAb) titers up to one year after mRNA-1273 boost in two-dose-CoronaVac-primed Indonesian healthcare workers (August 2021-August 2022). We used linear mixed modeling to estimate the rate of change in antibody levels, and logistic regression to examine associations between antibody levels and VBI. RESULTS: Of 138 participants, 52 (37.7%) had a prior infection and 78 (56.5%) received an mRNA-1273 booster. After two-dose CoronaVac, antibody titers had significantly declined within 180 days, irrespective of prior infection. After mRNA-1273 booster, anti-spike IgG (1.47% decline/day) and Omicron B.1.1.529/BA.2 nAbs declined between day 28-90, and IgG titers plateaued between day 90-360. During the BA.1/BA.2 wave (February-March 2022), 34.6% (27/78) of individuals experienced a VBI (median 181 days after mRNA-1273), although none developed severe illness. VBI was associated with low pre-VBI anti-spike IgG and B.1.1.529/BA.2 nAbs, which were restored post-VBI. CONCLUSIONS: mRNA-1273 booster after two-dose CoronaVac did not prevent BA.1/BA.2 VBI. Periodic vaccine boosters may be warranted against emerging SARS-CoV-2 variants.

Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium.

A strong and effective COVID-19 and future pandemic responses rely on global efforts to carry out surveillance of infections and emerging SARS-CoV-2 variants and to act accordingly in real time. Many countries in Southeast Asia lack capacity to determine the potential threat of new variants, or other emerging infections. Funded by Wellcome, the Southeast Asia initiative to combat SARS-CoV-2 variants (SEACOVARIANTS) consortium aims to develop and apply a multidisciplinary research platform in Southeast Asia (SEA) for rapid assessment of the biological significance of SARS-CoV-2 variants, thereby informing coordinated local, regional and global responses to the COVID-19 pandemic. Our proposal is delivered by the Vietnam and Thailand Wellcome Africa Asia Programmes, bringing together a multidisciplinary team in Indonesia, Thailand and Vietnam with partners in Singapore, the UK and the USA. Herein we outline five work packages to deliver strengthened regional scientific capacity that can be rapidly deployed for future outbreak responses.

Our project strengthens local scientific capacity in South East Asia (SEA) and therefore enables the rapid assessment of SARS-CoV-2 variants as they emerge within the region. While COVID-19 remains a global pandemic, future emerging infections caused by a novel virus is an inevitable event, with SEA being a global hot-spot for pathogen emergence. Consequently, the research capacity built, the scientists trained and the research network formed as part of this project will lay the foundation for future locally-led outbreak responses. Our project will demonstrate that novel research platforms can be set up in other low and middle income countries to address the unprecedented challenges presented by emerging infections.

Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.

Fusarium species,Scedosporium species, and Lomentospora prolificans: A systematic review to inform the World Health Organization priority list of fungal pathogens.

Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of infections caused by Fusarium spp., Scedosporium spp., and Lomentospora prolificans to inform the first FPPL. PubMed and Web of Sciences databases were searched to identify studies published between January 1, 2011 and February 23, 2021, reporting on mortality, complications and sequelae, antifungal susceptibility, preventability, annual incidence, and trends. Overall, 20, 11, and 9 articles were included for Fusarium spp., Scedosporium spp., and L. prolificans, respectively. Mortality rates were high in those with invasive fusariosis, scedosporiosis, and lomentosporiosis (42.9%-66.7%, 42.4%-46.9%, and 50.0%-71.4%, respectively). Antifungal susceptibility data, based on small isolate numbers, showed high minimum inhibitory concentrations (MIC)/minimum effective concentrations for most currently available antifungal agents. The median/mode MIC for itraconazole and isavuconazole were ≥16 mg/l for all three pathogens. Based on limited data, these fungi are emerging. Invasive fusariosis increased from 0.08 cases/100 000 admissions to 0.22 cases/100 000 admissions over the time periods of 2000-2009 and 2010-2015, respectively, and in lung transplant recipients, Scedosporium spp. and L. prolificans were only detected from 2014 onwards. Global surveillance to better delineate antifungal susceptibility, risk factors, sequelae, and outcomes is required.

Social cohesion among healthcare workers during COVID-19: Qualitative research in Indonesia, Nepal, and Vietnam.

Existing literature has portrayed numerous challenges that healthcare workers (HCWs) faced during the COVID-19 pandemic, such as heightened risks of transmission against the scarcity of protective equipment, burgeoning workload, and emotional distress, to name a few. However, most studies explored HCWs' experiences at the individual level rather than examining the collective responses. Exploring these experiences could reveal the social-cultural locality of the pandemic while identifying the system constraints in public health emergencies. As part of a mixed-method study on COVID-19 pandemic impacts, we analysed qualitative interview data with 129 HCWs and health-related staff to explore their experiences during the pandemic between 2020 and 2021 in Vietnam, Indonesia, and Nepal. Using Bahers' sociological framework, Community of Fate, we describe five themes reflecting the formation of a community of HCWs and the social cohesion underlying their efforts to survive hardship. The first three themes characterise the HCW community of fate, including (1) Recognition of extreme work-related danger, (2) physical and figurative closures where HCWs restrict themselves from the outside world, (3) chronic ordeals with overwhelming workload and responsibilities, encompassing recurrent mental health challenges. Against such extreme hardship, cohesive bonding and social resilience are reflected through two additional themes: (4) a mutual sense of moral and professional duty to protect communities, (5) the vertical and horizontal convergence among HCWs across levels and among government departments. We discuss these HCWs' challenges in relation to systemic vulnerabilities while advocating for increasing investment in public health and collaboration across government sectors to prepare for emergency situations.

Antimicrobial resistance among common bacterial pathogens in Indonesia: a systematic review.

Background: The WHO Global Antimicrobial Resistance Surveillance System (GLASS) aims to describe antimicrobial resistance (AMR) patterns and trends in common bacterial pathogens, but data remain limited in many low and middle-income countries including Indonesia. Methods: We systematically searched Embase, PubMed and Global Health Database and three Indonesian databases for original peer-reviewed articles in English and Indonesian, published between January 1, 2000 and May 25, 2023, that reported antimicrobial susceptibility for the 12 GLASS target pathogens from human samples. Pooled AMR prevalence estimates were calculated for relevant pathogen-antimicrobial combinations accounting for the sampling weights of the studies (PROSPERO: CRD42019155379). Findings: Of 2182 search hits, we included 102 papers, comprising 19,517 bacterial isolates from hospitals (13,647) and communities (5870). In hospital settings, 21.6% of Klebsiella pneumoniae isolates, 18.3% of Escherichia coli isolates, 35.8% of Pseudomonas aeruginosa isolates and 70.7% of Acinetobacter baumannii isolates were carbapenem-resistant; 29.9% of Streptococcus pneumoniae isolates were penicillin-resistant; and 22.2% of Staphylococcus aureus isolates were methicillin-resistant. Hospital prevalence of carbapenem-resistant K. pneumoniae and E. coli, and penicillin-resistant S. pneumoniae increased over time. In communities, 28.3% of K. pneumoniae isolates and 15.7% of E. coli isolates were carbapenem-resistant, 23.9% of S. pneumoniae isolates were penicillin-resistant, and 11.1% of S. aureus isolates were methicillin-resistant. Data were limited for the other pathogens. Interpretation: AMR prevalence estimates were high for critical gram-negative bacteria. However, data were insufficient to draw robust conclusions about the full contemporary AMR situation in Indonesia. Implementation of national AMR surveillance is a priority to address these gaps and inform context-specific interventions. Funding: Wellcome Africa Asia Programme Vietnam.

Diagnostic and antibiotic use practices among COVID-19 and non-COVID-19 patients in the Indonesian National Referral Hospital.

BACKGROUND: Little is known about diagnostic and antibiotic use practices in low and middle-income countries (LMICs) before and during COVID-19 pandemic. This information is crucial for monitoring and evaluation of diagnostic and antimicrobial stewardships in healthcare facilities. METHODS: We linked and analyzed routine databases of hospital admission, microbiology laboratory and drug dispensing of Indonesian National Referral Hospital from 2019 to 2020. Patients were classified as COVID-19 cases if their SARS-CoV-2 RT-PCR result were positive. Blood culture (BC) practices and time to discontinuation of parenteral antibiotics among inpatients who received a parenteral antibiotic for at least four consecutive days were used to assess diagnostic and antibiotic use practices, respectively. Fine and Grey subdistribution hazard model was used. RESULTS: Of 1,311 COVID-19 and 58,917 non-COVID-19 inpatients, 333 (25.4%) and 18,837 (32.0%) received a parenteral antibiotic for at least four consecutive days. Proportion of patients having BC taken within ±1 calendar day of parenteral antibiotics being started was higher in COVID-19 than in non-COVID-19 patients (21.0% [70/333] vs. 18.7% [3,529/18,837]; p<0.001). Cumulative incidence of having a BC taken within 28 days was higher in COVID-19 than in non-COVID-19 patients (44.7% [149/333] vs. 33.2% [6,254/18,837]; adjusted subdistribution-hazard ratio [aSHR] 1.71, 95% confidence interval [CI] 1.47-1.99, p<0.001). The median time to discontinuation of parenteral antibiotics was longer in COVID-19 than in non-COVID-19 patients (13 days vs. 8 days; aSHR 0.73, 95%Cl 0.65-0.83, p<0.001). CONCLUSIONS: Routine electronic data could be used to inform diagnostic and antibiotic use practices in LMICs. In Indonesia, the proportion of timely blood culture is low in both COVID-19 and non-COVID-19 patients, and duration of parenteral antibiotics is longer in COVID-19 patients. Improving diagnostic and antimicrobial stewardship is critically needed.

Characteristics and clinical outcomes of patients with pre-delta, delta and omicron SARS-CoV-2 infection in Indonesia (2020-2023): a multicentre prospective cohort study.

Background: Limited data exist from southeast Asia on the impact of SARS-CoV-2 variants and inactivated vaccines on disease severity and death among patients hospitalised with COVID-19. Methods: A multicentre hospital-based prospective cohort was enrolled from September 2020 through January 2023, spanning pre-delta, delta, and omicron periods. The participant hospitals were conveniently sampled based on existing collaborations, site willingness and available study resources, and included six urban and two rural general hospitals from East Nusa Tenggara, Jakarta, and North Sumatra provinces. Factors associated with severe disease and day-28 mortality were examined using logistic and Cox regression. Findings: Among 822 participants, the age-adjusted percentage of severe disease was 26.8% (95% CI 22.7-30.9) for pre-delta, 50.1% (44.0-56.2) for delta, and 15.2% (9.7-20.7) for omicron. The odds of severe disease were 64% (18-84%) lower for omicron than delta (p < 0.001). One or more vaccine doses reduced the odds of severe disease by 89% (65-97%) for delta and 98% (91-100%) for omicron. Age-adjusted mortality was 11.9% (8.8-15.0) for pre-delta, 24.4% (18.8-29.9) for delta and 9.6% (5.2-14.0) for omicron. The day-28 cumulative incidence of death was lower for omicron (9.2% [5.6-13.9%]) than delta (28.6% [22.0-35.5%]) (p < 0.001). Severe disease on admission was the predominant prognostic factor for death (aHR34.0 [16.6-69.9] vs mild-or-moderate; p < 0.001). After controlling for disease severity on admission as an intermediate, the risk of death was 48% (32-60%) lower for omicron than delta (p < 0.001); and 51% (38-61%; p < 0.001) lower for vaccinated participants than unvaccinated participants overall, and 56% (37-69%; p < 0.001) for omicron, 46% (-5 to 73%; p = 0.070) for pre-delta (not estimable for delta). Interpretation: Infections by omicron variant resulted in less severe and fatal outcomes than delta in hospitalised patients in Indonesia. However, older, and unvaccinated individuals remained at greater risk of adverse outcomes. Funding: University of Oxford and Wellcome Trust.

Specific plasma microRNAs are associated with CD4 + T-cell recovery during suppressive antiretroviral therapy for HIV-1.

OBJECTIVE: This study investigated the association of plasma microRNAs before and during antiretroviral therapy (ART) with poor CD4 + T-cell recovery during the first year of ART. DESIGN: MicroRNAs were retrospectively measured in stored plasma samples from people with HIV (PWH) in sub-Saharan Africa who were enrolled in a longitudinal multicountry cohort and who had plasma viral-load less than 50 copies/ml after 12 months of ART. METHODS: First, the levels of 179 microRNAs were screened in a subset of participants from the lowest and highest tertiles of CD4 + T-cell recovery (ΔCD4) ( N  = 12 each). Next, 11 discordant microRNAs, were validated in 113 participants (lowest tertile ΔCD4: n  = 61, highest tertile ΔCD4: n  = 52). For discordant microRNAs in the validation, a pathway analysis was conducted. Lastly, we compared microRNA levels of PWH to HIV-negative controls. RESULTS: Poor CD4 + T-cell recovery was associated with higher levels of hsa-miR-199a-3p and hsa-miR-200c-3p before ART, and of hsa-miR-17-5p and hsa-miR-501-3p during ART. Signaling by VEGF and MET, and RNA polymerase II transcription pathways were identified as possible targets of hsa-miR-199a-3p, hsa-200c-3p, and hsa-miR-17-5p. Compared with HIV-negative controls, we observed lower hsa-miR-326, hsa-miR-497-5p, and hsa-miR-501-3p levels before and during ART in all PWH, and higher hsa-miR-199a-3p and hsa-miR-200c-3p levels before ART in all PWH, and during ART in PWH with poor CD4 + T-cell recovery only. CONCLUSION: These findings add to the understanding of pathways involved in persistent HIV-induced immune dysregulation during suppressive ART.

Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Barriers and enablers to blood culture sampling in Indonesia, Thailand and Viet Nam: a Theoretical Domains Framework-based survey.

OBJECTIVE: Blood culture (BC) sampling is recommended for all suspected sepsis patients prior to antibiotic administration. We examine barriers and enablers to BC sampling in three Southeast Asian countries. DESIGN: A Theoretical Domains Framework (TDF)-based survey, comprising a case scenario of a patient presenting with community-acquired sepsis and all 14 TDF domains of barriers/enablers to BC sampling. SETTING: Hospitals in Indonesia, Thailand and Viet Nam, December 2021 to 30 April 2022. PARTICIPANTS: 1070 medical doctors and 238 final-year medical students were participated in this study. Half of the respondents were women (n=680, 52%) and most worked in governmental hospitals (n=980, 75.4%). OUTCOME MEASURES: Barriers and enablers to BC sampling. RESULTS: The proportion of respondents who answered that they would definitely take BC in the case scenario was highest at 89.8% (273/304) in Thailand, followed by 50.5% (252/499) in Viet Nam and 31.3% (157/501) in Indonesia (p<0.001). Barriers/enablers in nine TDF domains were considered key in influencing BC sampling, including 'priority of BC (TDF-goals)', 'perception about their role to order or initiate an order for BC (TDF-social professional role and identity)', 'perception that BC is helpful (TDF-beliefs about consequences)', 'intention to follow guidelines (TDF-intention)', 'awareness of guidelines (TDF-knowledge)', 'norms of BC sampling (TDF-social influence)', 'consequences that discourage BC sampling (TDF-reinforcement)', 'perceived cost-effectiveness of BC (TDF-environmental context and resources)' and 'regulation on cost reimbursement (TDF-behavioural regulation)'. There was substantial heterogeneity between the countries. In most domains, the lower (higher) proportion of Thai respondents experienced the barriers (enablers) compared with that of Indonesian and Vietnamese respondents. A range of suggested intervention types and policy options was identified. CONCLUSIONS: Barriers and enablers to BC sampling are varied and heterogenous. Cost-related barriers are more common in more resource-limited countries, while many barriers are not directly related to cost. Context-specific multifaceted interventions at both hospital and policy levels are required to improve diagnostic stewardship practices.

Teledermatology to Improve Access to and Quality of Skin Care in Eastern Indonesia.

Skin diseases are a major public health concern in Indonesia, although access to specialized care in remote areas is limited. We initiated a low-cost teledermatology service in Sumba, a remote island in eastern Indonesia. Eighteen healthcare workers (HCWs) at five primary healthcare centers received training to manage common skin diseases and submit clinical cases beyond their expertise to an online platform. Submitted cases were reviewed by at least one dermatologist. Diagnostic agreement between HCWs and dermatologists was calculated. The HCWs participated in a satisfaction survey 2 years after project initiation. Since October 2020, of 10,384 patients presenting with skin complaints in a 24-month period, 307 (3%) were submitted for a teledermatology consultation. The most frequent skin diseases were infections and infestations (n = 162, 52.8%) and eczematous (85, 27.7%) and inflammatory (17, 5.5%) conditions. Fifty-three patients (17.3%) were diagnosed with a neglected tropical skin disease, including leprosy and scabies. Dermatologist advice was provided within a median of 50 minutes (interquartile range, 18-255 minutes), with 91.9% of consultations occurring within 24 hours. The diagnostic agreement level between HCWs and dermatologists significantly improved over time, from 46.9% in the first 6-month period (κ = 0.45; 95% CI, 0.37-0.54) to 77.2% in the last 6-month period (κ = 0.76; 95% CI, 0.67-0.86; global P < 0.001). The HCWs reported that the teledermatology service was extremely/very useful in supporting daily practice (100%) and improved their knowledge of skin diseases tremendously/a lot (92%). Teledermatology can improve accessibility and quality of skin services in medically underserved areas, providing opportunities for scalability and knowledge transfer to frontline HCWs.

Adjunctive Dexamethasone for Tuberculous Meningitis in HIV-Positive Adults.

BACKGROUND: Adjunctive glucocorticoids are widely used to treat human immunodeficiency virus (HIV)-associated tuberculous meningitis despite limited data supporting their safety and efficacy. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving HIV-positive adults (≥18 years of age) with tuberculous meningitis in Vietnam and Indonesia. Participants were randomly assigned to receive a 6-to-8-week tapering course of either dexamethasone or placebo in addition to 12 months of antituberculosis chemotherapy. The primary end point was death from any cause during the 12 months after randomization. RESULTS: A total of 520 adults were randomly assigned to receive either dexamethasone (263 participants) or placebo (257 participants). The median age was 36 years; 255 of 520 participants (49.0%) had never received antiretroviral therapy, and 251 of 484 participants (51.9%) with available data had a baseline CD4 count of 50 cells per cubic millimeter or less. Six participants withdrew from the trial, and five were lost to follow-up. During the 12 months of follow-up, death occurred in 116 of 263 participants (44.1%) in the dexamethasone group and in 126 of 257 participants (49.0%) in the placebo group (hazard ratio, 0.85; 95% confidence interval, 0.66 to 1.10; P = 0.22). Prespecified analyses did not reveal a subgroup that clearly benefited from dexamethasone. The incidence of secondary end-point events, including cases of immune reconstitution inflammatory syndrome during the first 6 months, was similar in the two trial groups. The numbers of participants with at least one serious adverse event were similar in the dexamethasone group (192 of 263 participants [73.0%]) and the placebo group (194 of 257 participants [75.5%]) (P = 0.52). CONCLUSIONS: Among HIV-positive adults with tuberculous meningitis, adjunctive dexamethasone, as compared with placebo, did not confer a benefit with respect to survival or any secondary end point. (Funded by the Wellcome Trust; ACT HIV ClinicalTrials.gov number, NCT03092817.).

ACORN (A Clinically-Oriented Antimicrobial Resistance Surveillance Network) II: protocol for case based antimicrobial resistance surveillance.

Background: Antimicrobial resistance surveillance is essential for empiric antibiotic prescribing, infection prevention and control policies and to drive novel antibiotic discovery. However, most existing surveillance systems are isolate-based without supporting patient-based clinical data, and not widely implemented especially in low- and middle-income countries (LMICs). Methods: A Clinically-Oriented Antimicrobial Resistance Surveillance Network (ACORN) II is a large-scale multicentre protocol which builds on the WHO Global Antimicrobial Resistance and Use Surveillance System to estimate syndromic and pathogen outcomes along with associated health economic costs. ACORN-healthcare associated infection (ACORN-HAI) is an extension study which focuses on healthcare-associated bloodstream infections and ventilator-associated pneumonia. Our main aim is to implement an efficient clinically-oriented antimicrobial resistance surveillance system, which can be incorporated as part of routine workflow in hospitals in LMICs. These surveillance systems include hospitalised patients of any age with clinically compatible acute community-acquired or healthcare-associated bacterial infection syndromes, and who were prescribed parenteral antibiotics. Diagnostic stewardship activities will be implemented to optimise microbiology culture specimen collection practices. Basic patient characteristics, clinician diagnosis, empiric treatment, infection severity and risk factors for HAI are recorded on enrolment and during 28-day follow-up. An R Shiny application can be used offline and online for merging clinical and microbiology data, and generating collated reports to inform local antibiotic stewardship and infection control policies. Discussion: ACORN II is a comprehensive antimicrobial resistance surveillance activity which advocates pragmatic implementation and prioritises improving local diagnostic and antibiotic prescribing practices through patient-centred data collection. These data can be rapidly communicated to local physicians and infection prevention and control teams. Relative ease of data collection promotes sustainability and maximises participation and scalability. With ACORN-HAI as an example, ACORN II has the capacity to accommodate extensions to investigate further specific questions of interest.

Impact of the COVID-19 pandemic on tuberculosis control in Indonesia: a nationwide longitudinal analysis of programme data.

BACKGROUND: The impact of the COVID-19 pandemic on tuberculosis control in high-burden countries has not been adequately assessed. We aimed to estimate the impact of the COVID-19 pandemic on the national tuberculosis programme in Indonesia, in association with indicators of human development and health-system capacity across all 514 districts in 34 provinces. METHODS: We did a nationwide longitudinal analysis to compare tuberculosis case notification, treatment coverage, and mortality rates in Indonesia before (2016-19) and during (2020-21) the COVID-19 pandemic. The following outcomes were assessed: the district-level quarterly reported tuberculosis case notification rate (number of all reported tuberculosis cases per 100 000 population), treatment coverage (proportion of tuberculosis patients who started treatment), and all-cause mortality rate in patients with tuberculosis (number of reported deaths per 100 000 population). District-level data on COVID-19 incidence and deaths, health-system capacity, and human development and sociodemographics were also analysed. Multilevel linear spline regression was done to assess quarterly time trends for the three outcomes. FINDINGS: During the COVID-19 pandemic, the tuberculosis case notification rate declined by 26% (case notification rate ratio 0·74, 95% CI 0·72-0·77) and treatment coverage declined by 11% (treatment coverage ratio 0·89, 95% CI 0·88-0·90), but there was no significant increase in all-cause mortality (all-cause mortality rate ratio 0·97, 95% CI 0·91-1·04) compared with the pre-pandemic period. In the second year of the pandemic, we observed a partial recovery of the case notification rate from Q1 to Q4 of 2021, a persistent decrease in treatment coverage, and a decrease in the all-cause mortality rate from Q2 of 2020 to Q4 of 2021. The multivariable analysis showed that the reduction in the tuberculosis case notification rate was associated with a higher COVID-19 incidence rate (adjusted odds ratio 3·1, 95% CI 1·1-8·6, for the highest compared with the lowest group) and fewer GeneXpert machines for tuberculosis diagnosis (3·1, 1·0-9·4, for the lowest compared with the highest group) per 100 000 population. The reduction in tuberculosis treatment coverage was associated with higher COVID-19 incidence (adjusted odds ratio 11·7, 95% CI 1·5-93·4, for the highest compared with the lowest group), fewer primary health centres (10·6, 4·1-28·0, for the lowest compared with the middle-high group), and a very low number of doctors (0·3, 0·1-0·9, for the low-middle compared with the lowest group) per 100 000 population. No factors were shown to be significantly associated with all-cause mortality. INTERPRETATION: The COVID-19 pandemic adversely and unevenly affected the national tuberculosis programme across Indonesia, with the greatest impacts observed in districts with the lowest health-system capacity. These disruptions could lead to an escalation in tuberculosis transmission in the coming years, warranting the need for intensified efforts to control tuberculosis and strengthen local health systems. FUNDING: Wellcome Africa Asia Programme Vietnam. TRANSLATION: For the Bahasa translation of the abstract see Supplementary Materials section.

Indonesian healthcare professionals' experiences in rural and urban settings during the first wave of COVID-19: A qualitative study.

INTRODUCTION: During the COVID-19 pandemic, healthcare workers (HCWs) faced unprecedented challenges, increased workload, and often struggled to provide healthcare services. We explored the experiences faced by HCWs working at primary healthcare centers (PHCs) and hospitals across urban and rural settings in Indonesia. METHODS: As part of a larger multi-country study, we conducted semi-structured in-depth interviews with a purposive sample of Indonesian HCWs. We used thematic analysis to identify the main challenges described by the participants. RESULTS: We interviewed 40 HCWs between December 2020 and March 2021. We identified that challenges varied depending on their role. i) For those in clinical roles, challenges included maintaining trust with communities, and patient referral issues; ii) for those in non-clinical roles, sub-optimal laboratory capacity and logistics, and lack of training were the main challenges; iii) for managerial roles, challenges included access to budget and supplies, and staff shortages due to isolation and overwork. There were also several cross-cutting challenges across all the roles including limited or rapidly changing information (in urban settings), and culture and communication (in rural settings). All of these challenges contributed to mental health issues among all HCW cadres. CONCLUSIONS: HCWs across roles and settings were confronted with unprecedented challenges. Understanding the various challenges across different healthcare cadres and within different settings is crucial for supporting HCWs during pandemic times. In rural areas, in particular, HCWs should be more sensitive to cultural and linguistic differences to enhance the effectiveness and awareness of public health messages.