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  1. A Statement of the MDS on Biological Definition, Staging, and Classification of Parkinson's Disease
    Cardoso F, Goetz CG, Mestre TA, Sampaio C, Adler CH, Berg D, et al.
    Mov Disord, 2024 Feb;39(2):259-266.
    PMID: 38093469 DOI: 10.1002/mds.29683
  2. Landscape of global urban environmental resistome and its association with local socioeconomic and medical status
    Wu J, Hu Y, Perlin MH, Danko D, Lu J, Oliveira M, et al.
    Sci China Life Sci, 2024 Mar 12.
    PMID: 38489008 DOI: 10.1007/s11427-023-2504-1
    Antimicrobial resistance (AMR) poses a critical threat to global health and development, with environmental factors-particularly in urban areas-contributing significantly to the spread of antibiotic resistance genes (ARGs). However, most research to date has been conducted at a local level, leaving significant gaps in our understanding of the global status of antibiotic resistance in urban environments. To address this issue, we thoroughly analyzed a total of 86,213 ARGs detected within 4,728 metagenome samples, which were collected by the MetaSUB International Consortium involving diverse urban environments in 60 cities of 27 countries, utilizing a deep-learning based methodology. Our findings demonstrated the strong geographical specificity of urban environmental resistome, and their correlation with various local socioeconomic and medical conditions. We also identified distinctive evolutionary patterns of ARG-related biosynthetic gene clusters (BGCs) across different countries, and discovered that the urban environment represents a rich source of novel antibiotics. Our study provides a comprehensive overview of the global urban environmental resistome, and fills a significant gap in our knowledge of large-scale urban antibiotic resistome analysis.
  3. Fulltext Genomic insights into the conservation status of the world's last remaining Sumatran rhinoceros populations
    von Seth J, Dussex N, Díez-Del-Molino D, van der Valk T, Kutschera VE, Kierczak M, et al.
    Nat Commun, 2021 Apr 26;12(1):2393.
    PMID: 33896938 DOI: 10.1038/s41467-021-22386-8
    Small populations are often exposed to high inbreeding and mutational load that can increase the risk of extinction. The Sumatran rhinoceros was widespread in Southeast Asia, but is now restricted to small and isolated populations on Sumatra and Borneo, and most likely extinct on the Malay Peninsula. Here, we analyse 5 historical and 16 modern genomes from these populations to investigate the genomic consequences of the recent decline, such as increased inbreeding and mutational load. We find that the Malay Peninsula population experienced increased inbreeding shortly before extirpation, which possibly was accompanied by purging. The populations on Sumatra and Borneo instead show low inbreeding, but high mutational load. The currently small population sizes may thus in the near future lead to inbreeding depression. Moreover, we find little evidence for differences in local adaptation among populations, suggesting that future inbreeding depression could potentially be mitigated by assisted gene flow among populations.
  4. Fulltext Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus
    Kandiah N, Chan YF, Chen C, Dasig D, Dominguez J, Han SH, et al.
    CNS Neurosci Ther, 2021 Feb;27(2):149-162.
    PMID: 33352000 DOI: 10.1111/cns.13536
    BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits.

    AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI.

    MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option.

    RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals.

    DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD.

    CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

  5. Fulltext The Practice of Gastrointestinal Motility Laboratory During COVID-19 Pandemic: Position Statements of the Asian Neurogastroenterology and Motility Association (ANMA-GML-COVID-19 Position Statements)
    Siah KTH, Rahman MM, Ong AML, Soh AYS, Lee YY, Xiao Y, et al.
    J Neurogastroenterol Motil, 2020 07 30;26(3):299-310.
    PMID: 32606253 DOI: 10.5056/jnm20107
    During the Coronavirus Disease 2019 (COVID-19) pandemic, practices of gastrointestinal procedures within the digestive tract require special precautions due to the risk of contraction of severe acute respiratoy syndrome coronavirus-2 (SARS-CoV-2) infection. Many procedures in the gastrointestinal motility laboratory may be considered moderate to high-risk for viral transmission. Healthcare staff working in gastrointestinal motility laboratories are frequently exposed to splashes, air droplets, mucus, or saliva during the procedures. Moreover, some are aerosol-generating and thus have a high risk of viral transmission. There are multiple guidelines on the practices of gastrointestinal endoscopy during this pandemic. However, such guidelines are still lacking and urgently needed for the practice of gastrointestinal motility laboratories. Hence, the Asian Neurogastroenterology and Motility Association had organized a group of gastrointestinal motility experts and infectious disease specialists to produce a position statement paper based-on current available evidence and consensus opinion with aims to provide a clear guidance on the practices of gastrointestinal motility laboratories during the COVID-19 pandemic. This guideline covers a wide range of topics on gastrointestinal motility activities from scheduling a motility test, the precautions at different steps of the procedure to disinfection for the safety and well-being of the patients and the healthcare workers. These practices may vary in different countries depending on the stages of the pandemic, local or institutional policy, and the availability of healthcare resources. This guideline is useful when the transmission rate of SARS-CoV-2 is high. It may change rapidly depending on the situation of the epidemic and when new evidence becomes available.
  6. Fulltext Gut microbiome of helminth-infected indigenous Malaysians is context dependent
    Tee MZ, Er YX, Easton AV, Yap NJ, Lee IL, Devlin J, et al.
    Microbiome, 2022 Dec 07;10(1):214.
    PMID: 36476263 DOI: 10.1186/s40168-022-01385-x
    BACKGROUND: While microbiomes in industrialized societies are well characterized, indigenous populations with traditional lifestyles have microbiomes that are more akin to those of ancient humans. However, metagenomic data in these populations remains scarce, and the association with soil-transmitted helminth infection status is unclear. Here, we sequenced 650 metagenomes of indigenous Malaysians from five villages with different prevalence of helminth infections.

    RESULTS: Individuals from villages with higher prevalences of helminth infections have more unmapped reads and greater microbial diversity. Microbial community diversity and composition were most strongly associated with different villages and the effects of helminth infection status on the microbiome varies by village. Longitudinal changes in the microbiome in response to albendazole anthelmintic treatment were observed in both helminth infected and uninfected individuals. Inference of bacterial population replication rates from origin of replication analysis identified specific replicating taxa associated with helminth infection.

    CONCLUSIONS: Our results indicate that helminth effects on the microbiota were highly dependent on context, and effects of albendazole on the microbiota can be confounding for the interpretation of deworming studies. Furthermore, a substantial quantity of the microbiome remains unannotated, and this large dataset from an indigenous population associated with helminth infections is a valuable resource for future studies. Video Abstract.

  7. Fulltext Priorities for cancer research in low- and middle-income countries: a global perspective
    Pramesh CS, Badwe RA, Bhoo-Pathy N, Booth CM, Chinnaswamy G, Dare AJ, et al.
    Nat Med, 2022 Apr;28(4):649-657.
    PMID: 35440716 DOI: 10.1038/s41591-022-01738-x
    Cancer research currently is heavily skewed toward high-income countries (HICs), with little research conducted in, and relevant to, the problems of low- and middle-income countries (LMICs). This regional discordance in cancer knowledge generation and application needs to be rebalanced. Several gaps in the research enterprise of LMICs need to be addressed to promote regionally relevant research, and radical rethinking is needed to address the burning issues in cancer care in these regions. We identified five top priorities in cancer research in LMICs based on current and projected needs: reducing the burden of patients with advanced disease; improving access and affordability, and outcomes of cancer treatment; value-based care and health economics; quality improvement and implementation research; and leveraging technology to improve cancer control. LMICs have an excellent opportunity to address important questions in cancer research that could impact cancer control globally. Success will require collaboration and commitment from governments, policy makers, funding agencies, health care organizations and leaders, researchers and the public.
  8. Rights and representation support justice across aquatic food systems
    Hicks CC, Gephart JA, Koehn JZ, Nakayama S, Payne HJ, Allison EH, et al.
    Nat Food, 2022 Oct;3(10):851-861.
    PMID: 37117898 DOI: 10.1038/s43016-022-00618-4
    Injustices are prevalent in food systems, where the accumulation of vast wealth is possible for a few, yet one in ten people remain hungry. Here, for 194 countries we combine aquatic food production, distribution and consumption data with corresponding national policy documents and, drawing on theories of social justice, explore whether barriers to participation explain unequal distributions of benefits. Using Bayesian models, we find economic and political barriers are associated with lower wealth-based benefits; countries produce and consume less when wealth, formal education and voice and accountability are lacking. In contrast, social barriers are associated with lower welfare-based benefits; aquatic foods are less affordable where gender inequality is greater. Our analyses of policy documents reveal a frequent failure to address political and gender-based barriers. However, policies linked to more just food system outcomes centre principles of human rights, specify inclusive decision-making processes and identify and challenge drivers of injustice.
  9. Quantitative Gait and Balance Outcomes for Ataxia Trials: Consensus Recommendations by the Ataxia Global Initiative Working Group on Digital-Motor Biomarkers
    Ilg W, Milne S, Schmitz-Hübsch T, Alcock L, Beichert L, Bertini E, et al.
    Cerebellum, 2024 Aug;23(4):1566-1592.
    PMID: 37955812 DOI: 10.1007/s12311-023-01625-2
    With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.
  10. Fulltext Ramadan intermittent fasting induced poorer training practices during the COVID-19 lockdown: A global cross-sectional study with 5529 athletes from 110 countries
    Washif JA, Pyne DB, Sandbakk Ø, Trabelsi K, Aziz AR, Beaven CM, et al.
    Biol Sport, 2022 Oct;39(4):1103-1115.
    PMID: 36247962 DOI: 10.5114/biolsport.2022.117576
    Ramadan intermittent fasting during the COVID-19 lockdown (RIFL) may present unique demands. We investigated training practices (i.e., training load and training times) of athletes, using pre-defined survey criteria/questions, during the 'first' COVID-19 lockdown, comparing RIFL to lockdown-alone (LD) in Muslim athletes. Specifically, a within-subject, survey-based study saw athletes (n = 5,529; from 110 countries/territories) training practices (comparing RIFL to LD) explored by comparative variables of: sex; age; continent; athlete classification (e.g., world-class); sport classification (e.g., endurance); athlete status (e.g., professional); and level of training knowledge and beliefs/attitudes (ranked as: good/moderate/poor). During RIFL (compared to LD), athlete perceptions (ranges presented given variety of comparative variables) of their training load decreased (46-62%), were maintained (31-48%) or increased (2-13%). Decreases (≥ 5%, p < 0.05) affected more athletes aged 30-39 years than those 18-29 years (60 vs 55%); more national than international athletes (59 vs 51%); more team sports than precision sports (59 vs 46%); more North American than European athletes (62 vs 53%); more semi-professional than professional athletes (60 vs 54%); more athletes who rated their beliefs/attitudes 'good' compared to 'poor' and 'moderate' (61 vs 54 and 53%, respectively); and more athletes with 'moderate' than 'poor' knowledge (58 vs 53%). During RIFL, athletes had different strategies for training times, with 13-29% training twice a day (i.e., afternoon and night), 12-26% at night only, and 18-36% in the afternoon only, with ranges depending on the comparative variables. Training loads and activities were altered negatively during RIFL compared to LD. It would be prudent for decision-makers responsible for RIFL athletes to develop programs to support athletes during such challenges.
  11. Fulltext COVID-19 impacts and adaptations in Asia and Africa's aquatic food value chains
    Belton B, Rosen L, Middleton L, Ghazali S, Mamun AA, Shieh J, et al.
    Mar Policy, 2021 Jul;129:104523.
    PMID: 34744258 DOI: 10.1016/j.marpol.2021.104523
    The COVID-19 pandemic is a shock affecting all areas of the global food system. We tracked the impacts of COVID-19 and associated policy responses on the availability and price of aquatic foods and production inputs during 2020, using a high frequency longitudinal survey of 768 respondents in Bangladesh, Egypt, India, Myanmar, Nigeria. We found the following: (1) Aquatic food value chains were severely disrupted but most effects on the availability and accessibility of aquatic foods and production inputs were short-lived. (2) Impacts on demand for aquatic foods, production inputs, and labor have been longer lasting than impacts on their supply. (3) Retail prices of aquatic foods spiked briefly during March-May 2020 but trended down thereafter, whereas prices of production inputs rose. These trends suggest a deepening 'squeeze' on the financial viability of producers and other value chain actors. (4) Survey respondents adapted to the challenges of COVID-19 by reducing production costs, sourcing alternative inputs, diversifying business activities, leveraging social capital, borrowing, seeking alternative employment, and reducing food consumption. Many of these coping strategies are likely to undermine well-being and longer-term resilience, but we also find some evidence of proactive strategies with potential to strengthen business performance. Global production of aquatic food likely contracted significantly in 2020. The importance of aquatic food value chains in supporting livelihoods and food and nutrition security in Asia and Africa makes their revitalization essential in the context of COVID-19 recovery efforts. We outline immediate and longer-term policies and interventions to support this goal.
  12. Fulltext A history of the MetaSUB consortium: Tracking urban microbes around the globe
    Ryon KA, Tierney BT, Frolova A, Kahles A, Desnues C, Ouzounis C, et al.
    iScience, 2022 Nov 18;25(11):104993.
    PMID: 36299999 DOI: 10.1016/j.isci.2022.104993
    The MetaSUB Consortium, founded in 2015, is a global consortium with an interdisciplinary team of clinicians, scientists, bioinformaticians, engineers, and designers, with members from more than 100 countries across the globe. This network has continually collected samples from urban and rural sites including subways and transit systems, sewage systems, hospitals, and other environmental sampling. These collections have been ongoing since 2015 and have continued when possible, even throughout the COVID-19 pandemic. The consortium has optimized their workflow for the collection, isolation, and sequencing of DNA and RNA collected from these various sites and processing them for metagenomics analysis, including the identification of SARS-CoV-2 and its variants. Here, the Consortium describes its foundations, and its ongoing work to expand on this network and to focus its scope on the mapping, annotation, and prediction of emerging pathogens, mapping microbial evolution and antibiotic resistance, and the discovery of novel organisms and biosynthetic gene clusters.
  13. Fulltext Candidate diagnostic biomarkers for neurodevelopmental disorders in children and adolescents: a systematic review
    Cortese S, Solmi M, Michelini G, Bellato A, Blanner C, Canozzi A, et al.
    World Psychiatry, 2023 Feb;22(1):129-149.
    PMID: 36640395 DOI: 10.1002/wps.21037
    Neurodevelopmental disorders - including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders - manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis of these disorders would be highly relevant from a clinical and public health standpoint. We conducted the first systematic review of studies on candidate diagnostic biomarkers for these disorders in children and adolescents. We searched Medline and Embase + Embase Classic with terms relating to biomarkers until April 6, 2022, and conducted additional targeted searches for genome-wide association studies (GWAS) and neuroimaging or neurophysiological studies carried out by international consortia. We considered a candidate biomarker as promising if it was reported in at least two independent studies providing evidence of sensitivity and specificity of at least 80%. After screening 10,625 references, we retained 780 studies (374 biochemical, 203 neuroimaging, 133 neurophysiological and 65 neuropsychological studies, and five GWAS), including a total of approximately 120,000 cases and 176,000 controls. While the majority of the studies focused simply on associations, we could not find any biomarker for which there was evidence - from two or more studies from independent research groups, with results going into the same direction - of specificity and sensitivity of at least 80%. Other important metrics to assess the validity of a candidate biomarker, such as positive predictive value and negative predictive value, were infrequently reported. Limitations of the currently available studies include mostly small sample size, heterogeneous approaches and candidate biomarker targets, undue focus on single instead of joint biomarker signatures, and incomplete accounting for potential confounding factors. Future multivariable and multi-level approaches may be best suited to find valid candidate biomarkers, which will then need to be validated in external, independent samples and then, importantly, tested in terms of feasibility and cost-effectiveness, before they can be implemented in daily clinical practice.
  14. Fulltext Hepatocyte apoptosis fragment product cytokeratin-18 M30 level and non-alcoholic steatohepatitis risk diagnosis: an international registry study
    Zhang H, Rios RS, Boursier J, Anty R, Chan WK, George J, et al.
    Chin Med J (Engl), 2023 Feb 05;136(3):341-350.
    PMID: 36848175 DOI: 10.1097/CM9.0000000000002603
    BACKGROUND: Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.

    METHODS: Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).

    RESULTS: A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69-1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension ( P  

  15. Fulltext Trends of CD4 cell count levels at the initiation of antiretroviral therapy over time and factors associated with late initiation of antiretroviral therapy among Asian HIV-positive patients
    Kiertiburanakul S, Boettiger D, Lee MP, Omar SF, Tanuma J, Ng OT, et al.
    J Int AIDS Soc, 2014;17(1):18804.
    PMID: 24598459 DOI: 18804
    INTRODUCTION: Although antiretroviral therapy (ART) has been rapidly scaled up in Asia, most HIV-positive patients in the region still present with late-stage HIV disease. We aimed to determine trends of pre-ART CD4 levels over time in Asian HIV-positive patients and to determine factors associated with late ART initiation.

    METHODS: Data from two regional cohort observational databases were analyzed for trends in median CD4 cell counts at ART initiation and the proportion of late ART initiation (CD4 cell counts <200 cells/mm(3) or prior AIDS diagnosis). Predictors for late ART initiation and mortality were determined.

    RESULTS: A total of 2737 HIV-positive ART-naïve patients from 22 sites in 13 Asian countries and territories were eligible. The overall median (IQR) CD4 cell count at ART initiation was 150 (46-241) cells/mm(3). Median CD4 cell counts at ART initiation increased over time, from a low point of 115 cells/mm(3) in 2008 to a peak of 302 cells/mm(3) after 2011 (p for trend 0.002). The proportion of patients with late ART initiation significantly decreased over time from 79.1% before 2007 to 36.3% after 2011 (p for trend <0.001). Factors associated with late ART initiation were year of ART initiation (e.g. 2010 vs. before 2007; OR 0.40, 95% CI 0.27-0.59; p<0.001), sex (male vs. female; OR 1.51, 95% CI 1.18-1.93; p=0.001) and HIV exposure risk (heterosexual vs. homosexual; OR 1.66, 95% CI 1.24-2.23; p=0.001 and intravenous drug use vs. homosexual; OR 3.03, 95% CI 1.77-5.21; p<0.001). Factors associated with mortality after ART initiation were late ART initiation (HR 2.13, 95% CI 1.19-3.79; p=0.010), sex (male vs. female; HR 2.12, 95% CI 1.31-3.43; p=0.002), age (≥51 vs. ≤30 years; HR 3.91, 95% CI 2.18-7.04; p<0.001) and hepatitis C serostatus (positive vs. negative; HR 2.48, 95% CI 1.-4.36; p=0.035).

    CONCLUSIONS: Median CD4 cell count at ART initiation among Asian patients significantly increases over time but the proportion of patients with late ART initiation is still significant. ART initiation at higher CD4 cell counts remains a challenge. Strategic interventions to increase earlier diagnosis of HIV infection and prompt more rapid linkage to ART must be implemented.

  16. Fulltext Four ways blue foods can help achieve food system ambitions across nations
    Crona BI, Wassénius E, Jonell M, Koehn JZ, Short R, Tigchelaar M, et al.
    Nature, 2023 Apr;616(7955):104-112.
    PMID: 36813964 DOI: 10.1038/s41586-023-05737-x
    Blue foods, sourced in aquatic environments, are important for the economies, livelihoods, nutritional security and cultures of people in many nations. They are often nutrient rich1, generate lower emissions and impacts on land and water than many terrestrial meats2, and contribute to the health3, wellbeing and livelihoods of many rural communities4. The Blue Food Assessment recently evaluated nutritional, environmental, economic and justice dimensions of blue foods globally. Here we integrate these findings and translate them into four policy objectives to help realize the contributions that blue foods can make to national food systems around the world: ensuring supplies of critical nutrients, providing healthy alternatives to terrestrial meat, reducing dietary environmental footprints and safeguarding blue food contributions to nutrition, just economies and livelihoods under a changing climate. To account for how context-specific environmental, socio-economic and cultural aspects affect this contribution, we assess the relevance of each policy objective for individual countries, and examine associated co-benefits and trade-offs at national and international scales. We find that in many African and South American nations, facilitating consumption of culturally relevant blue food, especially among nutritionally vulnerable population segments, could address vitamin B12 and omega-3 deficiencies. Meanwhile, in many global North nations, cardiovascular disease rates and large greenhouse gas footprints from ruminant meat intake could be lowered through moderate consumption of seafood with low environmental impact. The analytical framework we provide also identifies countries with high future risk, for whom climate adaptation of blue food systems will be particularly important. Overall the framework helps decision makers to assess the blue food policy objectives most relevant to their geographies, and to compare and contrast the benefits and trade-offs associated with pursuing these objectives.
  17. Publisher Correction: Landscape-scale benefits of protected areas for tropical biodiversity
    Brodie JF, Mohd-Azlan J, Chen C, Wearn OR, Deith MCM, Ball JGC, et al.
    Nature, 2024 Jan;625(7996):E28.
    PMID: 38182924 DOI: 10.1038/s41586-023-07007-2
  18. Fulltext Kidney function in tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis users: a systematic review and meta-analysis of published literature and a multi-country meta-analysis of individual participant data
    Schaefer R, Amparo da Costa Leite PH, Silva R, Abdool Karim Q, Akolo C, Cáceres CF, et al.
    Lancet HIV, 2022 Apr;9(4):e242-e253.
    PMID: 35271825 DOI: 10.1016/S2352-3018(22)00004-2
    BACKGROUND: Previous WHO guidance on tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards, which might represent barriers to PrEP implementation and uptake. We aimed to systematically review published literature on kidney toxicity among tenofovir disoproxil fumarate-based oral PrEP users and conducted an individual participant data meta-analysis (IPDMA) on kidney function among PrEP users in a global implementation project dataset.

    METHODS: In this systematic review and meta-analysis we searched PubMed up to June 30, 2021, for randomised controlled trials (RCTs) or cohort studies that reported on graded kidney-related adverse events among oral PrEP users (tenofovir disoproxil fumarate-based PrEP alone or in combination with emtricitabine or lamivudine). We extracted summary data and conducted meta-analyses with random-effects models to estimate relative risks of grade 1 and higher and grade 2 and higher kidney-related adverse events, measured by elevated serum creatinine or decline in estimated creatinine clearance or estimated glomerular filtration rate. The IPDMA included (largely unpublished) individual participant data from 17 PrEP implementation projects and two RCTs. Estimated baseline creatinine clearance and creatinine clearance change after initiation were described by age, gender, and comorbidities. We used random-effects regressions to estimate the risk in decline of creatinine clearance to less than 60 mL/min.

    FINDINGS: We identified 62 unique records and included 17 articles reporting on 11 RCTs with 13 523 participants in meta-analyses. PrEP use was associated with increased risk of grade 1 and higher kidney adverse events (pooled odds ratio [OR] 1·49, 95% CI 1·22-1·81; I2=25%) and grade 2 and higher events (OR 1·75, 0·68-4·49; I2=0%), although the grade 2 and higher association was not statistically significant and events were rare (13 out of 6764 in the intervention group vs six out of 6782 in the control group). The IPDMA included 18 676 individuals from 15 countries (1453 [7·8%] from RCTs) and 79 (0·42%) had a baseline estimated creatinine clearance of less than 60 mL/min (increasing proportions with increasing age). Longitudinal analyses included 14 368 PrEP users and 349 (2·43%) individuals had a decline to less than 60 mL/min creatinine clearance, with higher risks associated with increasing age and baseline creatinine clearance of 60·00-89·99 mL/min (adjusted hazard ratio [aHR] 8·49, 95% CI 6·44-11·20) and less than 60 mL/min (aHR 20·83, 12·83-33·82).

    INTERPRETATION: RCTs suggest that risks of kidney-related adverse events among tenofovir disoproxil fumarate-based oral PrEP users are increased but generally mild and small. Our global PrEP user analysis found varying risks by age and baseline creatinine clearance. Kidney function screening and monitoring might focus on older individuals, those with baseline creatinine clearance of less than 90 mL/min, and those with kidney-related comorbidities. Less frequent or optional screening among younger individuals without kidney-related comorbidities may reduce barriers to PrEP implementation and use.

    FUNDING: Unitaid, Bill & Melinda Gates Foundation, WHO.

  19. Fulltext Cancer disparities in Southeast Asia: intersectionality and a call to action
    Feliciano EJG, Ho FDV, Yee K, Paguio JA, Eala MAB, Robredo JPG, et al.
    Lancet Reg Health West Pac, 2023 Dec;41:100971.
    PMID: 38053740 DOI: 10.1016/j.lanwpc.2023.100971
  20. Fulltext Human IFNAR2 deficiency: Lessons for antiviral immunity
    Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC, et al.
    Sci Transl Med, 2015 Sep 30;7(307):307ra154.
    PMID: 26424569 DOI: 10.1126/scitranslmed.aac4227
    Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.
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