Displaying publications 21 - 40 of 60 in total

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  1. Fulltext Comparison of Recommendations in Clinical Practice Guidelines for Acute Gastroenteritis in Children
    Lo Vecchio A, Dias JA, Berkley JA, Boey C, Cohen MB, Cruchet S, et al.
    J Pediatr Gastroenterol Nutr, 2016 Aug;63(2):226-35.
    PMID: 26835905 DOI: 10.1097/MPG.0000000000001133
    OBJECTIVE: Acute gastroenteritis (AGE) is a major cause of child mortality and morbidity. This study aimed at systematically reviewing clinical practice guidelines (CPGs) on AGE to compare recommendations and provide the basis for developing single universal guidelines.

    METHODS: CPGs were identified by searching MEDLINE, Cochrane-Library, National Guideline Clearinghouse and Web sites of relevant societies/organizations producing and/or endorsing CPGs.

    RESULTS: The definition of AGE varies among the 15 CPGs identified. The parameters most frequently recommended to assess dehydration are skin turgor and sunken eyes (11/15, 73.3%), general appearance (11/15, 66.6%), capillary refill time, and mucous membranes appearance (9/15, 60%). Oral rehydration solution is universally recognized as first-line treatment. The majority of CPGs recommend hypo-osmolar (Na 45-60 mmol/L, 11/15, 66.6 %) or low-osmolality (Na 75 mmol/L, 9/15, 60%) solutions. In children who fail oral rehydration, most CPGs suggest intravenous rehydration (66.6%). However, nasogastric tube insertion for fluid administration is preferred according by 5/15 CPGs (33.3%). Changes in diet and withdrawal of food are discouraged by all CPGs, and early refeeding is strongly recommended in 13 of 15 (86.7%). Zinc is recommended as an adjunct to ORS by 10 of 15 (66.6%) CPGs, most of them from low-income countries. Probiotics are considered by 9 of 15 (60%) CPGs, 5 from high-income countries. Antiemetics are not recommended in 9 of 15 (60%) CPGs. Routine use of antibiotics is discouraged.

    CONCLUSIONS: Key recommendations for the management of AGE in children are similar in CPGs. Together with accurate review of evidence-base this may represent a starting point for developing universal recommendations for the management of children with AGE worldwide.

  2. Fulltext Characterization of Nipah virus from outbreaks in Bangladesh, 2008-2010
    Lo MK, Lowe L, Hummel KB, Sazzad HM, Gurley ES, Hossain MJ, et al.
    Emerg Infect Dis, 2012 Feb;18(2):248-55.
    PMID: 22304936 DOI: 10.3201/eid1802.111492
    Nipah virus (NiV) is a highly pathogenic paramyxovirus that causes fatal encephalitis in humans. The initial outbreak of NiV infection occurred in Malaysia and Singapore in 1998-1999; relatively small, sporadic outbreaks among humans have occurred in Bangladesh since 2001. We characterized the complete genomic sequences of identical NiV isolates from 2 patients in 2008 and partial genomic sequences of throat swab samples from 3 patients in 2010, all from Bangladesh. All sequences from patients in Bangladesh comprised a distinct genetic group. However, the detection of 3 genetically distinct sequences from patients in the districts of Faridpur and Gopalganj indicated multiple co-circulating lineages in a localized region over a short time (January-March 2010). Sequence comparisons between the open reading frames of all available NiV genes led us to propose a standardized protocol for genotyping NiV; this protcol provides a simple and accurate way to classify current and future NiV sequences.
  3. Fulltext The RyR2-P2328S mutation downregulates Nav1.5 producing arrhythmic substrate in murine ventricles
    Ning F, Luo L, Ahmad S, Valli H, Jeevaratnam K, Wang T, et al.
    Pflugers Arch, 2016 Apr;468(4):655-65.
    PMID: 26545784 DOI: 10.1007/s00424-015-1750-0
    Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca(2+) homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2 (S/S)) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2 (S/S) hearts to connexin-43 (Cx43) and Nav1.5 expression and Na(+) current (I Na). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2 (S/S) hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2 (S/S) than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2 (S/S) compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced I Na in RyR2 (S/S) ventricles. We thus attribute arrhythmogenesis in RyR2 (S/S) ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing I Na, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak I Na of the AP but nonlinear relationships between peak I Na and maximum Na(+) permeability.
  4. Fulltext Molecular investigations of a locally acquired case of melioidosis in Southern AZ, USA
    Engelthaler DM, Bowers J, Schupp JA, Pearson T, Ginther J, Hornstra HM, et al.
    PLoS Negl Trop Dis, 2011 Oct;5(10):e1347.
    PMID: 22028940 DOI: 10.1371/journal.pntd.0001347
    Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative bacillus, primarily found in soils in Southeast Asia and northern Australia. A recent case of melioidosis in non-endemic Arizona was determined to be the result of locally acquired infection, as the patient had no travel history to endemic regions and no previous history of disease. Diagnosis of the case was confirmed through multiple microbiologic and molecular techniques. To enhance the epidemiological analysis, we conducted several molecular genotyping procedures, including multi-locus sequence typing, SNP-profiling, and whole genome sequence typing. Each technique has different molecular epidemiologic advantages, all of which provided evidence that the infecting strain was most similar to those found in Southeast Asia, possibly originating in, or around, Malaysia. Advancements in new typing technologies provide genotyping resolution not previously available to public health investigators, allowing for more accurate source identification.
  5. Fulltext Lipid Metabolism Links Nutrient-Exercise Timing to Insulin Sensitivity in Men Classified as Overweight or Obese
    Edinburgh RM, Bradley HE, Abdullah NF, Robinson SL, Chrzanowski-Smith OJ, Walhin JP, et al.
    J Clin Endocrinol Metab, 2020 03 01;105(3).
    PMID: 31628477 DOI: 10.1210/clinem/dgz104
    CONTEXT: Pre-exercise nutrient availability alters acute metabolic responses to exercise, which could modulate training responsiveness.

    OBJECTIVE: To assess acute and chronic effects of exercise performed before versus after nutrient ingestion on whole-body and intramuscular lipid utilization and postprandial glucose metabolism.

    DESIGN: (1) Acute, randomized, crossover design (Acute Study); (2) 6-week, randomized, controlled design (Training Study).

    SETTING: General community.

    PARTICIPANTS: Men with overweight/obesity (mean ± standard deviation, body mass index: 30.2 ± 3.5 kg⋅m-2 for Acute Study, 30.9 ± 4.5 kg⋅m-2 for Training Study).

    INTERVENTIONS: Moderate-intensity cycling performed before versus after mixed-macronutrient breakfast (Acute Study) or carbohydrate (Training Study) ingestion.

    RESULTS: Acute Study-exercise before versus after breakfast consumption increased net intramuscular lipid utilization in type I (net change: -3.44 ± 2.63% versus 1.44 ± 4.18% area lipid staining, P < 0.01) and type II fibers (-1.89 ± 2.48% versus 1.83 ± 1.92% area lipid staining, P < 0.05). Training Study-postprandial glycemia was not differentially affected by 6 weeks of exercise training performed before versus after carbohydrate intake (P > 0.05). However, postprandial insulinemia was reduced with exercise training performed before but not after carbohydrate ingestion (P = 0.03). This resulted in increased oral glucose insulin sensitivity (25 ± 38 vs -21 ± 32 mL⋅min-1⋅m-2; P = 0.01), associated with increased lipid utilization during exercise (r = 0.50, P = 0.02). Regular exercise before nutrient provision also augmented remodeling of skeletal muscle phospholipids and protein content of the glucose transport protein GLUT4 (P < 0.05).

    CONCLUSIONS: Experiments investigating exercise training and metabolic health should consider nutrient-exercise timing, and exercise performed before versus after nutrient intake (ie, in the fasted state) may exert beneficial effects on lipid utilization and reduce postprandial insulinemia.

  6. Lions and brown bears colonized North America in multiple synchronous waves of dispersal across the Bering Land Bridge
    Salis AT, Bray SCE, Lee MSY, Heiniger H, Barnett R, Burns JA, et al.
    Mol Ecol, 2022 Dec;31(24):6407-6421.
    PMID: 34748674 DOI: 10.1111/mec.16267
    The Bering Land Bridge connecting North America and Eurasia was periodically exposed and inundated by oscillating sea levels during the Pleistocene glacial cycles. This land connection allowed the intermittent dispersal of animals, including humans, between Western Beringia (far northeast Asia) and Eastern Beringia (northwest North America), changing the faunal community composition of both continents. The Pleistocene glacial cycles also had profound impacts on temperature, precipitation and vegetation, impacting faunal community structure and demography. While these palaeoenvironmental impacts have been studied in many large herbivores from Beringia (e.g., bison, mammoths, horses), the Pleistocene population dynamics of the diverse guild of carnivorans present in the region are less well understood, due to their lower abundances. In this study, we analyse mitochondrial genome data from ancient brown bears (Ursus arctos; n = 103) and lions (Panthera spp.; n = 39), two megafaunal carnivorans that dispersed into North America during the Pleistocene. Our results reveal striking synchronicity in the population dynamics of Beringian lions and brown bears, with multiple waves of dispersal across the Bering Land Bridge coinciding with glacial periods of low sea levels, as well as synchronous local extinctions in Eastern Beringia during Marine Isotope Stage 3. The evolutionary histories of these two taxa underline the crucial biogeographical role of the Bering Land Bridge in the distribution, turnover and maintenance of megafaunal populations in North America.
  7. Genetic characterization of Nipah virus, Bangladesh, 2004
    Harcourt BH, Lowe L, Tamin A, Liu X, Bankamp B, Bowden N, et al.
    Emerg Infect Dis, 2005 Oct;11(10):1594-7.
    PMID: 16318702
    Until 2004, identification of Nipah virus (NV)-like outbreaks in Bangladesh was based on serology. We describe the genetic characterization of a new strain of NV isolated during outbreaks in Bangladesh (NV-B) in 2004, which confirms that NV was the etiologic agent responsible for these outbreaks.
  8. TRAIL-based tumor sensitizing galactoxyloglucan, a novel entity for targeting apoptotic machinery
    Aravind SR, Joseph MM, George SK, Dileep KV, Varghese S, Rose-James A, et al.
    Int J Biochem Cell Biol, 2015 Feb;59:153-66.
    PMID: 25541375 DOI: 10.1016/j.biocel.2014.11.019
    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive target for cancer therapy due to its ability to selectively induce apoptosis in cancer cells, without causing significant toxicity in normal tissues. We previously reported that galactoxyloglucan (PST001) possesses significant antitumor and immunomodulatory properties. However, the exact mechanism in mediating this anticancer effect is unknown. This study, for the first time, indicated that PST001 sensitizes non-small cell lung cancer (A549) and nasopharyngeal (KB) cells to TRAIL-mediated apoptosis. In vitro studies suggested that PST001 induced apoptosis primarily via death receptors and predominantly activated caspases belonging to the extrinsic apoptotic cascade. Microarray profiling of PST001 treated A549 and KB cells showed the suppression of survivin (BIRC5) and anti-apoptotic Bcl-2, as well as increased cytochrome C. TaqMan low density array analysis of A549 cells also confirmed that the induction of apoptosis by the polysaccharide occurred through the TRAIL-DR4/DR5 pathways. This was finally confirmed by in silico analysis, which revealed that PST001 binds to TRAIL-DR4/DR5 complexes more strongly than TNF and Fas ligand-receptor complexes. In summary, our results suggest the potential of PST001 to be developed as an anticancer agent that not only preserves innate biological activity of TRAIL, but also sensitizes cancer cells to TRAIL-mediated apoptosis.
  9. Chromosomal alterations in Malaysian patients with nasopharyngeal carcinoma analyzed by comparative genomic hybridization
    Natasya Naili MN, Hasnita CH, Shamim AK, Hasnan J, Fauziah MI, Narazah MY, et al.
    Cancer Genet. Cytogenet., 2010 Dec;203(2):309-12.
    PMID: 21156250 DOI: 10.1016/j.cancergencyto.2010.07.136
    Nasopharyngeal carcinoma (NPC) is one of the most common cancers in Malaysia, mainly occurring among the Chinese population. To detect common genetic alterations in NPC, we screened seven cases of NPC using the comparative genomic hybridization (CGH) technique. Before proceeding to the CGH technique, the tumors were first confirmed to consist of 75% tumor cells or more. In brief, the technique consists of binding tumor DNA with normal DNA and human Cot-1 DNA, which is then hybridized to normal metaphase spreads. The slides were then counterstained with 4,6 diamino-2-phenylindole (DAPI II) for detection. Analyses were performed using CGH software (Cytovision). We found genetic alterations in all seven NPC samples. The common chromosomal gains (57%, four cases) were found on chromosome arms 1q, 4p, 5, 7q, 11, 14p, 15q, 18p, and 21p, and common chromosomal losses (43%, three cases) were found on chromosome arm 16p. Our results showed chromosomal alterations in all seven NPC cases in the Malaysian population. This result provides the platform for further investigations to locate tumor suppressor genes and oncogenes at specific chromosomal regions in Malaysian NPC patients.
  10. Fulltext Development and Testing of a Community-Based Intervention to Address Intimate Partner Violence among Rohingya and Syrian Refugees: A Social Norms-Based Mental Health-Integrated Approach
    James LE, Welton-Mitchell C, Michael S, Santoadi F, Shakirah S, Hussin H, et al.
    Int J Environ Res Public Health, 2021 11 07;18(21).
    PMID: 34770188 DOI: 10.3390/ijerph182111674
    Intimate partner violence (IPV) is the leading form of gender-based violence globally and increases during times of conflict and displacement. To reduce IPV and encourage help-seeking, a two-phase community-based intervention was co-designed with Rohingya in Malaysia and Syrians in Lebanon. Three day workshops, utilizing a social norms-based mental health-integrated approach, were implemented for women and men in each country (n = 148). Pre- to post-measures indicated reductions in beliefs about acceptability of violence and rigid gender norms, and improvements in mental health, functioning, coping, and self-efficacy for women and men following workshop participation. Workshop participation was also associated with increased help-seeking intent, for both mental health and IPV (victims and perpetrators). Workshops included community design of poster campaigns to address IPV, which were then tested in each setting using a randomized controlled trial in Malaysia (n = 240) and a matched cluster comparison in Lebanon (n = 260). Women in both settings found IPV less acceptable in the poster condition. Help-seeking preferences were also influenced by the poster for women and men in both countries. This participatory intervention research can provide a roadmap for use in other settings, emphasizing the value of community-generated solutions to IPV among displaced populations.
  11. Strategies for the Construction of Cassava Brown Streak Disease Viral Infectious Clones
    Duff-Farrier CRA, Mbanzibwa DR, Nanyiti S, Bunawan H, Pablo-Rodriguez JL, Tomlinson KR, et al.
    Mol Biotechnol, 2019 Feb;61(2):93-101.
    PMID: 30484144 DOI: 10.1007/s12033-018-0139-7
    Cassava brown streak disease (CBSD) has major impacts on yield and quality of the tuberous roots of cassava in Eastern and Central Arica. At least two Potyviridae species cause the disease: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Cloned viral genome sequences known as infectious clones (ICs) have been important in the study of other viruses, both as a means of standardising infectious material and characterising viral gene function. IC construction is often technically challenging for Potyviridae due to sequence instability in E. coli. Here, we evaluate three methods for the construction of infectious clones for CBSD. Whilst a simple IC for in vitro transcription was made for UCBSV isolate 'Kikombe', such an approach failed to deliver full-length clones for CBSV isolates 'Nampula' or 'Tanza', necessitating more complex approaches for their construction. The ICs successfully generated symptomatic infection in the model host N. benthamiana and in the natural host cassava. This shows that whilst generating ICs for CBSV is still a technical challenge, a structured approach, evaluating both in vitro and in planta transcription systems should successfully deliver ICs, allowing further study into the symptomology and virulence factors in this important disease complex.
  12. Fulltext Aerobiology Over Antarctica - A New Initiative for Atmospheric Ecology
    Pearce DA, Alekhina IA, Terauds A, Wilmotte A, Quesada A, Edwards A, et al.
    Front Microbiol, 2016;7:16.
    PMID: 26909068 DOI: 10.3389/fmicb.2016.00016
    The role of aerial dispersal in shaping patterns of biodiversity remains poorly understood, mainly due to a lack of coordinated efforts in gathering data at appropriate temporal and spatial scales. It has been long known that the rate of dispersal to an ecosystem can significantly influence ecosystem dynamics, and that aerial transport has been identified as an important source of biological input to remote locations. With the considerable effort devoted in recent decades to understanding atmospheric circulation in the south-polar region, a unique opportunity has emerged to investigate the atmospheric ecology of Antarctica, from regional to continental scales. This concept note identifies key questions in Antarctic microbial biogeography and the need for standardized sampling and analysis protocols to address such questions. A consortium of polar aerobiologists is established to bring together researchers with a common interest in the airborne dispersion of microbes and other propagules in the Antarctic, with opportunities for comparative studies in the Arctic.
  13. Active restoration accelerates the carbon recovery of human-modified tropical forests
    Philipson CD, Cutler MEJ, Brodrick PG, Asner GP, Boyd DS, Moura Costa P, et al.
    Science, 2020 08 14;369(6505):838-841.
    PMID: 32792397 DOI: 10.1126/science.aay4490
    More than half of all tropical forests are degraded by human impacts, leaving them threatened with conversion to agricultural plantations and risking substantial biodiversity and carbon losses. Restoration could accelerate recovery of aboveground carbon density (ACD), but adoption of restoration is constrained by cost and uncertainties over effectiveness. We report a long-term comparison of ACD recovery rates between naturally regenerating and actively restored logged tropical forests. Restoration enhanced decadal ACD recovery by more than 50%, from 2.9 to 4.4 megagrams per hectare per year. This magnitude of response, coupled with modal values of restoration costs globally, would require higher carbon prices to justify investment in restoration. However, carbon prices required to fulfill the 2016 Paris climate agreement [$40 to $80 (USD) per tonne carbon dioxide equivalent] would provide an economic justification for tropical forest restoration.
  14. Fulltext Germline TET2 loss of function causes childhood immunodeficiency and lymphoma
    Stremenova Spegarova J, Lawless D, Mohamad SMB, Engelhardt KR, Doody G, Shrimpton J, et al.
    Blood, 2020 Aug 27;136(9):1055-1066.
    PMID: 32518946 DOI: 10.1182/blood.2020005844
    Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.
  15. Fulltext Evidence-based cardiovascular magnetic resonance cost-effectiveness calculator for the detection of significant coronary artery disease
    Pandya A, Yu YJ, Ge Y, Nagel E, Kwong RY, Bakar RA, et al.
    J Cardiovasc Magn Reson, 2022 01 06;24(1):1.
    PMID: 34986851 DOI: 10.1186/s12968-021-00833-1
    BACKGROUND: Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs.

    METHODS: We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography.

    RESULTS: CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model.

    CONCLUSIONS: Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.

  16. Fulltext Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis
    Rajasekhar M, Simpson JA, Ley B, Edler P, Chu CS, Abreha T, et al.
    Lancet Infect Dis, 2024 Feb;24(2):184-195.
    PMID: 37748497 DOI: 10.1016/S1473-3099(23)00431-0
    BACKGROUND: Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.

    METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680.

    FINDINGS: Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias.

    INTERPRETATION: Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.

    FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

  17. Electrodiagnostic subtyping in Guillain-Barré syndrome patients in the International Guillain-Barré Outcome Study
    Arends S, Drenthen J, de Koning L, van den Bergh P, Hadden RDM, Kuwabara S, et al.
    Eur J Neurol, 2024 Jul 04.
    PMID: 38965709 DOI: 10.1111/ene.16335
    BACKGROUND AND PURPOSE: Various electrodiagnostic criteria have been developed in Guillain-Barré syndrome (GBS). Their performance in a broad representation of GBS patients has not been evaluated. Motor conduction data from the International GBS Outcome Study (IGOS) cohort were used to compare two widely used criterion sets and relate these to diagnostic amyotrophic lateral sclerosis criteria.

    METHODS: From the first 1500 patients in IGOS, nerve conduction studies from 1137 (75.8%) were available for the current study. These patients were classified according to nerve conduction studies criteria proposed by Hadden and Rajabally.

    RESULTS: Of the 1137 studies, 68.3% (N = 777) were classified identically according to criteria by Hadden and Rajabally: 111 (9.8%) axonal, 366 (32.2%) demyelinating, 195 (17.2%) equivocal, 35 (3.1%) inexcitable and 70 (6.2%) normal. Thus, 360 studies (31.7%) were classified differently. The areas of differences were as follows: 155 studies (13.6%) classified as demyelinating by Hadden and axonal by Rajabally; 122 studies (10.7%) classified as demyelinating by Hadden and equivocal by Rajabally; and 75 studies (6.6%) classified as equivocal by Hadden and axonal by Rajabally. Due to more strictly defined cutoffs fewer patients fulfilled demyelinating criteria by Rajabally than by Hadden, making more patients eligible for axonal or equivocal classification by Rajabally. In 234 (68.6%) axonal studies by Rajabally the revised El Escorial (amyotrophic lateral sclerosis) criteria were fulfilled; in axonal cases by Hadden this was 1.8%.

    CONCLUSIONS AND DISCUSSION: This study shows that electrodiagnosis in GBS is dependent on the criterion set utilized, both of which are based on expert opinion. Reappraisal of electrodiagnostic subtyping in GBS is warranted.

  18. Fulltext Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis
    Commons RJ, Rajasekhar M, Edler P, Abreha T, Awab GR, Baird JK, et al.
    Lancet Infect Dis, 2024 Feb;24(2):172-183.
    PMID: 37748496 DOI: 10.1016/S1473-3099(23)00430-9
    BACKGROUND: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence.

    METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470.

    FINDINGS: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias.

    INTERPRETATION: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms.

    FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

  19. Human milk oligosaccharides are associated with maternal genetics and respiratory health of human milk-fed children
    Ambalavanan A, Chang L, Choi J, Zhang Y, Stickley SA, Fang ZY, et al.
    Nat Commun, 2024 Sep 04;15(1):7735.
    PMID: 39232002 DOI: 10.1038/s41467-024-51743-6
    Breastfeeding provides many health benefits, but its impact on respiratory health remains unclear. This study addresses the complex and dynamic nature of the mother-milk-infant triad by investigating maternal genomic factors regulating human milk oligosaccharides (HMOs), and their associations with respiratory health among human milk-fed infants. Nineteen HMOs are quantified from 980 mothers of the CHILD Cohort Study. Genome-wide association studies identify HMO-associated loci on chromosome 19p13.3 and 19q13.33 (lowest P = 2.4e-118), spanning several fucosyltransferase (FUT) genes. We identify novel associations on chromosome 3q27.3 for 6'-sialyllactose (P = 2.2e-9) in the sialyltransferase (ST6GAL1) gene. These, plus additional associations on chromosomes 7q21.32, 7q31.32 and 13q33.3, are replicated in the independent INSPIRE Cohort. Moreover, gene-environment interaction analyses suggest that fucosylated HMOs may modulate overall risk of recurrent wheeze among preschoolers with variable genetic risk scores (P 
  20. Fulltext Regional variation of Guillain-Barré syndrome
    Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al.
    Brain, 2018 10 01;141(10):2866-2877.
    PMID: 30247567 DOI: 10.1093/brain/awy232
    Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: 'Europe/Americas', 'Asia' (without Bangladesh), and 'Bangladesh'. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.
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