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Displaying publications 641 - 660 of 1087 in total

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Genome sequences and population genomics reveal climatic adaptation and genomic divergence between two closely related sweetgum species

Xu WQ, Ren CQ, Zhang XY, Comes HP, Liu XH, Li YG, et al.

Plant J, 2024 Feb 11.
PMID: 38343032 DOI: 10.1111/tpj.16675

Understanding the genetic basis of population divergence and adaptation is an important goal in population genetics and evolutionary biology. However, the relative roles of demographic history, gene flow, and/or selective regime in driving genomic divergence, climatic adaptation, and speciation in non-model tree species are not yet fully understood. To address this issue, we generated whole-genome resequencing data of Liquidambar formosana and L. acalycina, which are broadly sympatric but altitudinally segregated in the Tertiary relict forests of subtropical China. We integrated genomic and environmental data to investigate the demographic history, genomic divergence, and climatic adaptation of these two sister species. We inferred a scenario of allopatric species divergence during the late Miocene, followed by secondary contact during the Holocene. We identified multiple genomic islands of elevated divergence that mainly evolved through divergence hitchhiking and recombination rate variation, likely fostered by long-term refugial isolation and recent differential introgression in low-recombination genomic regions. We also found some candidate genes with divergent selection signatures potentially involved in climatic adaptation and reproductive isolation. Our results contribute to a better understanding of how late Tertiary/Quaternary climatic change influenced speciation, genomic divergence, climatic adaptation, and introgressive hybridization in East Asia's Tertiary relict flora. In addition, they should facilitate future evolutionary, conservation genomics, and molecular breeding studies in Liquidambar, a genus of important medicinal and ornamental values.
Fulltext Analysis of nuclear and organellar genomes of Plasmodium knowlesi in humans reveals ancient population structure and recent recombination among host-specific subpopulations

Diez Benavente E, Florez de Sessions P, Moon RW, Holder AA, Blackman MJ, Roper C, et al.

PLoS Genet, 2017 Sep;13(9):e1007008.
PMID: 28922357 DOI: 10.1371/journal.pgen.1007008

The macaque parasite Plasmodium knowlesi is a significant concern in Malaysia where cases of human infection are increasing. Parasites infecting humans originate from genetically distinct subpopulations associated with the long-tailed (Macaca fascicularis (Mf)) or pig-tailed macaques (Macaca nemestrina (Mn)). We used a new high-quality reference genome to re-evaluate previously described subpopulations among human and macaque isolates from Malaysian-Borneo and Peninsular-Malaysia. Nuclear genomes were dimorphic, as expected, but new evidence of chromosomal-segment exchanges between subpopulations was found. A large segment on chromosome 8 originating from the Mn subpopulation and containing genes encoding proteins expressed in mosquito-borne parasite stages, was found in Mf genotypes. By contrast, non-recombining organelle genomes partitioned into 3 deeply branched lineages, unlinked with nuclear genomic dimorphism. Subpopulations which diverged in isolation have re-connected, possibly due to deforestation and disruption of wild macaque habitats. The resulting genomic mosaics reveal traits selected by host-vector-parasite interactions in a setting of ecological transition.
Chemsex and Harm Reduction Practices Among Men Who Have Sex with Men in Malaysia: Findings from a Qualitative Study

Palmer L, Maviglia F, Wickersham JA, Khati A, Kennedy O, Copenhaver NM, et al.

J Psychoactive Drugs, 2023 Aug 23.
PMID: 37610135 DOI: 10.1080/02791072.2023.2250342

Chemsex is a form of sexualized drug use commonly practiced among MSM with psychoactive substances, such as methamphetamine. While this phenomenon has gained global attention in the past two decades, there is a dearth of empirical data to inform culturally competent interventions. The current work investigates the socio-contextual factors related to chemsex and harm reduction practices among Malaysian MSM. Between February and August 2022, we conducted six online focus group sessions with Malaysian MSM who had engaged in chemsex during the previous 6 months (N = 22). We queried participants about perceived benefits and harms, harm reduction practices, and informational needs. Most participants' first chemsex experience occurred in a casual sexual encounter, often facilitated by mobile technology. Participants reported engaging in harm reduction practices before (e.g. medication reminders), during (e.g. peer support), and after (e.g. rest) chemsex. These findings have implications for future efforts to develop and implement tailored interventions to address the specific and acute needs of Malaysian MSM engaging in chemsex.
Fulltext Next-generation, personalised, model-based critical care medicine: a state-of-the art review of in silico virtual patient models, methods, and cohorts, and how to validation them

Chase JG, Preiser JC, Dickson JL, Pironet A, Chiew YS, Pretty CG, et al.

Biomed Eng Online, 2018 Feb 20;17(1):24.
PMID: 29463246 DOI: 10.1186/s12938-018-0455-y

Critical care, like many healthcare areas, is under a dual assault from significantly increasing demographic and economic pressures. Intensive care unit (ICU) patients are highly variable in response to treatment, and increasingly aging populations mean ICUs are under increasing demand and their cohorts are increasingly ill. Equally, patient expectations are growing, while the economic ability to deliver care to all is declining. Better, more productive care is thus the big challenge. One means to that end is personalised care designed to manage the significant inter- and intra-patient variability that makes the ICU patient difficult. Thus, moving from current "one size fits all" protocolised care to adaptive, model-based "one method fits all" personalised care could deliver the required step change in the quality, and simultaneously the productivity and cost, of care. Computer models of human physiology are a unique tool to personalise care, as they can couple clinical data with mathematical methods to create subject-specific models and virtual patients to design new, personalised and more optimal protocols, as well as to guide care in real-time. They rely on identifying time varying patient-specific parameters in the model that capture inter- and intra-patient variability, the difference between patients and the evolution of patient condition. Properly validated, virtual patients represent the real patients, and can be used in silico to test different protocols or interventions, or in real-time to guide care. Hence, the underlying models and methods create the foundation for next generation care, as well as a tool for safely and rapidly developing personalised treatment protocols over large virtual cohorts using virtual trials. This review examines the models and methods used to create virtual patients. Specifically, it presents the models types and structures used and the data required. It then covers how to validate the resulting virtual patients and trials, and how these virtual trials can help design and optimise clinical trial. Links between these models and higher order, more complex physiome models are also discussed. In each section, it explores the progress reported up to date, especially on core ICU therapies in glycemic, circulatory and mechanical ventilation management, where high cost and frequency of occurrence provide a significant opportunity for model-based methods to have measurable clinical and economic impact. The outcomes are readily generalised to other areas of medical care.
Review of quorum-quenching probiotics: A promising non-antibiotic-based strategy for sustainable aquaculture

Lubis AR, Sumon MAA, Dinh-Hung N, Dhar AK, Delamare-Deboutteville J, Kim DH, et al.

J Fish Dis, 2024 Mar 24.
PMID: 38523339 DOI: 10.1111/jfd.13941

The emergence of antibiotic-resistant bacteria (ARBs) and genes (ARGs) in aquaculture underscores the urgent need for alternative veterinary strategies to combat antimicrobial resistance (AMR). These measures are vital to reduce the likelihood of entering a post-antibiotic era. Identifying environmentally friendly biotechnological solutions to prevent and treat bacterial diseases is crucial for the sustainability of aquaculture and for minimizing the use of antimicrobials, especially antibiotics. The development of probiotics with quorum-quenching (QQ) capabilities presents a promising non-antibiotic strategy for sustainable aquaculture. Recent research has demonstrated the effectiveness of QQ probiotics (QQPs) against a range of significant fish pathogens in aquaculture. QQ disrupts microbial communication (quorum sensing, QS) by inhibiting the production, replication, and detection of signalling molecules, thereby reducing bacterial virulence factors. With their targeted anti-virulence approach, QQPs have substantial promise as a potential alternative to antibiotics. The application of QQPs in aquaculture, however, is still in its early stages and requires additional research. Key challenges include determining the optimal dosage and treatment regimens, understanding the long-term effects, and integrating QQPs with other disease control methods in diverse aquaculture systems. This review scrutinizes the current literature on antibiotic usage, AMR prevalence in aquaculture, QQ mechanisms and the application of QQPs as a sustainable alternative to antibiotics.
Fulltext Efficacy of Artesunate-mefloquine for Chloroquine-resistant Plasmodium vivax Malaria in Malaysia: An Open-label, Randomized, Controlled Trial

Grigg MJ, William T, Menon J, Barber BE, Wilkes CS, Rajahram GS, et al.

Clin Infect Dis, 2016 Jun 01;62(11):1403-1411.
PMID: 27107287 DOI: 10.1093/cid/ciw121

BACKGROUND: Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown.
METHODS: A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan-Meier analysis.
RESULTS: From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8-75.6) after CQ and 0% (95% CI, 0-.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5-9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P =001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5-9.3; P =005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60-.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment.
CONCLUSIONS: High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.Clinical Trials Registration NCT01708876.
Fulltext The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells

Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam MU, et al.

PLoS One, 2017;12(8):e0182357.
PMID: 28771532 DOI: 10.1371/journal.pone.0182357

Nature has provided us with a wide spectrum of disease healing phytochemicals like Artonin E, obtained from the root bark of Artocarpus elasticus. This molecule had been predicted to be drug-like, possessing unique medicinal properties. Despite strides made in chemotherapy, prognosis of the heterogenous aggressive triple negative breast cancer is still poor. This study was conducted to investigate the mechanism of inhibition of Artonin E, a prenylated flavonoid on MDA-MB 231 triple negative breast cancer cell, with a view of mitigating the hallmarks displayed by these tumors. The anti-proliferative effect, mode of cell death and the mechanism of apoptosis induction were investigated. Artonin E, was seen to effectively relinquish MDA-MB 231 breast cancer cells of their apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after the tested time points (24, 48 and 72 hours), respectively. The mode of cell death was observed to be apoptosis with defined characteristics. Artonin E was seen to induce the activation of both extrinsic and intrinsic caspases initiators of apoptosis. It also enhanced the release of total reactive oxygen species which polarized the mitochondrial membrane, compounding the release of cytochrome c. Gene expression studies revealed the upregulation of TNF-related apoptosis inducing ligand and proapoptotic genes with down regulation of anti-apoptotic genes and proteins. A G2/M cell cycle arrest was also observed and was attributed to the observed upregulation of p21 independent of the p53 status. Interestingly, livin, a new member of the inhibitors of apoptosis was confirmed to be significantly repressed. In all, Artonin E showed the potential as a promising candidate to combat the aggressive triple negative breast cancer.
Fulltext Physician Decisions to Defer Antiretroviral Therapy in Key Populations: Implications for Reducing Human Immunodeficiency Virus Incidence and Mortality in Malaysia

Ferro EG, Culbert GJ, Wickersham JA, Marcus R, Steffen AD, Pauls HA, et al.

Open Forum Infect Dis, 2017;4(1):ofw219.
PMID: 28480230 DOI: 10.1093/ofid/ofw219

BACKGROUND: Antiretroviral therapy (ART) is recommended for all people living with human immunodeficiency virus (HIV), yet physician attitudes and prescribing behaviors toward members of key risk populations may limit ART access and undermine treatment as prevention strategies.
METHODS: Physicians in Malaysia (N = 214) who prescribe antiretroviral therapy (ART) responded in an Internet-based survey to hypothetical clinical scenarios of HIV patients, varying by key risk population and CD4+ T-cell count, on whether they would initiate or defer ART compared with a control patient with sexually acquired HIV.
RESULTS: The proportion of physicians who would defer ART in patients with advanced HIV (CD4 = 17 cells/μL) was significantly higher (P < .0001) for 4 key populations, including people who inject drugs ([PWID] 45.3%) or consume alcohol (42.1%), released prisoners (35.0%), and those lacking social support (26.6%), compared with a control patient (4.2%). People who inject drugs with advanced HIV (CD4 = 17 cells/μL) were 19-fold (adjusted odds ratio [AOR] = 18.9; 95% confidence interval [CI], 9.8-36.5) more likely to have ART deferred compared with the control. This effect was partially mitigated for PWID receiving methadone (AOR = 2.9; 95% CI, 1.5-5.7). At the highest CD4+ T-cell count (CD4 = 470 cells/μL), sex workers (AOR = 0.55; 95% CI, .44-.70) and patients with an HIV-uninfected sexual partner (AOR = 0.43; 95% CI, .34-.57) were significantly less likely to have ART deferred.
CONCLUSIONS: Physicians who prescribe antiretroviral therapy in Malaysia may defer ART in some key populations including PWID and released prisoners, regardless of CD4+ T-cell count, which may help to explain very low rates of ART coverage among PWID in Malaysia. Reducing HIV incidence and mortality in Malaysia, where HIV is concentrated in PWID and other key populations, requires clinician-level interventions and monitoring physician adherence to international evidence-based treatment guidelines.
Fulltext Implementation of Brain Breaks® in the Classroom and Its Effects on Attitudes towards Physical Activity in a Chinese School Setting

Zhou K, He S, Zhou Y, Popeska B, Kuan G, Chen L, et al.

Int J Environ Res Public Health, 2021 01 01;18(1).
PMID: 33401384 DOI: 10.3390/ijerph18010272

This study aimed to examine the effects of three-months of classroom-based Brain Breaks Physical Activity Solution (Brain Breaks®) on attitudes toward physical activity levels of primary school children in Henan Province, China. The participants were 704 children enrolled in grades 3-5 who were randomly assigned to either an experimental or a control group. The experimental group participated in Brain Breaks® video intervention for 3-5 min daily, at low-to-moderate intensity for three consecutive months. The control group resumed their normal routine. The children's attitudes in both groups towards physical activity (PA) were evaluated using the self-reported Attitudes toward Physical Activity Scale (APAS), before and after the intervention. The effects of the intervention on APAS scores were analyzed using mixed model analysis of variance with Time as within-subject, and Group as between-subject factors. The analysis revealed evidence in support of the positive effect of classroom video interventions such as Brain Break on children's attitudes toward importance, fun, and trying to do their personal best in physical activity. Also revealed was the important role the teacher plays in this process.
Kidney Transplantation Outcomes From Uncontrolled Donation After Circulatory Death: A Systematic Review and Meta-analysis

Vijayan K, Schroder HJ, Hameed A, Hitos K, Lo W, Laurence JM, et al.

Transplantation, 2024 Feb 16.
PMID: 38361237 DOI: 10.1097/TP.0000000000004937

BACKGROUND: Uncontrolled donation after circulatory death (uDCD) is a potential additional source of donor kidneys. This study reviewed uDCD kidney transplant outcomes to determine if these are comparable to controlled donation after circulatory death (cDCD).
METHODS: MEDLINE, Cochrane, and Embase databases were searched. Data on demographic information and transplant outcomes were extracted from included studies. Meta-analyses were performed, and risk ratios (RR) were estimated to compare transplant outcomes from uDCD to cDCD.
RESULTS: Nine cohort studies were included, from 2178 uDCD kidney transplants. There was a moderate degree of bias, as 4 studies did not account for potential confounding factors. The median incidence of primary nonfunction in uDCD was 12.3% versus 5.7% for cDCD (RR, 1.85; 95% confidence intervals, 1.06-3.23; P = 0.03, I2 = 75). The median rate of delayed graft function was 65.1% for uDCD and 52.0% for cDCD. The median 1-y graft survival for uDCD was 82.7% compared with 87.5% for cDCD (RR, 1.43; 95% confidence intervals, 1.02-2.01; P = 0.04; I2 = 71%). The median 5-y graft survival for uDCD and cDCD was 70% each. Notably, the use of normothermic regional perfusion improved primary nonfunction rates in uDCD grafts.
CONCLUSIONS: Although uDCD outcomes may be inferior in the short-term, the long-term outcomes are comparable to cDCD.
Cortical glutamate and GABA are related to compulsive behaviour in individuals with obsessive compulsive disorder and healthy controls

Biria M, Banca P, Healy MP, Keser E, Sawiak SJ, Rodgers CT, et al.

Nat Commun, 2023 Jun 27;14(1):3324.
PMID: 37369695 DOI: 10.1038/s41467-023-38695-z

There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.
Psychometric properties of instruments for measuring abuse of older people in community and institutional settings: A systematic review

Mohd Mydin FH, Mikton C, Choo WY, Shunmugam RH, Murray A, Yon Y, et al.

Campbell Syst Rev, 2024 Sep;20(3):e1419.
PMID: 39211334 DOI: 10.1002/cl2.1419

BACKGROUND: The examination of psychometric properties in instruments measuring abuse of older people (AOP) is a crucial area of study that has, unfortunately, received relatively little attention. Poor psychometric properties in AOP measurement instruments can significantly contribute to inconsistencies in prevalence estimates, casting a shadow of uncertainty over the magnitude of the problem at national, regional, and global levels.
OBJECTIVES: This review rigorously employed the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) guideline on the quality of outcome measures. It was designed to identify and review the instruments used to measure AOP, assess the instruments' measurement properties, and identify the definitions of AOP and abuse subtypes measured by these instruments, ensuring the reliability and validity of the findings.
SEARCH METHODS: A comprehensive search was conducted up to May 2023 across various online databases, including AgeLine via EBSCOhost, ASSIA via ProQuest, CINAHL via EBSCOhost, EMBASE, LILACS, ProQuest Dissertation & Theses Global, PsycINFO via EBSCOhost, PubMed, SciELO, Scopus, Sociological Abstract via ProQuest, Chinese National Knowledge Infrastructure (CNKI), Google Scholar and WHO Global Index Medicus. Additionally, relevant studies were identified by thoroughly searching the grey literature from resources such as Campbell Collaboration, OpenAIRE, and GRAFT.
SELECTION CRITERIA: All quantitative, qualitative (addressing face and content validity), and mixed-method empirical studies published in peer-reviewed journals or grey literature were included in this review. The included studies were primary studies that (1) evaluated one or more psychometric properties, (2) contained information on instrument development, or (3) examined the content validity of the instruments designed to measure AOP in community or institutional settings. The selected studies describe at least one psychometric property: reliability, validity, and responsiveness. Study participants represent the population of interest, including males and females aged 60 or older in community or institutional settings.
DATA COLLECTION AND ANALYSIS: Two reviewers evaluated the screening of the selected studies' titles, abstracts, and full texts based on the preset selection criteria. Two reviewers assessed the quality of each study using the COSMIN Risk of Bias checklist and the overall quality of evidence for each psychometric property of the instrument against the updated COSMIN criteria of good measurement properties. Disagreements were resolved through consensus discussion or with assistance from a third reviewer. The overall quality of the measurement instrument was graded using a modified GRADE approach. Data extraction was performed using data extraction forms adapted from the COSMIN Guideline for Systematic Reviews of Outcome Measurement Instruments. The extracted data included information on the characteristics of included instruments (name, adaptation, language used, translation and country of origin), characteristics of the tested population, instrument development, psychometric properties listed in the COSMIN criteria, including details on content validity, structural validity, internal consistency, cross-cultural validity/measurement invariance, reliability, measurement error, criterion validity, hypotheses testing for construct validity, responsiveness, and interoperability. All data were synthesised and summarised qualitatively, and no meta-analysis was performed.
MAIN RESULTS: We found 15,200 potentially relevant records, of which 382 were screened in full text. A total of 114 studies that met the inclusion criteria were included. Four studies reported on more than one instrument. The primary reasons for excluding studies were their focus on instruments used solely for screening and diagnostic purposes, those conducted in hospital settings, or those without evaluating psychometric properties. Eighty-seven studies reported on 46 original instruments and 29 studies on 22 modified versions of an original instrument. The majority of the studies were conducted in community settings (97 studies) from the perspective of older adults (90 studies) and were conducted in high-income countries (69 studies). Ninety-five studies assessed multiple forms of abuse, ranging from 2 to 13 different subscales; four studies measured overall abuse and neglect among older adults, and 14 studies measured one specific type of abuse. Approximately one-quarter of the included studies reported on the psychometric properties of the most frequently used measurement instruments: HS-EAST (assessed in 11 studies), VASS-12 items (in 9 studies), and CASE (in 9 studies). The instruments with the most evidence available in studies reporting on instrument development and content validity in all domains (relevance, comprehensiveness and comprehensibility) were the DEAQ, OAPAM, *RAAL-31 items, *ICNH (Norwegian) and OAFEM. For other psychometric properties, instruments with the most evidence available in terms of the number of studies were the HS-EAST (11 studies across 5 of 9 psychometric properties), CASE (9 studies across 6 of 9 psychometric properties), VASS-12 items (9 studies across 5 of 9 psychometric properties) and GMS (5 studies across 4 of 9 psychometric properties). Based on the overall rating and quality of evidence, the psychometric properties of the AOP measurement instruments used for prevalence measurement in community and institutional settings were insufficient and of low quality.
AUTHORS' CONCLUSIONS: This review aimed to assess the overall rating and quality of evidence for instruments measuring AOP in the community and institutional settings. Our findings revealed various measurement instruments, with ratings and evidence quality predominantly indicating insufficiency and low quality. In summary, the psychometric properties of AOP measurement instruments have not been comprehensively investigated, and existing instruments lack sufficient evidence to support their validity and reliability.
An Integrated Module Performs Selective 'Online' Epoxidation in the Biosynthesis of the Antibiotic Mupirocin

Winter AJ, de Courcy-Ireland F, Phillips AP, Barker JM, Bakar NA, Akter N, et al.

Angew Chem Int Ed Engl, 2024 Dec 02;63(49):e202410502.
PMID: 39105412 DOI: 10.1002/anie.202410502

The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges, and the timing and mechanisms of several key transformations remain elusive. Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA-B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid side chain required for biological activity. Herein, we show that the mini-module MmpE performs a rare online (ACP-substrate) epoxidation and is integrated ('in-cis') into the polyketide synthase via a docking domain. A linear polyketide fragment with six asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP-bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA-B.
Microstructural white matter changes mediate age-related cognitive decline on the Montreal Cognitive Assessment (MoCA)

Jolly TA, Cooper PS, Badwi SA, Phillips NA, Rennie JL, Levi CR, et al.

Psychophysiology, 2016 Feb;53(2):258-67.
PMID: 26511789 DOI: 10.1111/psyp.12565

Although the relationship between aging and cognitive decline is well established, there is substantial individual variability in the degree of cognitive decline in older adults. The present study investigates whether variability in cognitive performance in community-dwelling older adults is related to the presence of whole brain or tract-specific changes in white matter microstructure. Specifically, we examine whether age-related decline in performance on the Montreal Cognitive Assessment (MoCA), a cognitive screening tool, is mediated by the white matter microstructural decline. We also examine if this relationship is driven by the presence of cardiovascular risk factors or variability in cerebral arterial pulsatility, an index of cardiovascular risk. Sixty-nine participants (aged 43-87) completed behavioral and MRI testing including T1 structural, T2-weighted FLAIR, and diffusion-weighted imaging (DWI) sequences. Measures of white matter microstructure were calculated using diffusion tensor imaging analyses on the DWI sequence. Multiple linear regression revealed that MoCA scores were predicted by radial diffusivity (RaD) of white matter beyond age or other cerebral measures. While increasing age and arterial pulsatility were associated with increasing RaD, these factors did not mediate the relationship between total white matter RaD and MoCA. Further, the relationship between MoCA and RaD was specific to participants who reported at least one cardiovascular risk factor. These findings highlight the importance of cardiovascular risk factors in the presentation of cognitive decline in old age. Further work is needed to establish whether medical or lifestyle management of these risk factors can prevent or reverse cognitive decline in old age.
Fulltext Rickettsioses as Major Etiologies of Unrecognized Acute Febrile Illness, Sabah, East Malaysia

Grigg MJ, William T, Clemens EG, Patel K, Chandna A, Wilkes CS, et al.

Emerg Infect Dis, 2020 Jul;26(7):1409-19.
PMID: 32568664 DOI: 10.3201/eid2607.191722

Orientia tsutsugamushi, spotted fever group rickettsioses, and typhus group rickettsioses (TGR) are reemerging causes of acute febrile illness (AFI) in Southeast Asia. To further delineate extent, we enrolled patients >4 weeks of age with nonmalarial AFI in Sabah, Malaysia, during 2013-2015. We confirmed rickettsioses (past or acute, IgG titer >160) in 126/354 (36%) patients. We confirmed acute rickettsioses (paired 4-fold IgG titer rise to >160) in 38/145 (26%) patients: 23 O. tsutsugamushi, 9 spotted fever group, 4 TGR, 1 O. tsutsugamushi/spotted fever group, and 1 O. tsutsugamushi/TGR. PCR results were positive in 11/319 (3%) patients. Confirmed rickettsioses were more common in male adults; agricultural/plantation work and recent forest exposure were risk factors. Dizziness and acute hearing loss but not eschars were reported more often with acute rickettsioses. Only 2 patients were treated with doxycycline. Acute rickettsioses are common (>26%), underrecognized, and untreated etiologies of AFI in East Malaysia; empirical doxycycline treatment should be considered.
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.
Fulltext Educating Future Generations of Surgeons across Borders: Novel Global Linked Hybrid Live Cadaveric Peripheral Nerve Surgical Training Course

Burahee AS, Duraku LS, Hundepool CA, Eberlin KR, Moore A, Dy CJ, et al.

Plast Reconstr Surg Glob Open, 2024 Jan;12(1):e5559.
PMID: 38264442 DOI: 10.1097/GOX.0000000000005559

BACKGROUND: This study aimed to evaluate a novel, multi-site, technology-facilitated education and training course in peripheral nerve surgery. The program was developed to address the training gaps in this specialized field by integrating a structured curriculum, high-fidelity cadaveric dissection, and surgical simulation with real-time expert guidance.
METHODS: A collaboration between the Global Nerve Foundation and Esser Masterclass facilitated the program, which was conducted across three international sites. The curriculum was developed by a panel of experienced peripheral nerve surgeons and included both text-based and multimedia resources. Participants' knowledge and skills were assessed using pre- and postcourse questionnaires.
RESULTS: A total of 73 participants from 26 countries enrolled and consented for data usage for research purposes. The professional background was diverse, including hand surgeons, plastic surgeons, orthopedic surgeons, and neurosurgeons. Participants reported significant improvements in knowledge and skills across all covered topics (p < 0.001). The course received a 100% recommendation rate, and 88% confirmed that it met their educational objectives.
CONCLUSIONS: This study underscores the potential of technology-enabled, collaborative expert-led training programs in overcoming geographical and logistical barriers, setting a new standard for globally accessible, high-quality surgical training. It highlights the practical and logistical challenges of multi-site training, such as time zone differences and participant fatigue. It also provides practical insights for future medical educational endeavors, particularly those that aim to be comprehensive, international, and technologically facilitated.
Fulltext PROTOCOL: Psychometric properties of instruments for measuring elder abuse and neglect in community and institutional settings: A systematic review

Mohd Mydin FH, Mikton C, Choo WY, Shanmugam RH, Murray A, Yon Y, et al.

Campbell Syst Rev, 2023 Sep;19(3):e1342.
PMID: 37383829 DOI: 10.1002/cl2.1342

BACKGROUND: The psychometric properties of elder abuse measurement instruments have not been well-studied. Poor psychometric properties of elder abuse measurement instruments may contribute to the inconsistency of elder abuse prevalence estimates and uncertainty about the magnitude of the problem at the national, regional, and global levels.
OBJECTIVES: The present review will utilise the COSMIN taxonomy on the quality of outcome measures to identify and review the instruments used in measuring elder abuse, assess the instrument's measurement properties, and identify the definitions of elder abuse and abuse subtypes measured by the instrument.
SEARCH METHODS: Searches will be conducted in the following online databases: Ageline, ASSIA, CINAHL, CNKI, EMBASE, Google Scholar, LILACS, Proquest Dissertation & Theses Global, PsycINFO, PubMed, SciELO, Scopus, Sociological Abstract and WHO Index Medicus. Relevant studies will also be identified by searching the grey literature from several resources such as OpenAIRE, BASE, OISter and Age Concern NZPotential studies by searching the references of related reviews. We will contact experts who have conducted similar work or are currently conducting ongoing studies. Enquiries will also be sent to the relevant authors if any important data is missing, incomplete or unclear.
SELECTION CRITERIA: All quantitative, qualitative (that address face and content validity), and mixed-method empirical studies published in peer-reviewed journals or the grey literature will be included in this review. Studies will be included if they are primary studies that (1) evaluate one or more psychometric properties; (2) contain information on instrument development, or (3) perform content validity of the instruments designed to measure elder abuse in the community or institutional settings. Studies should describe at least one of the psychometric properties, such as reliability, validity and responsiveness. Study participants represent the population of interest, including males and females aged 60 or older in community or institutional settings (i.e., nursing homes, long-term care facilities, assisted living, residential care institutions, and residential facilities).
DATA COLLECTION AND ANALYSIS: Screening of titles, abstracts, and full texts of the selected studies will be evaluated based on the preset inclusion criteria by two reviewers. Two reviewers will be assessing the quality appraisal of each study using the COSMIN Risk of Bias checklist and the overall quality of evidence of each psychometric property of the instrument against the updated criteria of good measurement properties. Any dispute between the two reviewers will be resolved through discussions or consensus with a third reviewer. The overall quality of the measurement instrument will be graded using a modified GRADE approach. Data extraction will be performed using the data extraction forms adapted from the COSMIN Guideline for Systematic Reviews of Outcome Measurement Instruments. The information includes the characteristic of included instruments (name, adaptation, language used, translation and country of origin), characteristics of the tested population, psychometric properties listed in the COSMIN criteria, including details on the instrument development, content validity, structural validity, internal consistency, cross-cultural validity/measurement invariance, reliability, measurement error, criterion validity, hypotheses testing for construct validity, responsiveness and interoperability. We will perform a meta-analysis to pool psychometric properties parameters (where possible) or summarise qualitatively.
Fulltext Influenza outbreaks during World Youth Day 2008 mass gathering

Blyth CC, Foo H, van Hal SJ, Hurt AC, Barr IG, McPhie K, et al.

Emerg Infect Dis, 2010 May;16(5):809-15.
PMID: 20409371 DOI: 10.3201/eid1605.091136

Influenza outbreaks during mass gatherings have been rarely described, and detailed virologic assessment is lacking. An influenza outbreak occurred during World Youth Day in Sydney, Australia, July 2008 (WYD2008). We assessed epidemiologic data and respiratory samples collected from attendees who sought treatment for influenza-like illness at emergency clinics in Sydney during this outbreak. Isolated influenza viruses were compared with seasonal influenza viruses from the 2008 influenza season. From 100 infected attendees, numerous strains were identified: oseltamivir-resistant influenza A (H1N1) viruses, oseltamivir-sensitive influenza A (H1N1) viruses, influenza A (H3N2) viruses, and strains from both influenza B lineages (B/Florida/4/2006-like and B/Malaysia/2506/2004-like). Novel viruses were introduced, and pre-WYD2008 seasonal viruses were amplified. Viruses isolated at mass gatherings can have substantial, complex, and unpredictable effects on community influenza activity. Greater flexibility by public health authorities and hospitals is required to appropriately manage and contain these outbreaks.
Fulltext High shear in situ exfoliation of 2D gallium oxide sheets from centrifugally derived thin films of liquid gallium

Vimalanathan K, Palmer T, Gardner Z, Ling I, Rahpeima S, Elmas S, et al.

Nanoscale Adv, 2021 Oct 12;3(20):5785-5792.
PMID: 36132680 DOI: 10.1039/d1na00598g

A diversity of two-dimensional nanomaterials has recently emerged with recent attention turning to the post-transition metal elements, in particular material derived from liquid metals and eutectic melts below 330 °C where processing is more flexible and in the temperature regime suitable for industry. This has been explored for liquid gallium using an angled vortex fluidic device (VFD) to fabricate ultrathin gallium oxide (Ga2O3) sheets under continuous flow conditions. We have established the nanosheets to form highly insulating material and have electrocatalytic activity for hydrogen evolution, with a Tafel slope of 39 mV dec-1 revealing promoting effects of the surface oxidation (passivation layer).

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