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  1. Fong FC, Smith DR
    Environ Res, 2022 Sep;212(Pt A):113099.
    PMID: 35305982 DOI: 10.1016/j.envres.2022.113099
    The exposure-lag response of air temperature on daily COVID-19 incidence is unclear and there have been concerns regarding the robustness of previous studies. Here we present an analysis of high spatial and temporal resolution using the distributed lag non-linear modelling (DLNM) framework. Utilising nearly two years' worth of data, we fit statistical models to twelve Italian cities to quantify the delayed effect of air temperature on daily COVID-19 incidence, accounting for several categories of potential confounders (meteorological, air quality and non-pharmaceutical interventions). Coefficients and covariance matrices for the temperature term were then synthesised using random effects meta-analysis to yield pooled estimates of the exposure-lag response with effects presented as the relative risk (RR) and cumulative RR (RRcum). The cumulative exposure response curve was non-linear, with peak risk at 15.1 °C and declining risk at progressively lower and higher temperatures. The lowest RRcum at 0.2 °C is 0.72 [0.56,0.91] times that of the highest risk. Due to this non-linearity, the shape of the lag response curve necessarily varied by temperature. This work suggests that on a given day, air temperature approximately 15 °C maximises the incidence of COVID-19, with the effects distributed in the subsequent ten days or more.
  2. Thomson PJ, Goodson ML, Smith DR
    J Oral Pathol Med, 2018 Jul;47(6):557-565.
    PMID: 29663518 DOI: 10.1111/jop.12716
    BACKGROUND: Clinically identifiable potentially malignant disorders (PMD) precede oral squamous cell carcinoma development. Oral lichenoid lesions (OLL) and proliferative verrucous leukoplakia (PVL) are specific precursor lesions believed to exhibit both treatment resistance and a high risk of malignant transformation (MT).

    METHODS: A retrospective review of 590 PMD patients treated in Northern England by CO2 laser surgery between 1996 and 2014 was carried out. Lesions exhibiting lichenoid or proliferative verrucous features were identified from the patient database and their clinicopathological features and outcome post-treatment determined at the study census date of 31 December 2014.

    RESULTS: One hundred and 98 patients were identified as follows: 118 OLL and 80 PVL, most frequently leukoplakia at ventrolateral tongue and floor of mouth sites, equally distributed between males and females. Most exhibited dysplasia on incision biopsy (72% OLL; 85% PVL) and were treated by laser excision rather than ablation (88.1% OLL; 86.25% PVL). OLL were more common in younger patients (OLL 57.1 year; PVL 62.25 years; P = .008) and more likely than PVL to present as erythroleukoplakia (OLL 15.3%; PVL 2.5%; P = .003). Whilst no significant difference was seen between OLL and PVL achieving disease-free status (69.5% and 65%, respectively; P = .55), this was less than the overall PMD cohort (74.2%). MT was identified in 2 OLL (1.7%) and 2 PVL (2.5%) during follow-up.

    CONCLUSION: One-third of PMD cases showed features of OLL or PVL, probably representing a disease presentation continuum. Post-treatment disease-free status was less common in OLL and PVL, although MT was infrequent.

  3. Behzadnia A, Smith DR, Goodson ML
    Educ Health (Abingdon), 2018 12 12;31(2):80-86.
    PMID: 30531049 DOI: 10.4103/efh.EfH_280_17
    Background: Learning approaches have been proposed to affect the experience of psychological stress among tertiary students in recent years. This relationship becomes important in stressful environments such as medical schools. However, the relationship between stress and learning approaches is not well understood, and often studies done cannot be generalized due to different sociocultural differences. In particular, no study in Malaysia has looked at learning approaches among medical students.

    Aims: To address this gap, we examined the relationship between perceived stress and learning approaches by considering sources of stress.

    Methodology: The Perceived Stress Scale (PSS-10), Medical Student Stressor Questionnaire, and the Revised Two-Factor Study Process Questionnaire were answered by the preclinical and final-year students studying MBBS in a Malaysian campus of British University.

    Results: Deep learning was positively and surface learning negatively associated with perception of coping with stress. In this study, neither approaches were associated with psychological stress as opposed to previous reports. We found surface learners to report higher level of stress associated with social stressors. We found students' self-perception of feeling incompetent and feeling they need to do well to be significant sources of stress.

    Discussion: Deep learning promotes psychological resilience. This is of paramount importance in learning environments where stress is highly prevalent such as medical school. Promotion of deep learning among medical students is required at earlier stages as they tend to solidify their approach through their university years and carry that approach beyond school into their workplace.
  4. Imawana RA, Smith DR, Goodson ML
    Ann Gastroenterol, 2020 06 06;33(5):485-494.
    PMID: 32879595 DOI: 10.20524/aog.2020.0507
    Background: The current literature suggests a protective benefit of Helicobacter pylori (H. pylori) infection against inflammatory bowel disease (IBD). Here we assessed whether this effect varied by IBD subtype-Crohn's disease (CD) or ulcerative colitis (UC)-and geographic region: East Asia, Europe (non-Mediterranean) or Mediterranean region.

    Methods: A database search was performed up to July 2019 inclusive for all studies that compared H. pylori infection in IBD patients vs. non-IBD controls. The relative risk (RR) was used to quantify the association between IBD and H. pylori, and the effects were combined across studies using a mixed-effects meta-regression model, which included IBD subtype and geographic region as categorical moderator variables.

    Results: Our meta-regression model exhibited moderate heterogeneity (I2=48.74%). Pooled RR depended on both region (P=0.02) and subtype (P<0.001). Pooled RRs were <1 for all subtype and region combinations, indicative of a protective effect of H. pylori against IBD. The pooled RR was 28% (9%, 50%; P=0.001) greater for UC vs. CD and 43% (4%, 96%; P=0.02) greater for Mediterranean countries vs. East Asia. The pooled RR was 18% (-13%, 60%; P=0.48) greater for Europe vs. East Asia and 21% (-13%, 68%; P=0.42) greater for Mediterranean vs. Europe, though these differences were not statistically significant.

    Conclusions: The protective effect of H. pylori on IBD varied by both subtype (more protection against CD vs. UC) and region (East Asia more protected than Mediterranean regions). Variation due to these effects could provide insight into IBD etiology.

  5. Goodson ML, Smith DR, Thomson PJ
    J Oral Pathol Med, 2019 Sep;48(8):662-668.
    PMID: 31125457 DOI: 10.1111/jop.12881
    BACKGROUND: Nomograms are graphical calculating devices used to predict risk of malignant transformation (MT) or response to treatment during cancer management. To date, a nomogram has not been used to predict clinical outcome during oral potentially malignant disorder (PMD) treatment. The aim of this study was to create a nomogram for use by clinicians to predict the probability of MT, thereby facilitating accurate assessment of risk and objective decision-making during individual patient management.

    METHODS: Clinico-pathological data from a previously treated cohort of 590 newly presenting PMD patients were reviewed and clinical outcomes categorized as disease free, persistent PMD or MT. Multiple logistic regression was used to predict the probability of MT in the cohort using age, gender, lesion type, site and incision biopsy histopathological diagnoses. Internal validation and calibration of the model was performed using the bootstrap method (n = 1000), and bias-corrected indices of model performance were computed.

    RESULTS: Potentially malignant disorders were predominantly leukoplakias (79%), presenting most frequently at floor of mouth and lateral tongue sites (51%); 99 patients (17%) developed oral squamous cell carcinoma during the study period. The nomogram performed well when MT predictions were compared with patient outcome data, demonstrating good bias-corrected discrimination and calibration (Dxy  = 0.58; C = 0.790), with a sensitivity of 87% and specificity 63%, and a positive predictive value of 32% and negative predictive value 96%.

    CONCLUSION: The "Newcastle Nomogram" has been developed to predict the probability of MT in PMD, based on an internally validated statistical model. Based upon readily available and patient-specific clinico-pathological data, it provides clinicians with a pragmatic diagrammatic aid for clinical decision-making during diagnosis and management of PMD.

  6. Goodson ML, Smith DR, Thomson PJ
    J Oral Pathol Med, 2017 Nov;46(10):896-901.
    PMID: 28833675 DOI: 10.1111/jop.12627
    BACKGROUND: Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to "high-risk" lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population.

    METHODS: Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex® brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15).

    RESULTS: A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome.

    CONCLUSIONS: Orcellex® brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics.

  7. Thomson PJ, Goodson ML, Smith DR
    J Oral Pathol Med, 2017 Nov;46(10):888-895.
    PMID: 28833670 DOI: 10.1111/jop.12625
    BACKGROUND: Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for "high-risk" lesions, clinicians are unable to predict malignant potential.

    METHODS: Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014).

    RESULTS: A total of 99 patients (16.8%) developed cancer: 71 (12%) seen "unexpectedly" upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. Thirty "unexpected" excisions were micro-invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. A total of 19 of 28 "progressive" cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (P = .0019). Nine (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. Three (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (P < .001).

    CONCLUSION: Squamous carcinoma may arise at the site of a precursor lesion as transformation or new-site development via field cancerisation. Whilst interventional surgery facilitates early diagnosis and treatment of occult disease, thus reducing risk from same-site transformation, new-site cancer is a significant long-term risk for patients with potentially malignant disorder.

  8. Thomson PJ, Goodson ML, Smith DR
    J Oral Pathol Med, 2017 Nov;46(10):902-910.
    PMID: 28891106 DOI: 10.1111/jop.12641
    BACKGROUND: Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention.

    METHODS: A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014).

    RESULTS: A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027).

    CONCLUSION: Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure.

  9. Pulmanausahakul R, Roytrakul S, Auewarakul P, Smith DR
    Int J Infect Dis, 2011 Oct;15(10):e671-6.
    PMID: 21775183 DOI: 10.1016/j.ijid.2011.06.002
    In the last few years, chikungunya has become a major problem in Southeast Asia, with large numbers of cases being reported in Singapore, Malaysia, and Thailand. Much of the current epidemic of chikungunya in Southeast Asia is being driven by the emergence of a strain of chikungunya virus that originated in Africa and spread to islands in the Indian Ocean, as well as to India and Sri Lanka, and then onwards to Southeast Asia. There is currently no specific treatment for chikungunya and no vaccine is available for this disease. This review seeks to provide a short update on the reemergence of chikungunya in Southeast Asia and the prospects for control of this disease.
  10. Smith DR, Behzadnia A, Imawana RA, Solim MN, Goodson ML
    Sci Rep, 2021 07 14;11(1):14478.
    PMID: 34262067 DOI: 10.1038/s41598-021-91644-y
    The prevalence of smokers is a major driver of lung cancer incidence in a population, though the "exposure-lag" effects are ill-defined. Here we present a multi-country ecological modelling study using a 30-year smoking prevalence history to quantify the exposure-lag response. To model the temporal dependency between smoking prevalence and lung cancer incidence, we used a distributed lag non-linear model (DLNM), controlling for gender, age group, country, outcome year, and population at risk, and presented the effects as the incidence rate ratio (IRR) and cumulative incidence rate ratio (IRRcum). The exposure-response varied by lag period, whilst the lag-response varied according to the magnitude and direction of changes in smoking prevalence in the population. For the cumulative lag-response, increments above and below the reference level was associated with an increased and decreased IRRcum respectively, with the magnitude of the effect varying across the lag period. Though caution should be exercised in interpretation of the IRR and IRRcum estimates reported herein, we hope our work constitutes a preliminary step towards providing policy makers with meaningful indicators to inform national screening programme developments. To that end, we have implemented our statistical model a shiny app and provide an example of its use.
  11. Lithanatudom SK, Chaowasku T, Nantarat N, Jaroenkit T, Smith DR, Lithanatudom P
    Sci Rep, 2017 07 27;7(1):6716.
    PMID: 28751754 DOI: 10.1038/s41598-017-07045-7
    Dimocarpus longan, commonly known as the longan, belongs to the family Sapindaceae, and is one of the most economically important fruits commonly cultivated in several regions in Asia. There are various cultivars of longan throughout the Thai-Malay peninsula region, but until now no phylogenetic analysis has been undertaken to determine the genetic relatedness of these cultivars. To address this issue, 6 loci, namely ITS2, matK, rbcL, trnH-psbA, trnL-I and trnL-trnF were amplified and sequenced from 40 individuals consisting of 26 longan cultivars 2 types of lychee and 8 herbarium samples. The sequencing results were used to construct a phylogenetic tree using the neighbor-joining (NJ), maximum likelihood (ML) and Bayesian inference (BI) criteria. The tree showed cryptic groups of D. longan from the Thailand-Malaysia region (Dimocarpus longan spp.). This is the first report of the genetic relationship of Dimocarpus based on multi-locus molecular markers and morphological characteristics. Multiple sequence alignments, phylogenetic trees and species delimitation support that Dimocarpus longan spp. longan var. obtusus and Dimocarpus longan spp. malesianus var. malesianus should be placed into a higher order and are two additional species in the genus Dimocarpus. Therefore these two species require nomenclatural changes as Dimocarpus malesianus and Dimocarpus obtusus, respectively.
  12. Petz LN, Turell MJ, Padilla S, Long LS, Reinbold-Wasson DD, Smith DR, et al.
    Am J Trop Med Hyg, 2014 Oct;91(4):666-71.
    PMID: 25114013 DOI: 10.4269/ajtmh.13-0218
    Tembusu virus (TMUV) is an important emerging arthropod-borne virus that may cause encephalitis in humans and has been isolated in regions of southeast Asia, including Malaysia, Thailand, and China. Currently, detection and identification of TMUV are limited to research laboratories, because quantitative rapid diagnostic assays for the virus do not exist. We describe the development of sensitive and specific conventional and real-time quantitative reverse transcription polymerase chain reaction assays for detecting TMUV RNA in infected cell culture supernatant and Culex tarsalis mosquitoes. We used this assay to document the replication of TMUV in Cx. tarsalis, where titers increased 1,000-fold 5 days after inoculation. These assays resulted in the detection of virus-specific RNA in the presence of copurified mosquito nucleic acids. The use of these rapid diagnostic assays may have future applications for field pathogen surveillance and may assist in early detection, diagnosis, and control of the associated arthropod-borne pathogens.
  13. Ho JY, Jong MC, Acharya K, Liew SSX, Smith DR, Noor ZZ, et al.
    J Hazard Mater, 2021 03 05;405:124687.
    PMID: 33301976 DOI: 10.1016/j.jhazmat.2020.124687
    River systems in developing and emerging countries are often fragmented relative to land and waste management in their catchment. The impact of inconsistent waste management and releases is a major challenge in water quality management. To examine how anthropogenic activities and estuarine effects impact water quality, we characterised water conditions, in-situ microbiomes, profiles of faecal pollution indicator, pathogenic and antibiotic resistant bacteria in the River Melayu, Southern Malaysia. Overall, upstream sampling locations were distinguished from those closer to the coastline by physicochemical parameters and bacterial communities. The abundances of bacterial DNA, total E. coli marker genes, culturable bacteria as well as antibiotic resistance ESBL-producing bacteria were elevated at upstream sampling locations especially near discharge of a wastewater oxidation pond. Furthermore, 85.7% of E. faecalis was multidrug-resistant (MDR), whereas 100% of E. cloacae, E. coli, K. pneumoniae were MDR. Overall, this work demonstrates how pollution in river estuaries does not monotonically change from inland towards the coast but varies according to local waste releases and tidal mixing. We also show that surrogate markers, such dissolved oxygen, Bacteroides and Prevotella abundances, and the rodA qPCR assay for total E. coli, can identify locations on a river that deserve immediate attention to mitigate AMR spread through improved waste management.
  14. Lim ST, Tobin WO, Murphy S, Kinsella JA, Smith DR, Lim SY, et al.
    Platelets, 2022 Jan 02;33(1):89-97.
    PMID: 33347340 DOI: 10.1080/09537104.2020.1850670
    Information regarding the profile of reticulated platelets (RP) in ischemic cerebrovascular disease (CVD) patients is limited. Data from two prospective, observational, case-control studies were combined to compare the %RP using whole blood flow cytometry in patients ≤ 4 weeks of TIA/stroke onset (baseline, N = 210), and 14 ±7 days (14d, N = 182) and ≥ 90 days (90d, N = 145) after starting or changing antiplatelet therapy with healthy controls (N = 34). There were no differences in median %RP between the overall CVD patient population at baseline or 14d vs. controls (P ≥ 0.2). However, the median %RP was significantly higher in CVD patients overall at 90d (P = .036), and in the subgroup of patients with "lacunar" TIA/ischemic stroke at baseline (P = .04) and at 90d (P = .01), but not at 14d (P = .06) vs. controls. There were no significant differences in the median %RP between other TIA/stroke subgroups and controls (P ≥ 0.05). Elevated circulating reticulated platelets, as a marker of increased platelet production/turnover, may occur following an ischemic event in a well-phenotyped TIA/ischemic stroke population overall, but may precede symptom onset at least in the subgroup with small vessel occlusion. These data improve our understanding of the profile of reticulated platelets in CVD patients.
  15. Smith ES, Smith DR, Eyring C, Braileanu M, Smith-Connor KS, Ei Tan Y, et al.
    Neurobiol Learn Mem, 2019 Nov;165:106962.
    PMID: 30502397 DOI: 10.1016/j.nlm.2018.11.007
    Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.
  16. Grace MK, Akçakaya HR, Bennett EL, Brooks TM, Heath A, Hedges S, et al.
    Conserv Biol, 2021 12;35(6):1833-1849.
    PMID: 34289517 DOI: 10.1111/cobi.13756
    Recognizing the imperative to evaluate species recovery and conservation impact, in 2012 the International Union for Conservation of Nature (IUCN) called for development of a "Green List of Species" (now the IUCN Green Status of Species). A draft Green Status framework for assessing species' progress toward recovery, published in 2018, proposed 2 separate but interlinked components: a standardized method (i.e., measurement against benchmarks of species' viability, functionality, and preimpact distribution) to determine current species recovery status (herein species recovery score) and application of that method to estimate past and potential future impacts of conservation based on 4 metrics (conservation legacy, conservation dependence, conservation gain, and recovery potential). We tested the framework with 181 species representing diverse taxa, life histories, biomes, and IUCN Red List categories (extinction risk). Based on the observed distribution of species' recovery scores, we propose the following species recovery categories: fully recovered, slightly depleted, moderately depleted, largely depleted, critically depleted, extinct in the wild, and indeterminate. Fifty-nine percent of tested species were considered largely or critically depleted. Although there was a negative relationship between extinction risk and species recovery score, variation was considerable. Some species in lower risk categories were assessed as farther from recovery than those at higher risk. This emphasizes that species recovery is conceptually different from extinction risk and reinforces the utility of the IUCN Green Status of Species to more fully understand species conservation status. Although extinction risk did not predict conservation legacy, conservation dependence, or conservation gain, it was positively correlated with recovery potential. Only 1.7% of tested species were categorized as zero across all 4 of these conservation impact metrics, indicating that conservation has, or will, play a role in improving or maintaining species status for the vast majority of these species. Based on our results, we devised an updated assessment framework that introduces the option of using a dynamic baseline to assess future impacts of conservation over the short term to avoid misleading results which were generated in a small number of cases, and redefines short term as 10 years to better align with conservation planning. These changes are reflected in the IUCN Green Status of Species Standard.
  17. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al.
    Autophagy, 2016;12(1):1-222.
    PMID: 26799652 DOI: 10.1080/15548627.2015.1100356
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