Publications by authors named "Sifat Sharmin"

18 Publications

  • Page 1 of 1

Predicting Infection Risk in Multiple Sclerosis Patients Treated with Ocrelizumab: A Retrospective Cohort Study.

CNS Drugs 2021 Apr 13. Epub 2021 Apr 13.

Department of Neurology, Melbourne MS Centre, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia.

Background: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting.

Objective: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS.

Methods: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models.

Results: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25-0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88-0.99), higher serum IgA (OR 0.37, 95% CI 0.17-0.80) and higher serum IgG (OR 0.81, 95% CI 0.67-0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75-0.96) and higher serum IgA (OR 0.23, 95% CI 0.07-0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06-1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02-3.86) were associated with increased odds of antimicrobial use.

Conclusions: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy.
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http://dx.doi.org/10.1007/s40263-021-00810-3DOI Listing
April 2021

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

Neurology 2021 02 28;96(5):e783-e797. Epub 2020 Dec 28.

From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.

Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, = 0.0016), worsening of disability (0.56, 0.38-0.82, = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, = 10) and worsening of disability (0.81, 0.67-0.99, = 0.043).

Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.

Classification Of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000011242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884998PMC
February 2021

Association of Sustained Immunotherapy With Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis.

JAMA Neurol 2020 Jul 27. Epub 2020 Jul 27.

Clinical Outcomes Research Unit (CORe), Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS).

Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation.

Design, Setting, And Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53 680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020.

Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated.

Main Outcomes And Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models).

Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P = .009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent.

Conclusions And Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
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http://dx.doi.org/10.1001/jamaneurol.2020.2453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385679PMC
July 2020

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Mult Scler 2021 Apr 15;27(5):755-766. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
April 2021

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020

Trajectories of Mini-Mental State Examination Scores over the Lifespan in General Populations: A Systematic Review and Meta-Regression Analysis.

Clin Gerontol 2020 May 6:1-10. Epub 2020 May 6.

Department of Medicine and Aged Care, @AgeMelbourne, The University of Melbourne, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

: Over the lifespan cumulative changes to the brain lead to cognitive decline and eventually to dementia in 20-25% of adults 85 years and older. A commonly used screening tool for cognitive function is the Standard 30 point Mini-Mental State Examination (MMSE). Though the MMSE is used to screen for dementia, little is known about the changes in scores over the lifespan in general populations.: A systematic search was conducted using Cochrane, EMBASE, MEDLINE and PsycINFO for articles published from January 1, 2007 to May 25, 2017. Articles were included if they had a longitudinal design reporting at least two MMSE scores. A mixed-effect meta-regression analysis was conducted to examine the influence of age on MMSE score followed by a change-point regression analysis determining the age at which MMSE declines.: 45 articles including 58,939 individuals (age range 18-108 years, 61.2% female) summarized 222 MMSE point estimates from 35 cohorts. The meta-regression demonstrated a significant decrease in MMSE scores with higher age (regression coefficient of age: -0.10 (Confidence Interval (CI) -0.15, -0.05)). The average annual decline in MMSE scores identified by the change-point analysis at the age of 41 years and 84 years were -0.04 (95% CI: -0.05, -0.03) and -0.53 (95% CI: -0.55, -0.50), respectively.: Between the age of 29 and 105 years MMSE scores decline, with the highest decline between age 84 and 105 years.: The use of MMSE should be restricted to higher age categories in aging general populations.
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http://dx.doi.org/10.1080/07317115.2020.1756021DOI Listing
May 2020

The histopathological staging of tau, but not amyloid, corresponds to antemortem cognitive status, dementia stage, functional abilities and neuropsychiatric symptoms.

Int J Neurosci 2020 Apr 30:1-10. Epub 2020 Apr 30.

Clinical Outcomes Research Unit (CORe), Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.

Alzheimer's disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies. We investigated this possibility using data from the National Alzheimer's Coordinating Center (NACC) database, which contains data from patients in the United States of America. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment. Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains. These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.
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http://dx.doi.org/10.1080/00207454.2020.1758087DOI Listing
April 2020

Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study.

Lancet Neurol 2020 04 18;19(4):307-316. Epub 2020 Mar 18.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address:

Background: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset.

Methods: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model.

Findings: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period.

Interpretation: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy.

Funding: National Health and Medical Research Council Australia and MS Society UK.
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http://dx.doi.org/10.1016/S1474-4422(20)30067-3DOI Listing
April 2020

Orthostatic hypotension and cognition in older adults: A systematic review and meta-analysis.

Exp Gerontol 2019 06 28;120:40-49. Epub 2019 Feb 28.

Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia; Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Van der Boechorststraat, Amsterdam, the Netherlands.

Background: Orthostatic hypotension (OH) is common in older adults with reported prevalence rates of 5-40%. A direct link between OH and cognitive performance has been proposed due to impaired vascular autoregulation.

Aim: To systematically assess the literature of the association between OH and cognitive performance in older adults.

Methods: Literature search of MEDLINE, Embase, Cochrane Central Register of Controlled Trials and PsycINFO from inception to May 2017. Studies were included if OH and cognition were assessed in subjects of mean or median age ≥65 years. Risk of bias was assessed with the Newcastle Ottawa Scale.

Results: Of 3266 studies screened, 32 studies (22 cross-sectional; 10 longitudinal) reporting data of 28,980 individuals were included. OH prevalence ranged from 3.3% to 58%. Of the 32 studies, 18 reported an association between OH and worse cognitive performance and 14 reported no association. Mini Mental State Examination (MMSE) was the most commonly used cognitive assessment tool. Studies using more than one cognitive assessment tool were more likely to find an association between OH and worse cognition. OH was significantly associated with a lower MMSE mean score (mean difference - 0.51 (95% CI: -0.85, -0.17, p = 0.003)) and an increased risk of cognitive impairment (OR 1.19 (95% CI, 1.00-1.42, p = 0.048)).

Conclusions: OH is common in older populations and is associated with worse cognition expressed as lower MMSE scores. Use of MMSE alone as a cognitive assessment tool may underestimate the association. It is yet unclear whether the association between OH and worse cognitive performance is causative.
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http://dx.doi.org/10.1016/j.exger.2019.02.017DOI Listing
June 2019

Orthostatic Hypotension and Falls in Older Adults: A Systematic Review and Meta-analysis.

J Am Med Dir Assoc 2019 05 21;20(5):589-597.e5. Epub 2018 Dec 21.

Department of Human Movement Sciences, @AgeAmsterdam, Amsterdam Movement Sciences, Vrije Universiteit, Amsterdam, the Netherlands; Department of Medicine and Aged Care, @AgeMelbourne, The Royal Melbourne Hospital, The University of Melbourne, City Campus, Parkville, Melbourne, Victoria, Australia. Electronic address:

Objectives: Orthostatic hypotension is a potential risk factor for falls in older adults, but existing evidence on this relationship is inconclusive. This study addresses the association between orthostatic hypotension and falls.

Design: Systematic review and meta-analysis of the cross-sectional and longitudinal studies assessing the association between orthostatic hypotension and falls, as preregistered in the PROSPERO database (CRD42017060134).

Setting And Participants: A literature search was performed on February 20, 2017, in MEDLINE (from 1946), PubMed (from 1966), and EMBASE (from 1947) using the terms orthostatic hypotension, postural hypotension, and falls. References of included studies were screened for other eligible studies. Study selection was performed independently by 2 reviewers using the following inclusion criteria: published in English; mean/median age of the population ≥65 years; blood pressure measurement before and after postural change; and assessment of the association of orthostatic hypotension with falls. The following studies were excluded: conference abstracts, case reports, reviews, and editorials. Data extraction was performed independently by 2 reviewers.

Measures: Unadjusted odds ratios of the association between orthostatic hypotension and falls were used for pooling using a random effects model. Studies were rated as high, moderate, or low quality using the Newcastle-Ottawa Scale.

Results: Out of 5646 studies, 63 studies (51,800 individuals) were included in the systematic review and 50 studies (49,164 individuals) in the meta-analysis. Out of 63 studies, 39 were cross-sectional and 24 were longitudinal. Orthostatic hypotension was positively associated with falls (odds ratio 1.73, 95% confidence interval 1.50-1.99). The result was independent of study population, study design, study quality, orthostatic hypotension definition, and blood pressure measurement method.

Conclusions And Implications: Orthostatic hypotension is significantly positively associated with falls in older adults, underpinning the clinical relevance to test for an orthostatic blood pressure drop and highlighting the need to investigate orthostatic hypotension treatment to potentially reduce falls.
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http://dx.doi.org/10.1016/j.jamda.2018.11.003DOI Listing
May 2019

Geostatistical mapping of the seasonal spread of under-reported dengue cases in Bangladesh.

PLoS Negl Trop Dis 2018 11 15;12(11):e0006947. Epub 2018 Nov 15.

National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Caberra, Australia.

Geographical mapping of dengue in resource-limited settings is crucial for targeting control interventions but is challenging due to the problem of zero-inflation because many cases are not reported. We developed a negative binomial generalised linear mixed effect model accounting for zero-inflation, spatial, and temporal random effects to investigate the spatial variation in monthly dengue cases in Bangladesh. The model was fitted to the district-level (64 districts) monthly reported dengue cases aggregated over the period 2000 to 2009 and Bayesian inference was performed using the integrated nested Laplace approximation. We found that mean monthly temperature and its interaction with mean monthly diurnal temperature range, lagged by two months were significantly associated with dengue incidence. Mean monthly rainfall at two months lag was positively associated with dengue incidence. Densely populated districts and districts bordering India or Myanmar had higher incidence than others. The model estimated that 92% of the annual dengue cases occurred between August and September. Cases were identified across the country with 94% in the capital Dhaka (located almost in the middle of the country). Less than half of the affected districts reported cases as observed from the surveillance data. The proportion reported varied by month with a higher proportion reported in high-incidence districts, but dropped towards the end of high transmission season.
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http://dx.doi.org/10.1371/journal.pntd.0006947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264868PMC
November 2018

Comparing indigenous mortality across urban, rural and very remote areas: a systematic review and meta-analysis.

Int Health 2018 07;10(4):219-227

Melbourne Academic Centre for Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.

Background: It remains unclear how indigenous mortality varies between residential areas. We conducted a systematic review and meta-analysis on mortality patterns in urban, rural and very remote areas for the adult and infant indigenous populations of Australia, Canada, New Zealand and the USA.

Methods: A literature search was performed using major online electronic publication repositories. Studies presenting indigenous mortality or disease incidence/prevalence in urban, rural or very remote areas were included. Indigenous mortality and disease incidence/prevalence in both urban and very remote areas were compared with those in rural areas. Studies that reported number of deaths or disease incidences along with population were included in the meta-analysis.

Results: Thirty-one studies were included with data from Australia (n=19), Canada (n=3), New Zealand (n=1) and the USA (n=8). Indigenous adult all-cause mortality, cervical cancer mortality, trauma mortality and incidence of myocardial infarction were all significantly lower in urban areas compared with rural areas. Likewise, indigenous adult cardiovascular mortality and renal disease mortality were significantly lower in very remote areas compared with rural areas, while indigenous infant all-cause mortality showed no significant difference in urban, rural or very remote areas.

Conclusions: Urban areas consistently experienced lower adult indigenous mortality compared with rural areas, as did some very remote areas. Indigenous infants, however, experience similar mortality rates across all residential areas.
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http://dx.doi.org/10.1093/inthealth/ihy021DOI Listing
July 2018

A Bayesian approach for estimating under-reported dengue incidence with a focus on non-linear associations between climate and dengue in Dhaka, Bangladesh.

Stat Methods Med Res 2018 04 13;27(4):991-1000. Epub 2016 May 13.

National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australia.

Determining the relation between climate and dengue incidence is challenging due to under-reporting of disease and consequent biased incidence estimates. Non-linear associations between climate and incidence compound this. Here, we introduce a modelling framework to estimate dengue incidence from passive surveillance data while incorporating non-linear climate effects. We estimated the true number of cases per month using a Bayesian generalised linear model, developed in stages to adjust for under-reporting. A semi-parametric thin-plate spline approach was used to quantify non-linear climate effects. The approach was applied to data collected from the national dengue surveillance system of Bangladesh. The model estimated that only 2.8% (95% credible interval 2.7-2.8) of all cases in the capital Dhaka were reported through passive case reporting. The optimal mean monthly temperature for dengue transmission is 29℃ and average monthly rainfall above 15 mm decreases transmission. Our approach provides an estimate of true incidence and an understanding of the effects of temperature and rainfall on dengue transmission in Dhaka, Bangladesh.
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http://dx.doi.org/10.1177/0962280216649216DOI Listing
April 2018

The emergence of dengue in Bangladesh: epidemiology, challenges and future disease risk.

Trans R Soc Trop Med Hyg 2015 Oct 1;109(10):619-27. Epub 2015 Sep 1.

National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, ACT 2601, Australia

Dengue occurred sporadically in Bangladesh from 1964 until a large epidemic in 2000 established the virus. We trace dengue from the time it was first identified in Bangladesh and identify factors favourable to future dengue haemorrhagic fever epidemics. The epidemic in 2000 was likely due to introduction of a dengue virus strain from a nearby endemic country, probably Thailand. Cessation of dichlorodiphenyltrichloroethane (DDT) spraying, climatic, socio-demographic, and lifestyle factors also contributed to epidemic transmission. The largest number of cases was notified in 2002 and since then reported outbreaks have generally declined, although with increased notifications in alternate years. The apparent decline might be partially due to public awareness with consequent reduction in mosquito breeding and increased prevalence of immunity. However, passive hospital-based surveillance has changed with mandatory serological confirmation now required for case reporting. Further, a large number of cases remain undetected because only patients with severe dengue require hospitalisation. Thus, the reduction in notification numbers may be an artefact of the surveillance system. Indeed, population-based serological survey indicates that dengue transmission continues to be common. In the future, the absence of active interventions, unplanned urbanisation, environmental deterioration, increasing population mobility, and economic factors will heighten dengue risk. Projected increases in temperature and rainfall may exacerbate this.
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http://dx.doi.org/10.1093/trstmh/trv067DOI Listing
October 2015

Interaction of Mean Temperature and Daily Fluctuation Influences Dengue Incidence in Dhaka, Bangladesh.

PLoS Negl Trop Dis 2015 10;9(7):e0003901. Epub 2015 Jul 10.

National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, Australian Capital Territory, Australia.

Local weather influences the transmission of the dengue virus. Most studies analyzing the relationship between dengue and climate are based on relatively coarse aggregate measures such as mean temperature. Here, we include both mean temperature and daily fluctuations in temperature in modelling dengue transmission in Dhaka, the capital of Bangladesh. We used a negative binomial generalized linear model, adjusted for rainfall, anomalies in sea surface temperature (an index for El Niño-Southern Oscillation), population density, the number of dengue cases in the previous month, and the long term temporal trend in dengue incidence. In addition to the significant associations of mean temperature and temperature fluctuation with dengue incidence, we found interaction of mean and temperature fluctuation significantly influences disease transmission at a lag of one month. High mean temperature with low fluctuation increases dengue incidence one month later. Besides temperature, dengue incidence was also influenced by sea surface temperature anomalies in the current and previous month, presumably as a consequence of concomitant anomalies in the annual rainfall cycle. Population density exerted a significant positive influence on dengue incidence indicating increasing risk of dengue in over-populated Dhaka. Understanding these complex relationships between climate, population, and dengue incidence will help inform outbreak prediction and control.
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http://dx.doi.org/10.1371/journal.pntd.0003901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498835PMC
May 2016

A stochastic model for early identification of infectious disease epidemics with application to measles cases in Bangladesh.

Asia Pac J Public Health 2015 Mar 18;27(2):NP816-23. Epub 2012 Nov 18.

University of Dhaka, Dhaka, Bangladesh.

In this article, a stochastic modeling approach was employed for the detection of epidemics in advance that was based on a negative binomial model with 2 components: an endemic component and an epidemic component. This study used monthly measles cases from January 2000 to August 2009 collected from the Expanded Program on Immunization, Bangladesh. General optimization routines provided the maximum likelihood estimates with corresponding standard errors. The negative binomial model with both seasonal endemic and epidemic components was shown to provide adequate fit with no measles epidemic during September 2008 to August 2009.
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http://dx.doi.org/10.1177/1010539512461668DOI Listing
March 2015

Profile: the Chakaria Health and Demographic Surveillance System.

Int J Epidemiol 2012 Jun;41(3):667-75

Centre for Equity and Health System, ICDDRB, Mohakhali, Dhaka, Bangladesh.

Chakaria Health and Demographic Surveillance System (CHDSS), located on the south-eastern coast of the Bay of Bengal, was established in 1999 and is one of the field sites of International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDRB). The surveillance covers 118 315 residents living in 19 847 households. Data on socio-demographic and health indicators including birth, death, migration, marriage, maternal health, education and employment are recorded through quarterly household visits. The primary objective of CHDSS is to monitor the changes in socio-demographic indicators, inequalities in health and impact of public health interventions. A demographic change was accompanied by a shift from traditional to modern society during the past decade, but inequality in health still persists. The findings from the surveillance are shared regularly among the local and global communities. Data are also available upon request to ICDDRB and INDEPTH for use by researchers and policy makers.
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http://dx.doi.org/10.1093/ije/dys089DOI Listing
June 2012

Modelling of infectious diseases for providing signal of epidemics: a measles case study in Bangladesh.

J Health Popul Nutr 2011 Dec;29(6):567-73

Institute of Statistical Research and Training, University of Dhaka, Ramna, Dhaka 1000, Bangladesh.

The detection of unusual patterns in the occurrence of diseases is an important challenge to health workers interested in early identification of epidemics. The objective of this study was to provide an early signal of infectious disease epidemics by analyzing the disease dynamics. A two-stage monitoring system was applied, which consists of univariate Box-Jenkins model or autoregressive integrated moving average model and subsequent tracking signals from several statistical process-control charts. The analyses were illustrated on January 2000-August 2009 national measles data reported monthly to the Expanded Programme on Immunization (EPI) in Bangladesh. The results of this empirical study revealed that the most adequate model for the occurrences of measles in Bangladesh was the seasonal autoregressive integrated moving average (3, 1, 0) (0, 1, 1)12 model, and the statistical process-control charts detected no measles epidemics during September 2007-August 2009. The two-stage monitoring system performed well to capture the measles dynamics in Bangladesh without detection of an epidemic because of high measles-vaccination coverage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259719PMC
http://dx.doi.org/10.3329/jhpn.v29i6.9893DOI Listing
December 2011