Duleeka W Knipe

Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis

Objective To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials. Design Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios. Data sources Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov. Eligibility criteria for selecting studies Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded. Results In the 39 randomised controlled trials (10 761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other). Conclusions This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, are already well recognised. Systematic review registration PROSPERO 2014:CRD42014009224.

Association of socio-economic position and suicide/attempted suicide in low and middle income countries in South and South-East Asia – a systematic review

BackgroundForty percent of the world’s suicide deaths occur in low and middle income countries (LAMIC) in Asia. There is a recognition that social factors, such as socioeconomic position (SEP), play an important role in determining suicidal risk in high income countries, but less is known about the association in LAMIC.MethodsThe objective of this systematic review was to synthesise existing evidence of the association between SEP and attempted suicide/suicide risk in LAMIC countries in South and South East Asia. Web of Science, MEDLINE, MEDLINE in Process, EMBASE, PsycINFO, and article reference lists/forward citations were searched for eligible studies. Epidemiological studies reporting on the association of individual SEP with suicide and attempted suicide were included. Study quality was assessed using an adapted rating tool and a narrative synthesis was conducted.ResultsThirty-one studies from nine countries were identified; 31 different measures of SEP were reported, with education being the most frequently recorded. Most studies suggest that lower levels of SEP are associated with an increased risk of suicide/attempted suicide, though findings are not always consistent between and within countries. Over half of the studies included in this review were of moderate/low quality. The SEP risk factors with the most consistent association across studies were asset based measures (e.g. composite measures); education; measures of financial difficulty and subjective measures of financial circumstance. Several studies show a greater than threefold increased risk in lower SEP groups with the largest and most consistent association with subjective measures of financial circumstance.ConclusionThe current evidence suggests that lower SEP increases the likelihood of suicide/attempted suicide in LAMIC in South and South East Asia. However, the findings are severely limited by study quality; larger better quality studies are therefore needed.Systematic review registrationPROSPERO 2014:CRD42014006521

Genetic Variation in Prostate-Specific Antigen–Detected Prostate Cancer and the Effect of Control Selection on Genetic Association Studies

Background: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls. Methods: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either “low” (PSA < 0.5 ng/mL) or “high” (PSA ≥ 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA. Results: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA. Conclusions: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA. Impact: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria. Cancer Epidemiol Biomarkers Prev; 23(7); 1356–65. ©2014 AACR.

Effectiveness of household lockable pesticide storage to reduce pesticide self-poisoning in rural Asia: a community-based, cluster-randomised controlled trial

Summary Background Agricultural pesticide self-poisoning is a major public health problem in rural Asia. The use of safer household pesticide storage has been promoted to prevent deaths, but there is no evidence of effectiveness. We aimed to test the effectiveness of lockable household containers for prevention of pesticide self-poisoning. Methods We did a community-based, cluster-randomised controlled trial in a rural area of North Central Province, Sri Lanka. Clusters of households were randomly assigned (1:1), with a sequence computer-generated by a minimisation process, to intervention or usual practice (control) groups. Intervention households that had farmed or had used or stored pesticide in the preceding agricultural season were given a lockable storage container. Further promotion of use of the containers was restricted to community posters and 6-monthly reminders during routine community meetings. The primary outcome was incidence of pesticide self-poisoning in people aged 14 years or older during 3 years of follow-up. Identification of outcome events was done by staff who were unaware of group allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT1146496. Findings Between Dec 31, 2010, and Feb 2, 2013, we randomly assigned 90 rural villages to the intervention group and 90 to the control group. 27 091 households (114 168 individuals) in the intervention group and 26 291 households (109 693 individuals) in the control group consented to participate. 20 457 household pesticide storage containers were distributed. In individuals aged 14 years or older, 611 cases of pesticide self-poisoning had occurred by 3 years in the intervention group compared with 641 cases in the control group; incidence of pesticide self-poisoning did not differ between groups (293·3 per 100 000 person-years of follow-up in the intervention group vs 318·0 per 100 000 in the control group; rate ratio [RR] 0·93, 95% CI 0·80–1·08; p=0·33). We found no evidence of switching from pesticide self-poisoning to other forms of self-harm, with no significant difference in the number of fatal (82 in the intervention group vs 67 in the control group; RR 1·22, 0·88–1·68]) or non-fatal (1135 vs 1153; RR 0·97, 0·86–1·08) self-harm events involving all methods. Interpretation We found no evidence that means reduction through improved household pesticide storage reduces pesticide self-poisoning. Other approaches, particularly removal of highly hazardous pesticides from agricultural practice, are likely to be more effective for suicide prevention in rural Asia. Funding Wellcome Trust, with additional support from the American Foundation for Suicide Prevention, Lister Institute of Preventive Medicine, Chief Scientist Office of Scotland, University of Copenhagen, and NHMRC Australia.

Suicide prevention through means restriction: impact of the 2008-2011 pesticide restrictions on suicide in Sri Lanka

Objective To investigate the effect of 3-year phased bans of the pesticides dimethoate and fenthion in 2008–2010, and paraquat in 2009–2011, on suicide mortality in Sri Lanka. Methods Age-standardised overall, sex-specific, and method-specific suicide rates were calculated using Sri Lankan police data (1989–2015). Using negative binomial regression models, we estimated the change in the rate and number of suicide deaths in post-ban years (2011–15) compared to those expected based on pre-ban trends (2001–10). Findings Overall suicide mortality dropped by 21% between 2011 and 2015, from 18.3 to 14.3 per 100,000. The decline in pesticide suicides during this same period was larger than for overall suicides: from 8.5 to 4.2 per 100,000, a 50% reduction. This was accompanied by a smaller concurrent rise in non-pesticide suicide mortality with a 2% increase (9.9 to 10.1 per 100,000). In 2015, the ratio between the observed and expected pesticide suicide rates was 0.49 (95% confidence interval [CI] 0.40, 0.62), corresponding to an estimated 937 (95% CI 574, 1389) fewer pesticide suicides than expected from pre-ban suicide rates. Findings were similar in sensitivity analyses using 2008 or 2012 as commencement of the post intervention period. Conclusion Bans of paraquat, dimethoate and fenthion in Sri Lanka were associated with a reduction in pesticide suicide mortality and in overall suicide mortality despite a small rise in other methods. This study provides further evidence for the effectiveness of pesticide regulation in limiting the availability of highly hazardous pesticides and thereby reducing the number of global suicides.

Prevention of suicide with regulations aimed at restricting access to highly hazardous pesticides: a systematic review of the international evidence

BACKGROUND Pesticide self-poisoning accounts for 14-20% of suicides worldwide. Regulation aimed at restricting access to pesticides or banning highly hazardous pesticides is one approach to reducing these deaths. We systematically reviewed the evidence of the effectiveness of pesticide regulation in reducing the incidence of pesticide suicides and overall suicides. METHODS We did a systematic review of the international evidence. We searched MEDLINE, PsycINFO, and Embase for studies published between Jan 1, 1960, and Dec 31, 2016, which investigated the effect of national or regional bans, and sales or import restrictions, on the availability of one or more pesticides and the incidence of suicide in different countries. We excluded other interventions aimed at limiting community access to pesticides. We extracted data from studies presenting pesticide suicide data and overall suicide data from before and after national sales restrictions. Two reviewers independently assessed papers for inclusion, extracted data, and assessed risk of bias. We undertook a narrative synthesis of the data in each report, and where data were available for the years before and after a ban, we pooled data for the 3 years before and the 3 years after to obtain a crude estimate of the effect of the ban. This study is registered through PROSPERO, number CRD42017053329. FINDINGS We identified 27 studies undertaken in 16 countries-five low-income or middle-income countries (Bangladesh, Colombia, India, Jordan and Sri Lanka), and 11 high-income countries (Denmark, Finland, Germany, Greece, Hungary, Ireland, Japan, South Korea, Taiwan, UK, and USA). Assessments largely focused on national bans of specific pesticides (12 studies of bans in six countries-Jordan, Sri Lanka, Bangladesh, Greece [Crete], South Korea, and Taiwan) or sales restrictions (eight studies of restrictions in five countries- India, Denmark, Ireland, the UK and the USA). Only five studies used optimum analytical methods. National bans on commonly ingested pesticides in five of the six countries studied, including four studies using optimum analytical methods, were followed by reductions in pesticide suicides and, in three of these countries, falls in overall suicide mortality. Greece was the only country studied that did not show a decrease in pesticide suicide following a ban. There were no high-quality studies of restricting sales to people for occupational uses; four of the seven studies (in three of the five countries studied-India, Denmark, and the USA) showed sales restrictions were followed by decreases in pesticide suicides; one of the two studies investigating trends in overall suicide mortality reported a fall in deaths in Denmark, but there were also decreases in suicide deaths from other methods. INTERPRETATION National bans on highly hazardous pesticides, which are commonly ingested in acts of self-poisoning, seem to be effective in reducing pesticide-specific and overall suicide rates. Evidence is less consistent for sales restrictions. A worldwide ban on the use of highly hazardous pesticides is likely to prevent tens of thousands of deaths every year. FUNDING None.

Challenges and opportunities of a paperless baseline survey in Sri Lanka

BackgroundPersonal digital assistants (PDAs) have been shown to reduce costs associated with survey implementation and digitisation, and to improve data quality when compared to traditional paper based data collection. Few studies, however, have shared their experiences of the use of these devices in rural settings in Asia. This paper reports on our experiences of using a PDA device for data collection in Sri Lanka as part of a large cluster randomised control trial.FindingsWe found that PDAs were useful for collecting data for a baseline survey of a large randomised control trial (54,000 households). We found that the PDA device and survey format was easy to use by inexperienced field staff, even though the survey was programmed in English. The device enabled the rapid digitisation of survey data, providing a good basis for continuous data quality assurance, supervision of staff and survey implementation. An unexpected advantage was the improved community opinion of the research project as a result of the device, because the use of the technology gave data collectors an elevated status amongst the community. In addition the global positioning system (GPS) functionality of the device allowed precise mapping of households, and hence distinct settlements to be identified as randomisation clusters. Future users should be mindful that to save costs the piloting should be completed before programming. In addition consideration of a local after-care service is important to avoid costs and time delays associated with sending devices back to overseas providers.DiscussionSince the start of this study, PDA devices have rapidly developed and are increasingly used. The use of PDA or similar devices for research is not without its problems; however we believe that the universal lessons learnt as part of this study are even more important for the effective utilisation of these rapidly developing technologies in resource poor settings.

Is socioeconomic position associated with risk of attempted suicide in rural Sri Lanka? A cross sectional study of 165,000 individuals

Background Lower socioeconomic position (SEP) is associated with an increased risk of suicidal behaviour in high-income countries, but this association is unclear in low-income and middle-income countries. Methods We investigated the association of SEP with attempted suicide in a cross-sectional survey of 165 233 Sri Lankans. SEP data were collected at the household (assets, social standing (highest occupation of a household member), foreign employment and young (≤40 years) female-headed households) and individual level (education and occupation). Respondent-reported data on suicide attempts in the past year were recorded. Random-effects logistic regression models, accounting for clustering, were used to investigate the association of SEP with attempted suicide. Results Households reported 398 attempted suicides in the preceding year (239 per 100 000). Fewer assets (OR 3.2, 95% CI 2.4 to 4.4) and having a daily wage labourer (ie, insecure/low-income job; OR 2.3, 95% CI 1.6 to 3.2) as the highest occupation increased the risk of an attempted suicide within households. At an individual level, daily wage labourers were at an increased risk of attempted suicide compared with farmers. The strongest associations were with low levels of education (OR 4.6, 95% CI 2.5 to 8.4), with a stronger association in men than women. Conclusions We found that indicators of lower SEP are associated with increased risk of attempted suicide in rural Sri Lanka. Longitudinal studies with objective measures of suicide attempts are needed to confirm this association. Trial registration number NCT01146496; Pre-results.

Bans of WHO Class I Pesticides in Bangladesh – Suicide Prevention without Hampering Agricultural output

Abstract Background Pesticide self-poisoning is a major problem in Bangladesh. Over the past 20-years, the Bangladesh government has introduced pesticide legislation and banned highly hazardous pesticides (HHPs) from agricultural use. We aimed to assess the impacts of pesticide bans on suicide and on agricultural production. Methods We obtained data on unnatural deaths from the Statistics Division of Bangladesh Police, and used negative binomial regression to quantify changes in pesticide suicides and unnatural deaths following removal of WHO Class I toxicity HHPs from agriculture in 2000. We assessed contemporaneous trends in other risk factors, pesticide usage and agricultural production in Bangladesh from 1996 to 2014. Results Mortality in hospital from pesticide poisoning fell after the 2000 ban: 15.1% vs 9.5%, relative reduction 37.1% [95% confidence interval (CI) 35.4 to 38.8%]. The pesticide poisoning suicide rate fell from 6.3/100 000 in 1996 to 2.2/100 000 in 2014, a 65.1% (52.0 to 76.7%) decline. There was a modest simultaneous increase in hanging suicides [20.0% (8.4 to 36.9%) increase] but the overall incidence of unnatural deaths fell from 14.0/100 000 to 10.5/100 000 [25.0% (18.1 to 33.0%) decline]. There were 35 071 (95% CI 25 959 to 45 666) fewer pesticide suicides in 2001 to 2014 compared with the number predicted based on trends between 1996 to 2000. This reduction in rate of pesticide suicides occurred despite increased pesticide use and no change in admissions for pesticide poisoning, with no apparent influence on agricultural output. Conclusions Strengthening pesticide regulation and banning WHO Class I toxicity HHPs in Bangladesh were associated with major reductions in deaths and hospital mortality, without any apparent effect on agricultural output. Our data indicate that removing HHPs from agriculture can rapidly reduce suicides without imposing substantial agricultural costs.

Feasibility of hair sampling to assess levels of organophosphate metabolites in rural areas of Sri Lanka

Measuring chronic pesticide exposure is important in order to investigate the associated health effects. Traditional biological samples (blood/urine) are difficult to collect, store and transport in large epidemiological studies in settings such as rural Asia. We assessed the acceptability of collecting hair samples from a rural Sri Lankan population and found that this method of data collection was feasible. We also assessed the level of non-specific metabolites (DAPS) of organophosphate pesticides in the hair samples. The median concentration (pg/mg) of each DAP was: diethyl phosphate: 83.3 (IQI 56.0, 209.4); diethyl thiophosphate: 34.7 (IQI 13.8, 147.9); diethyl dithiophosphate: 34.5 (IQI 23.4, 55.2); and dimethyl phosphate: 3 (IQI 3, 109.7). Total diethylphosphates were recovered in >80% of samples and were positively correlated with self-reported pesticide exposure.