Competing risks analysis for neutrophil to lymphocyte ratio as a predictor of diabetic retinopathy incidence in the Scottish population.

BACKGROUND: Diabetic retinopathy (DR) is a major sight-threatening microvascular complication in individuals with diabetes. Systemic inflammation combined with oxidative stress is thought to capture most of the complexities involved in the pathology of diabetic retinopathy. A high level of neutrophil-lymphocyte ratio (NLR) is an indicator of abnormal immune system activity. Current estimates of the association of NLR with diabetes and its complications are almost entirely derived from cross-sectional studies, suggesting that the nature of the reported association may be more diagnostic than prognostic. Therefore, in the present study, we examined the utility of NLR as a biomarker to predict the incidence of DR in the Scottish population. METHODS: The incidence of DR was defined as the time to the first diagnosis of R1 or above grade in the Scottish retinopathy grading scheme from type 2 diabetes diagnosis. The effect of NLR and its interactions were explored using a competing risks survival model adjusting for other risk factors and accounting for deaths. The Fine and Gray subdistribution hazard model (FGR) was used to predict the effect of NLR on the incidence of DR. RESULTS: We analysed data from 23,531 individuals with complete covariate information. At 10 years, 8416 (35.8%) had developed DR and 2989 (12.7%) were lost to competing events (death) without developing DR and 12,126 individuals did not have DR. The median (interquartile range) level of NLR was 2.04 (1.5 to 2.7). The optimal NLR cut-off value to predict retinopathy incidence was 3.04. After accounting for competing risks at 10 years, the cumulative incidence of DR and deaths without DR were 50.7% and 21.9%, respectively. NLR was associated with incident DR in both Cause-specific hazard (CSH = 1.63; 95% CI: 1.28-2.07) and FGR models the subdistribution hazard (sHR = 2.24; 95% CI: 1.70-2.94). Both age and HbA1c were found to modulate the association between NLR and the risk of DR. CONCLUSIONS: The current study suggests that NLR has a promising potential to predict DR incidence in the Scottish population, especially in individuals less than 65 years and in those with well-controlled glycaemic status.

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records.

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored. Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy. Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001). Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.

Association of Guillain-Barre syndrome with COVID-19 infection: An updated systematic review.

OBJECTIVE: The systematic review aimed to determine demographic characteristics, clinical features, lab evaluation, management and complications of the studies focusing on Guillain-Barre syndrome (GBS) as a sequele of novel coronavirus (COVID-19) infection. METHODS: After protocol registration, PubMed, Web of Science and Cumulative Index to Nursing & Allied Health Literature (CINHAL) databases were searched for relevant articles using MeSH key-words and imported into referencing/review softwares. The data, regarding demographic and clinical characteristics, diagnostic workup and management, was analyzed in International Business Machines (IBM) Statistics SPSS 21. Many statistical tests, such as t-test and the Mann-Whitney U test, were used. P < 0.05 was considered significant. RESULTS: We identified 64 relevant articles. The mean age of the patients was 56 ± 16 years; the majority were males (64.9%). Among the neurological findings, paresthesia was the most typical symptom (48.9%). Most of the patients had been diagnosed by reverse transcriptase-polymerase chain reaction (RT-PCR) (69.2%). Two-third of the patients received immunoglobulins (IVIg) (77.7%). Although functions recovered in most patients, there were four patients with facial diplegia during follow-up (4.26%). Acute inflammatory demyelinating polyneuropathy (AIDP) was more likely to be associated with paresis of the lower extremity (p < 0.05) and higher levels of glucose on cerebrospinal fluid (CSF) analysis (p < 0.05). These patients were more likely to receive IVIg (p < 0.05) and develop respiratory insufficiency, subsequently (p < 0.05). CONCLUSIONS: GBS is being recognized as one of the many presentations of the COVID-19 infection. Although the common form is AIDP that might lead to complications, other variants are possible as well, and more studies are needed to focus on those subvariants.

Knowledge Attitude and Practices of Mitanin's (Community Health Workers) in Chhattisgarh: Malaria Elimination Perspective.

Background: For the success of any program, its implementation plays a crucial role. Community health workers are of immense importance for malaria elimination from India. Objective: This study was aimed to assess the knowledge gaps and the responsible factors for mitanins' knowledge on various aspects of and problems faced by mitanins during their work. Methods: Structured interviewer-based questionnaire was used to collect the data, and ordinal regression was applied to analyze the data. Results: Only 26% of the mitanins were having a good knowledge attitude and practices (KAP) score about malaria. Malaria endemicity of area [odds ratio (OR) = 0.26, 95% CI = 0.13-0.50), P < 0.001] and education (OR = 0.35, 95% CI = 0.18-0.69, P = 0.002) were the two significant factors affecting the KAP of mitanins. Conclusion: This study shows that prioritizing education while recruiting the mitanins and training them in the low endemic areas with a focus on malaria, which will help achieve the malaria elimination goal.

Epidemic Landscape and Forecasting of SARS-CoV-2 in India.

BACKGROUND: India was one of the countries to institute strict measures for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) control in the early phase. Since, then, the epidemic growth trajectory was slow before registering an explosion of cases due to local cluster transmissions. METHODS: We estimated the growth rate and doubling time of SARS-CoV-2 for India and high burden states using crowdsourced time series data. Further, we also estimated the Basic Reproductive Number (R0) and Time-dependent Reproductive number (Rt) using serial intervals from the data. We compared the R0 estimated from five different methods and R0 from SB was further used in the analysis. We modified standard Susceptible-Infectious-Recovered (SIR) models to SIR/Death (SIRD) model to accommodate deaths using R0 with the sequential Bayesian method for simulation in SIRD models. RESULTS: On average, 2.8 individuals were infected by an index case. The mean serial interval was 3.9 days. The R0 estimated from different methods ranged from 1.43 to 1.85. The mean time to recovery was 14 ± 5.3 days. The daily epidemic growth rate of India was 0.16 [95% CI; 0.14, 0.17] with a doubling time of 4.30 days [95% CI; 3.96, 4.70]. From the SIRD model, it can be deduced that the peak of SARS-CoV-2 in India will be around mid-July to early August 2020 with around 12.5% of the population likely to be infected at the peak time. CONCLUSION: The pattern of spread of SARS-CoV-2 in India is suggestive of community transmission. There is a need to increase funds for infectious disease research and epidemiologic studies. All the current gains may be reversed if air travel and social mixing resume rapidly. For the time being, these must be resumed only in a phased manner and should be back to normal levels only after we are prepared to deal with the disease with efficient tools like vaccines or medicine. KEY POINTS: . QUESTION: What are the estimates of infectious disease parameters of early phase of novel SARS-CoV-2 epidemic in India? FINDINGS: Incidence pattern SARS-CoV-2 shows possible evidence of community transmission. However, the estimated Basic Reproductive Number (R0) is relatively lower than those observed in high burden regions (range 1.43-1.85). Our simulation using susceptible-infectious-recovered/death model shows that peak of SARS-CoV-2 in India is farther than currently projected and is likely to affect around 12.5% of population. MEANING: The lower estimated R0 is indicative of the effectiveness of early social distancing measures and lockdown. Premature relaxation of the current control measures may result in large numbers of cases in India.

Characterization and monitoring of deltamethrin-resistance in Anopheles culicifacies in the presence of a long-lasting insecticide-treated net intervention.

BACKGROUND: Deltamethrin-impregnated, long-lasting insecticidal nets (LLINs) were distributed in the study area from November 2014 to January 2015 to evaluate their impact on malaria transmission in the presence of insecticide-resistant vectors. Studies were carried out in 16 selected clusters in Keshkal sub-district, Chhattisgarh State, India to monitor and characterize deltamethrin resistance in Anopheles culicifacies sensu lato. RESULTS: Deltamethrin susceptibility of An. culicifacies decreased in a post-LLIN survey compared to a pre-LLIN survey and was not significant (p > 0.05) while, the knockdown values showed significant increase (p < 0.05). Pre-exposure to piperonyl butoxide, triphenyl phosphate showed synergism against deltamethrin (p < 0.001). Biochemical assays showed significantly (p < 0.05) elevated monooxygenases in 3 of 5 clusters in post-LLIN survey-I that increased to 10 of 11 clusters in post-LLIN survey-II, while esterases were found significantly elevated in all clusters and both enzymes were involved in conferring pyrethroid resistance, not discounting the involvement of kdr (L1014L/S) gene that was heterozygous and at low frequency (4-5%). CONCLUSION: This field study, in a tribal district of India, after distribution of deltamethrin-impregnated LLINs showed decrease in deltamethrin susceptibility in An. culicifacies, a major vector of malaria in this study area and in India. Results indicated development of resistance as imminent with the increase in insecticide selection pressure. There is an urgent need to develop new vector control tools, with insecticide classes having novel mechanisms of resistance, to avoid or delay the onset of resistance. Regular insecticide resistance monitoring and mechanistic studies should be the priority for the malaria control programmes to suggest strategies for insecticide resistance management. The global commitment to eliminate malaria by 2030 needs various efforts that include development of combination vector control products and interventions and few are becoming available.

Implications of insecticide resistance for malaria vector control with long-lasting insecticidal nets: a WHO-coordinated, prospective, international, observational cohort study.

BACKGROUND: Scale-up of insecticide-based interventions has averted more than 500 million malaria cases since 2000. Increasing insecticide resistance could herald a rebound in disease and mortality. We aimed to investigate whether insecticide resistance was associated with loss of effectiveness of long-lasting insecticidal nets and increased malaria disease burden. METHODS: This WHO-coordinated, prospective, observational cohort study was done at 279 clusters (villages or groups of villages in which phenotypic resistance was measurable) in Benin, Cameroon, India, Kenya, and Sudan. Pyrethroid long-lasting insecticidal nets were the principal form of malaria vector control in all study areas; in Sudan this approach was supplemented by indoor residual spraying. Cohorts of children from randomly selected households in each cluster were recruited and followed up by community health workers to measure incidence of clinical malaria and prevalence of infection. Mosquitoes were assessed for susceptibility to pyrethroids using the standard WHO bioassay test. Country-specific results were combined using meta-analysis. FINDINGS: Between June 2, 2012, and Nov 4, 2016, 40 000 children were enrolled and assessed for clinical incidence during 1·4 million follow-up visits. 80 000 mosquitoes were assessed for insecticide resistance. Long-lasting insecticidal net users had lower infection prevalence (adjusted odds ratio [OR] 0·63, 95% CI 0·51-0·78) and disease incidence (adjusted rate ratio [RR] 0·62, 0·41-0·94) than did non-users across a range of resistance levels. We found no evidence of an association between insecticide resistance and infection prevalence (adjusted OR 0·86, 0·70-1·06) or incidence (adjusted RR 0·89, 0·72-1·10). Users of nets, although significantly better protected than non-users, were nevertheless subject to high malaria infection risk (ranging from an average incidence in net users of 0·023, [95% CI 0·016-0·033] per person-year in India, to 0·80 [0·65-0·97] per person year in Kenya; and an average infection prevalence in net users of 0·8% [0·5-1·3] in India to an average infection prevalence of 50·8% [43·4-58·2] in Benin). INTERPRETATION: Irrespective of resistance, populations in malaria endemic areas should continue to use long-lasting insecticidal nets to reduce their risk of infection. As nets provide only partial protection, the development of additional vector control tools should be prioritised to reduce the unacceptably high malaria burden. FUNDING: Bill & Melinda Gates Foundation, UK Medical Research Council, and UK Department for International Development.

Monitoring of long-lasting insecticidal nets (LLINs) coverage versus utilization: a community-based survey in malaria endemic villages of Central India.

BACKGROUND: Despite the known effectiveness of long-lasting insecticidal nets (LLINs) in providing protection against malaria, high level of ownership and use are very difficult to achieve and maintain. Nearly 40,000 LLINs were distributed in 2014 as an intervention tool against malaria transmission in 80 villages of Keshkal sub-district in Chhattisgarh, India. This study assessed LLIN coverage, access, utilization pattern, and key determinants for the net use 1 year after mass distribution. METHODS: In 2015, a cross-sectional household survey was carried out in 80 study clusters (whole village or part of village). From each cluster, 40 households were randomly selected and interviewed using a structured questionnaire adapted from the malaria indicator survey of Roll Back Malaria guidelines. Information on demographic characteristics, LLIN ownership, and its use on the night before the survey, and physical condition of LLINs were recorded. RESULTS: 2970 households were interviewed with a total of 15,003 individuals present in the households during the night before the survey. Nearly 98% of households had at least one LLIN and 59.4% of the surveyed population reportedly used an LLIN the previous night. LLIN use varied from 41 to 94% between the study clusters. Nearly 89% of the LLINs were found in good physical condition (without holes). However, proportion of household with at least one LLIN per two persons was only 39%. CONCLUSION: Universal coverage of LLINs was inadequate in the study clusters making it difficult for all household members to use an LLIN. LLIN use varied between clusters and was highest in children under 5 years of age. Health education campaigns and creating awareness about the benefit of sleeping under the LLINs in providing protection against malaria is required not only to high risk groups of pregnant women and children below 5 years of age but all the members of the family to have an epidemiological impact of this intervention at the community level. Relatively high net use despite poor access to LLINs indicates an overall desire to use nets when they are available. The main barrier to increased use of nets is the low coverage at household level.

Additional burden of asymptomatic and sub-patent malaria infections during low transmission season in forested tribal villages in Chhattisgarh, India.

BACKGROUND: The burden of sub-patent malaria is difficult to recognize in low endemic areas due to limitation of diagnostic tools, and techniques. Polymerase chain reaction (PCR), a molecular based technique, is one of the key methods for detection of low parasite density infections. The study objective was to assess the additional burden of asymptomatic and sub-patent malaria infection among tribal populations inhabiting three endemic villages in Keshkal sub-district, Chhattisgarh, India. A cross-sectional survey was conducted in March-June 2016, during the low transmission season, to measure and compare prevalence of malaria infection using three diagnostics: rapid diagnostic test, microscopy and nested-PCR. RESULTS: Out of 437 individuals enrolled in the study, 103 (23.6%) were malaria positive by PCR and/or microscopy of whom 89.3% were Plasmodium falciparum cases, 77.7% were afebrile and 35.9% had sub-patent infections. CONCLUSIONS: A substantial number of asymptomatic and sub-patent malaria infections were identified in the survey. Hence, strategies for identifying and reducing the hidden burden of asymptomatic and sub-patent infections should focus on forest rural tribal areas using more sensitive molecular diagnostic methods to curtail malaria transmission.

Involvement of Mitanins (female health volunteers) in active malaria surveillance, determinants and challenges in tribal populated malaria endemic villages of Chhattisgarh, India.

BACKGROUND: Accredited Social Health Activists (ASHA), female health volunteers working at village level have become an integral component of National Health Mission (NHM) in India in the past two decades. Mitanin (meaning female friend in local dialect), a precursor of ASHA, play an indispensable role in early detection of health related problems and are helping in improving overall community health status in Chhattisgarh state. The current study was carried out to evaluate the feasibility of involving Mitanin in active malaria surveillance work in 80 tribal villages of Chhattisgarh and to explore the challenges and determinants to perform malaria surveillance activities by the Mitanins. METHODS: A total of 162 Mitanins were selected and divided into two age and village matched groups. The first group (training plus) of Mitanins were given additional training in malaria surveillance activities in whilst the second (standard) group received routine training. All Mitanins were interviewed using a structured questionnaire. In-depth interviews were also conducted among randomly selected sub groups of Mitanins (five from each group) after the completion of the quantitative survey. Performance of Mitanins was evaluated using pre-defined grading scores (A-E) which included various factors such as educational qualifications and knowledge about malaria, its signs and symptoms and knowledge, attitude and treatment practices. RESULTS: More number of Mitanins in training plus group has showed better performance (≥ B) than those in the standard group of Mitanins (80% vs 43.5%, p = 0.001) after adjusting for socio-demographic factors. Based on the outcome of in-depth interviews, Mitanin's lack of adequate support from supervisors, delayed payment of incentives and lack of appreciation were the major challenges mentioned. CONCLUSION: Mitanins can play an effective role in active fever surveillance for malaria besides performing other health related tasks at sub-village level after focused education on malaria related activities and proper supervision.

Impact of long-lasting insecticidal nets on prevalence of subclinical malaria among children in the presence of pyrethroid resistance in Anopheles culicifacies in Central India.

BACKGROUND: Subclinical (asymptomatic) cases of malaria could be a major barrier to the success of malaria elimination programs. This study has evaluated the impact of long-lasting insecticidal nets (LLINs) on the prevalence of subclinical malaria in the presence of pyrethroid resistance in the main malaria vector Anopheles culicifacies on malaria transmission among a cohort of children in villages of the Keshkal sub-district in Chhattisgarh state. METHODS: A cohort of 6582 children ages less than 14 years was enrolled from 80 study clusters. Post monsoon survey was carried out at baseline before LLIN distribution, and 5862 children were followed up in the subsequent year. Study outcomes included assessment of subclinical malarial infections and use of LLINs among the study cohort in the presence of varied levels of pyrethroid resistance. FINDINGS: In the baseline survey, the proportion of subclinical malaria was 6·1%. LLIN use during the previous night was 94·8%. Overall, prevalence of subclinical malaria was significantly reduced to 1% (p<0·001) in the second survey. LLIN users were protected from malaria (OR: 0·25, 95% CI=0·12-0·52, p<0.001) and subclinical malaria (OR: 0·25, 95% CI=0·11-0·58, p=0·001) despite the presence of pyrethroid resistance in the study area. INTERPRETATION: In this low transmission area, sleeping under LLINs significantly reduced the burden of malaria among children. In the presence of pyrethroid resistant malaria vector, a high LLIN use of 94·5% was observed to have significantly brought down the proportion of subclinical malaria among the cohort children.

Household training vs. mass campaigns: a better method of health communication for preventing malaria.

Malaria is endemic in several states of India with high tribal population. Effective use of long-lasting insecticide treated bed nets (LLITNs) can reduce the burden of malaria in these settings. This study assessed the knowledge and behaviour regarding malaria in a tribal population and compared two health education strategies for enhancing effective utilisation of bed nets. A community-based intervention study was carried out among 218 households in two villages. One community received household level training on effective utilisation of LLITNs while the others received training in a mass campaign and outcomes were measured after 2 months. The study showed that the proportion utilising LLITNs was significantly higher among those receiving household level training as compared to those who received the mass campaign. Household level training appears to be a more effective form of health education for improving knowledge and promoting use of LLITNs in these isolated community groups.