Stella G. Muthuri

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data

BACKGROUND Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each days delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each days delay). INTERPRETATION We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING F Hoffmann-La Roche.

Impact of Neuraminidase Inhibitor Treatment on Outcomes of Public Health Importance During the 2009–2010 Influenza A(H1N1) Pandemic: A Systematic Review and Meta-Analysis in Hospitalized Patients

Background. The impact of neuraminidase inhibitor (NAI) treatment on clinical outcomes of public health importance during the 2009–2010 pandemic has not been firmly established. Methods. We conducted a systematic review and meta-analysis, searching 11 databases (2009 through April 2012) for relevant studies. We used standard methods conforming to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random effects models. Results. Regarding mortality we observed a nonsignificant reduction associated with NAI treatment (at any time) versus none (OR, 0.72 [95% CI, .51–1.01]). However we observed significant reductions for early treatment (≤48 hours after symptom onset) versus late (OR, 0.38 [95% CI, .27–.53]) and for early treatment versus none (OR, 0.35 [95% CI, .18–.71]). NAI treatment (at any time) versus none was associated with an elevated risk of severe outcome (OR, 1.76 [95% CI, 1.22–2.54]), but early versus late treatment reduced the likelihood (OR, 0.41 [95% CI, .30–.56]). Conclusions. During the 2009–2010 influenza A(H1N1) pandemic, early initiation of NAI treatment reduced the likelihood of severe outcomes compared with late or no treatment. PROSPERO Registration. CRD42011001273.

Occupational risk factors for osteoarthritis of the knee: a meta-analysis

INTRODUCTION Systematic reviews agree that knee osteoarthritis (OA) is related to occupational activities, but have not quantified the overall risks. METHODS Systematic review of observational studies of knee OA and occupation. Job titles, elite sport, heavy work, kneeling, and other activities were included. Relative risk estimate and 95% confidence interval (CI) compared to sedentary work were retrieved or calculated for meta-analysis. Publication bias was examined with Egger tests and heterogeneity was determined with I(2) values and Q tests. Subgroup analysis was performed to examine causes of heterogeneity. A random effects model was performed to combine the data. RESULTS Studies of knee OA (n=51), persistent knee pain (n=12) and knee OA progression (n=3) were retrieved. Occupational risks for knee OA were examined in a total of 526,343 subjects in 8 cohort/prospective/longitudinal studies, 25 cross-sectional studies and 18 case control studies. The overall odds ratio (OR) was 1.61 (95% CI 1.45-1.78) with significant heterogeneity (I(2)=83.6%). Study designs showed a positive association between knee OA and occupational activities; cohort (OR 1.38, 95% CI 1.10-1.74), cross-sectional (OR 1.57, 95% CI 1.37-1.81) and case control (OR 1.80, 95% CI 1.48-2.19). Overall there was evidence of publication bias (P<0.0001) which was apparent in the cross-sectional and case control studies (P<0.0001 and P=0.0247 respectively). CONCLUSIONS Some occupational activities increase the risk of knee OA, although the influences of publication bias and heterogeneity are important limitations of this study. Prospective studies would greatly improve the evidence base.

What if we prevent obesity? Risk reduction in knee osteoarthritis estimated through a meta-analysis of observational studies.

To summarize the overall relative risk of knee osteoarthritis (OA) associated with body mass index, and to estimate the potential risk reduction due to the control of this risk factor.

Nottingham knee osteoarthritis risk prediction models

Objectives (1) To develop risk prediction models for knee osteoarthritis (OA) and (2) to estimate the risk reduction that results from modification of potential risk factors. Method This was a 12-year retrospective cohort study undertaken in the general population in Nottingham, UK. Baseline risk factors were collected by questionnaire. Incident radiographic knee OA was defined by Kellgren and Lawrence (KL) score ≥2. Incident symptomatic knee OA was defined by KL ≥2 plus knee pain. Progression of knee OA was defined by KL ≥1 grade increase from baseline. A logistic regression model was used for prediction. Calibration and discrimination of the models were tested in the Osteoarthritis Initiative (OAI) population and Genetics of Osteoarthritis and Lifestyle (GOAL) population. ORs of the models were compared with those obtained from meta-analysis of existing literature. Results From a community sample of 424 people aged over 40, 3 risk prediction models were developed. These included incidence of radiographic knee OA, incidence of symptomatic knee OA and progression of knee OA. All models had good calibration and moderate discrimination power in OAI and GOAL. The ORs lied within the 95% CIs of the published studies. The risk reduction due to modifying obesity at the individual and the population levels were demonstrated. Conclusions Risk prediction of knee OA based on the well established, common modifiable risk factors has been established. The models may be used to predict the risk of knee OA, and risk reduction due to preventing a specific risk factor.

Neuraminidase inhibitors: who, when, where?

Although the neuraminidase inhibitors (NIs), oseltamivir and zanamivir were first licensed in 1999, their clinical effectiveness is still hotly debated. Two rigorous systematic reviews and meta-analyses of the data from clinical trials conducted in community settings against relatively benign influenza, both suggest that reductions in symptom duration are extremely modest, under one day. Whilst one of these reviews could find no evidence of reductions in complications, the most recent review reported clinically meaningful and statistically significant reductions in the likelihood of requiring antibiotics (44%) and hospitalizations (63%) in adult patients with confirmed influenza, treated with oseltamivir. A further meta-analysis of observational data from the 2009 influenza A(H1N1) pandemic suggested that, in hospitalised patients, NIs significantly reduced mortality in adults by 25% overall, and by 62% if started within 48 hours of symptom onset, compared with no treatment. But, the effectiveness of NIs in children is far less clear. Taken together, these data suggest that NIs should be reserved for patients with influenza who are at high-risk of complications, or when clinically assessed found to be markedly unwell, or rapidly deteriorating. In such patients, treatment should be initiated empirically, as soon as possible, preferably with follow-on virological confirmation.

Pubertal timing and bone phenotype in early old age: findings from a British birth cohort study

Abstract Objectives: To investigate the effect of pubertal timing, assessed in adolescence, on bone size, strength and density in men and women in early old age. Design: A British birth cohort study with prospective indicators of pubertal timing based on age at menarche, clinical assessment of pubertal stage, and growth tempo from serial height measures, and bone measures derived from peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA) at 60-64 years of age among 866 women and 792 men. Methods: A first set of regression models investigated the relationships between pubertal timing and bone size, strength and density, adjusting for current height and weight, smoking and adult socioeconomic position. To make an equivalent comparison between men and women, the percentage difference in bone outcomes was calculated for a 5-year difference in age at menarche, and in men a comparison between those who were fully mature or pre-adolescent at 14.5 years. A second set of models investigated the percentage difference in bone outcomes for a 5-year difference in timing of peak height velocity (height tempo) derived from longitudinal growth modelling (Superimposition by Translation and Rotation model; SITAR). Results: After adjustment for current height and weight, a 5-year increase in age at menarche was associated with an 8% [95% confidence interval (CI) -17%, 0.5%, P = 0.07) lower trabecular volumetric bone mineral density (vBMD); men who were pre-adolescent at 14.5 years had a 9%, (95% CI -14%, -4%; P = 0.001) lower trabecular vBMD compared with those who had been fully mature. Other confounders did not attenuate these estimates further. Patterns of association were similar but somewhat weaker for lumbar spine and total hip areal BMD. Age at peak height velocity was associated with even larger differences in BMD in men and women, and was negatively associated with bone size and strength. Conclusions: The association between later puberty and lower BMD persists into early old age. The 9-10% lower trabecular vBMD in later compared with earlier maturers could be clinically important given a rate of bone loss from midlife of 1-2% a year and the negative association between BMD and fracture.

Impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza A(H1N1)pdm09 at high risk of hospitalization: an Individual Participant Data (IPD) meta-analysis

Summary Our findings suggest that in populations at high risk for hospital admission, patients with laboratory-confirmed or clinically diagnosed A(H1N1)pdm09 infection, NAI treatment in the community or outpatient settings is associated with reduced likelihood of subsequent hospital admission.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

The impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.

Gene-environment interaction between body mass index and transforming growth factor beta 1 ( TGFβ1 ) gene in knee and hip osteoarthritis

IntroductionThe objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA).MethodsWe conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.Results2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P <0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P <0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).ConclusionTGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.