Summary
This paper provides guidance for researchers with some mathematical background on the conduct of time‐to‐event analysis in observational studies based on intensity (hazard) models. ...Discussions of basic concepts like time axis, event definition and censoring are given. Hazard models are introduced, with special emphasis on the Cox proportional hazards regression model. We provide check lists that may be useful both when fitting the model and assessing its goodness of fit and when interpreting the results. Special attention is paid to how to avoid problems with immortal time bias by introducing time‐dependent covariates. We discuss prediction based on hazard models and difficulties when attempting to draw proper causal conclusions from such models. Finally, we present a series of examples where the methods and check lists are exemplified. Computational details and implementation using the freely available R software are documented in Supplementary Material. The paper was prepared as part of the STRATOS initiative.
The In2Care EaveTube is a house modification designed to block and kill malaria mosquitoes using an electrostatic netting treated with insecticide powder. A previous study demonstrated prolonged ...duration of effective action of insecticide-treated electrostatic netting in a semi-field setting. As part of a cluster randomized controlled trial (CRT) of the EaveTube intervention in Côte d'Ivoire, we investigated the residual efficacy of a pyrethroid insecticide deployed in EaveTubes under village conditions of use. We also explored the scope of using existing malaria control technologies including LLINs and IRS as alternative methods to deliver insecticides in the lethal house lure. The efficacy of beta-cyfluthrin was monitored over time using the "eave tube bioassay" method. Mortality of beta-cyfluthrin exposed pyrethroid resistant Anopheles gambiae mosquitoes was > 80% after 4 months. The impact (mosquito mortality) of PVC tubes coated with pirimiphos methyl was similar to that of beta-cyfluthrin treated insert (66.8 vs. 62.8%) in release-recapture experiments in experimental huts. Efficacy was significantly lower with all the LLINs tested; however, the roof of PermaNet 3.0 induced significantly higher mosquito mortality (50.4%) compared to Olyset Plus (25.9%) and Interceptor G2 (21.6%) LLINs. The efficacy of the alternative delivery methods was short-lived with mortality decreasing below 50% within 2 months in residual activity bioassays. None of the products tested appeared superior to the powder treatments. Further research is therefore required to identify suitable insecticide delivery options in EaveTube for malaria vector control.
The 5th National Audit Project (NAP5) of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland into accidental awareness during general anaesthesia ...(AAGA) yielded data related to psychological aspects from the patient, and the anaesthetist, perspectives; patients' experiences ranged from isolated auditory or tactile sensations to complete awareness. A striking finding was that 75% of experiences were for <5 min, yet 51% of patients 95% confidence interval (CI) 43–60% experienced distress and 41% (95% CI 33–50%) suffered longer term adverse effect. Distress and longer term harm occurred across the full range of experiences but were particularly likely when the patient experienced paralysis (with or without pain). The patient's interpretation of what is happening at the time of the awareness seemed central to later impact; explanation and reassurance during suspected AAGA or at the time of report seemed beneficial. Quality of care before the event was judged good in 26%, poor in 39%, and mixed in 31%. Three-quarters of cases of AAGA (75%) were judged preventable. In 12%, AAGA care was judged good and the episode not preventable. The contributory and human factors in the genesis of the majority of cases of AAGA included medication, patient, and education/training. The findings have implications for national guidance, institutional organization, and individual practice. The incidence of ‘accidental awareness' during sedation (∼1:15 000) was similar to that during general anaesthesia (∼1:19 000). The project raises significant issues about information giving and consent for both sedation and anaesthesia. We propose a novel approach to describing sedation from the patient's perspective which could be used in communication and consent. Eight (6%) of the patients had resorted to legal action (12, 11%, to formal complaint) at the time of reporting. NAP5 methodology provides a standardized template that might usefully inform the investigation of claims or serious incidents related to AAGA.
Summary
Cranial cruciate ligament rupture (CCLR) is one of the leading causes of pelvic limb lameness in dogs. About 6% of Labrador Retrievers suffer from this orthopedic problem. The aim of this ...study was to determine the heritability of CCLR in this breed using SNP array genotyping data. DNA samples were collected from CCLR‐affected dogs (n = 190) and unaffected dogs over the age of 8 years (n = 143). All 333 dogs were genotyped directly or imputed up to approximately 710k SNPs on the Affymetrix Axiom CanineHD SNP array. Heritability of CCLR was calculated using multiple methodologies, including linear mixed models, Bayesian models and a model that incorporates LD. The covariates of sex and sterilization status were added to each analysis to assess their impact. Across the algorithms of these models, heritability ranged from 0.550 to 0.886, depending on covariate inclusion. The relatively high heritability for this disease indicates that a substantial genetic component contributes to CCLR in the Labrador Retriever.
At the global scale, reconstructions of cool season temperature over past centuries are relatively rare. Here we present 277-year reconstructions of cool season (July–October) temperatures for ...southern Australia based on three different data sets: a spatial field reconstruction based on highly resolved temperature data from the Australian Water Availability Product data; reconstructions for the four southeast Australian states based on the Berkeley Earth mean temperature data for each state; and reconstructions for individual stations in southeastern Australia from the Australian Bureau of Meteorology’s Australian Climate Observations Reference Network–Surface Air Temperature data. Our reconstructions typically capture 25–50% of the variation over the late twentieth Century calibration period and are strongest for the southern state of Tasmania and the southeastern part of mainland Australia. All three use Tasmanian tree-rings sensitive to cool season temperatures and display similar variability. In the context of our reconstructions, the persistent warming in the observed record since ~ 1950 is unprecedented. While the low frequency variability of winter temperatures is generally in step with that in summer (December–February) temperatures, high frequency variability is not, illustrating the need for seasonal reconstructions to help improve understanding of variability in inter-seasonal dynamics and the historical importance of this on the environment. The reconstructions covary with changes in the Southern Annular Mode and may be useful for future reconstructions of this phenomenon.
Summary
Ten volunteers evaluated the performance of four currently available manikins: Airway Management TrainerTM, Airway TrainerTM, Airsim™ and Bill 1™ as simulators for the 16 procedures described ...in the Difficult Airway Society Guidelines (DAS techniques) and eight other advanced airway techniques (non‐DAS techniques), by scoring and ranking each manikin and procedure. Manikin performance was unequal (p < 0.0001 for both SCORE and RANK data for both DAS and non‐DAS techniques). Post hoc analysis ranked the manikins for DAS techniques as: 1st Laerdal, 2nd Trucorp, 3rd equal VBM and Ambu. For non‐DAS techniques, the ranking was: 1st equal Laerdal and Trucorp, 3rd equal VBM and Ambu. The power to discriminate for individual procedures was considerably lower but for 15 of 16 DAS techniques and 6 of 8 non‐DAS techniques, manikin performance differed significantly. Post hoc tests showed significant performance differences between individual manikins for 10 DAS procedures, with the Laerdal manikin performing best.
This phase II trial describes the use of TIP chemotherapy (paclitaxel, ifosfamide and cisplatin) as salvage for patients with metastatic germ cell cancer (GCC) who have failed initial BEP (bleomycin, ...etoposide and cisplatin) chemotherapy. Patients with first relapse following BEP for metastatic GCC, confirmed by biopsy or sequentially rising markers, received four courses of TIP (paclitaxel 175 mg m(-2) day 1, followed on days 1-5 by ifosfamide 1 g m(-2) intravenously (i.v.) and cisplatin 20 mg2 i.v.) at 3-weekly intervals. The primary outcome measure was response to TIP. In all, 51 patients were registered, of whom 43 were eligible for response assessment. Eight achieved complete remission (CR) and 18 a partial remission with negative markers (PR(-ve)); favourable response rate (FRR = CR + PR(-ve)) 60%, 95% CI (44-75%); survival at 1 year was 70% (56-84%) and failure-free survival 36% (22-50%). In the group of 26 patients meeting the 'good-risk' criteria described by the Memorial Hospital, the FRR was 73% (52-88%) compared with 41% (18-67%) for the 17 'poor-risk' patients. These results are inferior to those previously reported for TIP in a single-centre study when it was given more intensively, at higher dose and with growth factor support. Nonetheless, TIP as described here can cure a substantial proportion of patients.
Objectives
The prevalence of obesity is rising among people living with HIV, which may synergistically increase inflammation and the risk of associated diseases. Disruption of gut bacterial ...communities may be one of the key drivers of this inflammation; however, the combined effects of HIV and obesity on the microbiome have not been explored.
Methods
This study included 381 men who have sex with men. Thirty‐nine were HIV‐positive and obese (H+O+), 143 were HIV‐positive and nonobese, 64 were HIV‐negative and obese, and 135 were HIV‐negative and nonobese. Microbiome composition was assessed by targeted sequencing of the V4 region of the 16S ribosomal RNA (rRNA) gene using rectal swab samples. Inverse probability of treatment‐weighted marginal structural models were used to investigate differences in microbial composition between groups while controlling for numerous clinical and behavioural confounders.
Results
Significant variability in microbial composition was explained by the combination of HIV and obesity, over and above each condition alone (R2 for the marginal contribution of the H+/O+ group = 0.008; P = 0.001). H+O+ participants had the highest ratios of Prevotella to Bacteroides, a pro‐inflammatory enterotype that has been described in HIV infection and obesity independently. H+O+ participants had lower levels of Bacteroides and Veillonella than all other groups, suggesting a synergistic effect of HIV and obesity on these genera.
Conclusions
Our findings support the hypothesis that HIV and obesity act together to disrupt gut microbial communities, which may help explain higher levels of generalized inflammation among people living with both HIV and obesity.
The PIN-domains are small proteins of ∼130 amino acids that are found in bacteria, archaea and eukaryotes and are defined by a group of three strictly conserved acidic amino acids. The conserved ...three-dimensional structures of the PIN-domains cluster these acidic residues in an enzymatic active site. PIN-domains cleave single-stranded RNA in a sequence-specific, Mg2+- or Mn2+-dependent manner. These ribonucleases are toxic to the cells which express them and to offset this toxicity, they are co-expressed with tight binding protein inhibitors. The genes encoding these two proteins are adjacent in the genome of all prokaryotic organisms where they are found. This sequential arrangement of inhibitor-RNAse genes conforms to that of the so-called toxin–antitoxin (TA) modules and the PIN-domain TAs have been named VapBC TAs (virulence associated proteins, VapB is the inhibitor which contains a transcription factor domain and VapC is the PIN-domain ribonuclease). The presence of large numbers of vapBC loci in disparate prokaryotes has motivated many researchers to investigate their biochemical and biological functions. For example, the devastating human pathogen Mycobacterium tuberculosis has 45 vapBC loci encoded in its genome whereas its non-pathogenic relative, Mycobacterium smegmatis has just one vapBC operon. On another branch of the prokaryotic tree, the nitrogen-fixing symbiont of legumes, Sinorhizobium meliloti has 21 vapBC loci and at least one of these loci have been implicated in the regulation of growth in the plant nodule. A range of biological functions has been suggested for these operons and this review sets out to survey the PIN-domains and summarise the current knowledge about the vapBC TA systems and their roles in diverse bacteria.
Abstract Objectives: To examine whether British South Asian children differ in insulin resistance, adiposity, and cardiovascular risk profile from white children. Design: Cross sectional study. ...Setting: Primary schools in 10 British towns. Participants: British children aged 8 to 11 years (227 South Asian and 3415 white); 73 South Asian and 1287 white children aged 10 and 11 years provided blood samples (half fasting, half after glucose load). Main outcome measures: Insulin concentrations, anthropometric measures, established cardiovascular risk factors. Results: Mean ponderal index was lower in South Asian children than in white children (mean difference −0.43 kg/m3, 95% confidence interval −0.13 kg/m3 to −0.73 kg/m3). Mean waist circumferences and waist:hip ratios were similar. Mean insulin concentrations were higher in South Asian children (percentage difference was 53%, 14% to 106%, after fasting and 54%, 19% to 99%, after glucose load), though glucose concentrations were similar. Mean heart rate and triglyceride and fibrinogen concentrations were higher among South Asian children; serum total, low density lipoprotein, and high density lipoprotein cholesterol concentrations were similar in the two groups. Differences in insulin concentrations remained after adjustment for adiposity and other potential confounders. However, the relations between adiposity and insulin concentrations (particularly fasting insulin) were much stronger among South Asian children than among white children. Conclusions: The tendency to insulin resistance observed in British South Asian adults is apparent in children, in whom it may reflect an increased sensitivity to adiposity. Action to prevent non-insulin dependent diabetes in South Asian adults may need to begin during childhood. What is already known on this topic Compared with white people British South Asians are at increased risk of coronary heart disease, stroke, and non-insulin dependent diabetes There is evidence that these conditions originate in early life What this study adds British South Asian children show higher average levels of insulin and insulin resistance than white children These ethnic differences in insulin resistance in childhood are not associated with corresponding differences in adiposity, particularly central adiposity Insulin metabolism seems to be more sensitive to a given degree of adiposity among the South Asian children compared with white children The prevention of insulin resistance and its consequences may need to begin during childhood, particularly in South Asians
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