Maximum likelihood estimation of influenza vaccine effectiveness against transmission from the household and from the community

Influenza vaccination is recommended as the best way to protect against influenza infection and illness. Due to seasonal changes in influenza virus types and subtypes, a new vaccine must be produced, and vaccine effectiveness (VE) must be estimated, annually. Since 2010, influenza vaccination has been recommended universally in the United States, making randomized clinical trials unethical. Recent studies have used a monitored household cohort study design to determine separate VE estimates against influenza transmission from the household and community. We developed a probability model and accompanying maximum likelihood procedure to estimate vaccine‐related protection against transmission of influenza from the household and the community. Using agent‐based stochastic simulations, we validated that we can obtain maximum likelihood estimates of transmission parameters and VE close to their true values. Sensitivity analyses to examine the effect of deviations from our assumptions were conducted. We used our method to estimate transmission parameters and VE from data from a monitored household study in Michigan during the 2012‐2013 influenza season and were able to detect a significant protective effect of influenza vaccination against community‐acquired transmission.     

Effect of graduated elastic compression stockings on leg symptoms and signs during exercise in patients with deep venous thrombosis: a randomized cross‐over trial1

Summary. Graduated elastic compression stockings (ECS) are often prescribed after deep venous thrombosis (DVT) to alleviate acute symptoms and to prevent and treat post‐thrombotic syndrome (PTS). In patients with DVT, leg symptoms tend to worsen with exercise. The effects of ECS use during exercise have not been studied. Objectives were to determine whether ECS improve symptoms and signs and increase exercise capacity when worn during treadmill exercise by patients with prior DVT, with or without PTS. The methods employed a randomized cross‐over trial. We recruited subjects who had a first episode of unilateral DVT at least 1 year earlier and categorized them as having, or not having, the PTS using a validated scale. Subjects underwent two identical treadmill exercise sessions at least 1 week apart, and were randomly assigned to wear knee‐length 30 mmHg ECS on the affected leg during one of the two sessions. Venous symptoms, leg volume, leg circumference and calf muscle flexibility were measured in the affected leg before and after both exercise sessions. Subjects achieved similar percentage maximum predicted heart rates during both sessions. Comparing the ECS to no ECS session, there were no significant differences in treadmill time (21.2 vs. 21.2 min, P = 0.94), gain in leg volume (71 vs. 73 mL, P = 0.83), or change in soleus or gastrocnemius flexibility, whether or not PTS was present. Symptoms in general worsened slightly with exercise regardless of whether or not ECS were worn and did not differ according to PTS status. Per‐subject analysis showed that use of ECS resulted in global improvement of symptoms in 25% of subjects, global worsening in 33% of subjects, and had no or inconsistent effects in 42% of subjects. Whether or not PTS was present, the use of ECS during exercise by patients with prior DVT did not improve symptoms and signs during exercise or increase exercise capacity.     

An overview of the patterns of prescription opioid use,costs and related harms in Australia

AimsTo report Australian population trends in subsidized prescribed opioid use, total costs to the Australian government to subsidize these medicines and opioid-related harms based on hospitalizations and accidental poisoning deaths.MethodsWe utilized three national aggregated data sources including dispensing claims from the Pharmaceutical Benefits Scheme, opioid-related hospitalizations from the National Hospital Morbidity Database and accidental poisoning deaths from the Australian Bureau of Statistics.ResultsBetween 1992 and 2012, opioid dispensing episodes increased 15-fold (500 000 to 7.5 million) and the corresponding cost to the Australian government increased 32-fold ($8.5 million to $271 million). Opioid-related harms also increased. Opioid-related hospitalizations increased from 605 to 1464 cases (1998–2009), outnumbering hospitalizations due to heroin poisonings since 2001. Deaths due to accidental poisoning (pharmaceutical opioids and illicit substances combined) increased from 151 to 266 (2002–2011), resulting in a rise in the death rate of 0.78 to 1.19 deaths/100 000 population over 10 years. Death rates increased 1.8 fold in males and 1.4 fold in females.ConclusionsThe striking increase in opioid use and related harms in Australia is consistent with trends observed in other jurisdictions. Further, there is no evidence to suggest these increases are plateauing. There is currently limited evidence in Australia about individual patterns of opioid use and the associated risk of adverse events. Further research should focus on these important issues so as to provide important evidence supporting effective change in policy and practice.     

A chemical compound that stimulates the human homologous recombination protein RAD51

RAD51 and other members of the RecA family of strand exchange proteins assemble on ssDNA to form presynaptic filaments, which carry out the central steps of homologous recombination. A microplate-based assay was developed for high-throughput measurement of hRAD51 filament formation on ssDNA. With this method, a 10,000 compound library was screened, leading to the identification of a small molecule (RS-1) that enhances hRAD51 binding in a wide range of biochemical conditions. Salt titration experiments showed that RS-1 can enhance filament stability. Ultrastructural analysis of filaments formed on ssDNA showed that RS-1 can increase both protein–DNA complex lengths and the pitch of helical filament turns. RS-1 stimulated hRAD51-mediated homologous strand assimilation (D-loop) activity by at least 5- to 11-fold, depending on the condition. This D-loop stimulation occurred even in the presence of Ca²⁺ or adenylyl-imidodiphosphate, indicating that the mechanism of stimulation was distinct from that conferred by Ca²⁺ and/or inhibition of ATPase. No D-loop activity was observed in the absence of a nucleotide triphosphate cofactor, indicating that the compound does not substitute for this requirement. These results indicate that RS-1 enhances the homologous recombination activity of hRAD51 by promoting the formation of active presynaptic filaments. Cell survival assays in normal neonatal human dermal fibroblasts demonstrated that RS-1 promotes a dose-dependent resistance to the cross-linking chemotherapeutic drug cisplatin. Given that RAD51-dependent recombination is a major determinant of cisplatin resistance, RS-1 seems to function in vivo to stimulate homologous recombination repair proficiency. RS-1 has many potential applications in both research and medical settings.     

Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication.

In wild-type diploid cells of Saccharomyces cerevisiae, an HO endonuclease-induced double-strand break (DSB) at the MAT locus can be efficiently repaired by gene conversion using the homologous chromosome sequences. Repair of the broken chromosome was nearly eliminated in rad52delta diploids; 99% lost the broken chromosome. However, in rad51delta diploids, the broken chromosomes were repaired approximately 35% of the time. None of these repair events were simple gene conversions or gene conversions with an associated crossover, instead, they created diploids homozygous for the MAT locus and all markers in the 100-kb region distal to the site of the DSB. In rad51delta diploids, the broken chromosome can apparently be inherited for several generations, as many of these repair events are found as sectored colonies, with one part being repaired and the other part being lost the broken chromosome. Similar events occur in about 2% of wild-type cells. We propose that a broken chromosome end can invade a homologous template in the absence of RAD51 and initiate DNA replication that may extend to the telomere, 100 or more kb away. Such break-induced replication appears to be similar to recombination-initiated replication in bacteria.     

Endurance exercise training in orthostatic intolerance: a randomized, controlled trial

Orthostatic intolerance is a syndrome characterized by chronic orthostatic symptoms of light-headedness, fatigue, nausea, orthostatic tachycardia, and aggravated norepinephrine levels while standing. The aim of this study was to assess the protective effect of exercise endurance training on orthostatic symptoms and to examine its usefulness in the treatment of orthostatic intolerance. 2768 military recruits were screened for orthostatic intolerance by questionnaire. Tilt-table testing identified 36 cases of orthostatic intolerance out of the 2768 soldiers. Subsequently, 31 of these subjects with orthostatic intolerance entered a randomized, controlled trial. The patients were allocated randomly to either a "training" (3 months jogging) or a "control" group. The influence of exercise training on orthostatic intolerance was assessed by determination of questionnaire scores and tilt-table testing before and after intervention. After training, only 6 individuals of 16 still had orthostatic intolerance compared with 10 of 11 in the control group. The Fisher exact test showed a highly significant difference in diagnosis between the 2 groups (P=0.008) at the end of the study. Analysis of the questionnaire-score showed significant interaction between time and group (P=0.001). The trained subjects showed an improvement in the average symptom score from 1.79+/-0.4 to 1.04+/-0.4, whereas the control subjects showed no significant change in average symptom score (2.09+/-0.6 and 2.14+/-0.5, respectively). Our data demonstrate that endurance exercise training leads to an improvement of symptoms in the majority of patients with orthostatic intolerance. Therefore, we suggest that endurance training should be considered in the treatment of orthostatic intolerance patients.