Abstract Aim To use published literature and experts’ opinion to investigate the clinical meaning and magnitude of changes in the Quality of Life (QOL) of groups of patients measured with the ...European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Methods An innovative method combining systematic review of published studies, expert opinions and meta-analysis was used to estimate large, medium, and small mean changes over time for QLQ-C30 scores. Results Nine hundred and eleven papers were identified, leading to 118 relevant papers. One thousand two hundred and thirty two mean changes in QOL over time were combined in the meta-analysis, with timescales ranging from four days to five years. Guidelines were produced for trivial, small, and medium size classes, for each subscale and for improving and declining scores separately. Estimates for improvements were smaller than respective estimates for declines. Conclusions These guidelines can be used to aid sample size calculations and interpretation of mean changes over time from groups of patients. Observed mean changes in the QLQ-C30 scores are generally small in most clinical situations, possibly due to response shift. Careful consideration is needed when planning studies where QOL changes over time are of primary interest; the timing of follow up, sample attrition, direction of QOL changes, and subscales of primary interest are key considerations.
Approval of Spinraza (nusinersen) for treatment of spinal muscular atrophy prompts consideration of a number of ethical issues that arise whenever a new treatment is proposed for a serious condition, ...especially one that is rare and can devastatingly affect children. Patients, families, clinicians, researchers, institutions and policymakers all must take account of the ways that newly available treatments affect informed and shared decision-making about therapeutic and research options. The issues to consider include: addressing what is still uncertain and unknown; the possibility that potential benefits will be exaggerated and potential harms underemphasized in the media, by advocacy organizations, and in consent forms and processes; the high cost of many novel drugs and biologics; the effects of including conditions of variable phenotype in state-mandated newborn screening panels; and how new treatments can change the standard of care, altering what is and is not known about a disorder and posing challenges for decision-making at both individual and policy levels. The good news that Spinraza brings thus requires additional attention to its ethical and policy implications, to improve counseling and shared decision-making about treatment and research options for patients and all involved in their care.
Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization ...for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention 'very cost-effective' by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.
Human epithelial tissues accumulate cancer-driver mutations with age
, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness ...of proliferating cells
. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours
. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.
A decline in resting energy expenditure (REE) beyond that predicted from changes in body composition has been noted following dietary-induced weight loss. However, it is unknown whether a ...compensatory downregulation in REE also accompanies exercise (EX)-induced weight loss, or whether this adaptive metabolic response influences energy intake (EI).
Thirty overweight and obese women (body mass index (BMI)=30.6±3.6 kg/m(2)) completed 12 weeks of supervised aerobic EX. Body composition, metabolism, EI and metabolic-related hormones were measured at baseline, week 6 and post intervention. The metabolic adaptation (MA), that is, difference between predicted and measured REE was also calculated post intervention (MApost), with REE predicted using a regression equation generated in an independent sample of 66 overweight and obese women (BMI=31.0±3.9 kg/m(2)).
Although mean predicted and measured REE did not differ post intervention, 43% of participants experienced a greater-than-expected decline in REE (-102.9±77.5 kcal per day). MApost was associated with the change in leptin (r=0.47; P=0.04), and the change in resting fat (r=0.52; P=0.01) and carbohydrate oxidation (r=-0.44; P=0.02). Furthermore, MApost was also associated with the change in EI following EX (r=-0.44; P=0.01).
Marked variability existed in the adaptive metabolic response to EX. Importantly, those who experienced a downregulation in REE also experienced an upregulation in EI, indicating that the adaptive metabolic response to EX influences both physiological and behavioural components of energy balance.
IMPORTANCE: Myopia (ie, nearsightedness) is becoming the most common eye disorder to cause blindness in younger persons in many parts of the world. Visual impairment due to myopia is associated with ...structural changes of the retina and the globe because of elongation of the eye axis. How axial length—a sum of the anterior chamber depth, lens thickness, and vitreous chamber depth—and myopia relate to the development of visual impairment over time is unknown. OBJECTIVES: To evaluate the association between axial length, spherical equivalent, and the risk of visual impairment and to make projections of visual impairment for regions with high prevalence rates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study uses population-based data from the Rotterdam Study I (1990 to 1993), II (2000 to 2002), and III (2006 to 2008) and the Erasmus Rucphen Family Study (2002 to 2005) as well as case-control data from the Myopia Study (2010 to 2012) from the Netherlands. In total, 15 404 individuals with data on spherical equivalent and 9074 individuals with data on axial length were included in the study; right eyes were used for analyses. Data were analyzed from September 2014 to May 2016. MAIN OUTCOMES AND MEASURES: Visual impairment and blindness (defined according to the World Health Organization criteria as a visual acuity less than 0.3) and predicted rates of visual impairment specifically for persons with myopia. RESULTS: Of the 15 693 individuals included in this study, the mean (SD) age was 61.3 (11.4) years, and 8961 (57.1%) were female. Axial length ranged from 15.3 to 37.8 mm; 819 individuals had an axial length of 26 mm or greater. Spherical equivalent ranged from −25 to +14 diopters; 796 persons had high myopia (ie, a spherical equivalent of −6 diopters or less). The prevalence of visual impairment varied from 1.0% to 4.1% in the population-based studies, was 5.4% in the Myopia Study, and was 0.3% in controls. The prevalence of visual impairment rose with increasing axial length and spherical equivalent, with a cumulative incidence (SE) of visual impairment of 3.8% (1.3) for participants aged 75 years with an axial length of 24 to less than 26 mm and greater than 90% (8.1) with an axial length of 30 mm or greater. The cumulative risk (SE) of visual impairment was 5.7% (1.3) for participants aged 60 years and 39% (4.9) for those aged 75 years with a spherical equivalent of −6 diopters or less. Projections of these data suggest that visual impairment will increase 7- to 13-fold by 2055 in high-risk areas. CONCLUSIONS AND RELEVANCE: This study demonstrated that visual impairment is associated with axial length and spherical equivalent and may be unavoidable at the most extreme values in this population. Developing strategies to prevent the development of myopia and its complications could help to avoid an increase of visual impairment in the working-age population.
Laser-plasma accelerators (LPAs) driven by picosecond-scale, kilojoule-class lasers can generate particle beams and x-ray sources that could be utilized in experiments driven by multi-kilojoule, ...high-energy-density science (HEDS) drivers such as the OMEGA laser at the Laboratory for Laser Energetics (LLE) or the National Ignition Facility at Lawrence Livermore National Laboratory. This paper reports on the development of the first LPA driven by a short-pulse, kilojoule-class laser (OMEGA EP) connected to a multi-kilojoule HEDS driver (OMEGA). In experiments, electron beams were produced with electron energies greater than 200 MeV, divergences as low as 32 mrad, charge greater than 700 nC, and conversion efficiencies from laser energy to electron energy up to 11%. The electron beam charge scales with both the normalized vector potential and plasma density. These electron beams show promise as a method to generate MeV-class radiography sources and improved-flux broadband x-ray sources at HEDS drivers.
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