What Determines the Shape of an EQ-5D Index Distribution?

Background. EQ-5D-3L index scores in patient and general populations typically have a nonnormal distribution, divided into 2 distinct groups. It is important to understand to what extent this is determined by the way that the EQ-5D-3L index is constructed rather than by the true distribution of ill health. Objective. This paper examines the determinants of the ‘‘2 groups’’ distribution pattern and the extent to which this pattern is attributable either to the EQ-5D-3L classification system used to create health state profiles or to the weights applied to profiles. Methods. Data from the English NHS PROMs program (hip and knee replacements and varicose vein and hernia repairs) and from a study of 2 chronic conditions (asthma and angina) were used to compare the distributions of EQ5D-3L index scores with distributions from which weights have been stripped; profile data decomposed into their constituent dimensions and levels; a condition-specific index; and using weights from different countries, based on both time tradeoff and visual analogue scale. Results. The EQ-5D-3L classification system generates differences between patients with the same condition in respect of dimensions that are mainly observed at level 2 or 3. The weights commonly used to calculate the index exacerbate this grouping by placing a larger weight on level 3 observations, generating a noticeable gap in index scores between the groups. Conclusions. Analyzing EQ-5D profile data enables a better understanding of the resulting distribution of EQ-5D scores. The distinctive shape observed for these distributions is the result of both the classification system and the weights applied to it

Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p> <p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p> <p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p> <p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p&gt

Noncommunicable disease and multimorbidity in young adults with cerebral palsy

Purpose: Individuals with cerebral palsy (CP) are at increased risk for frailty and chronic disease due to factors experienced throughout the lifespan, such as excessive sedentary behaviors and malnutrition. However, little is known about noncommunicable diseases (NCDs) and multimorbidity profiles in young adults with CP. The study objective was to compare NCD and multimorbidity profiles between young adults with and without CP. Methods: A clinic-based sample of adults (18–30 years) with (n=452) and without (n=448) CP was examined at the University of Michigan Medical Center. The prevalence and predictors of 13 NCDs were evaluated, including existing diagnoses or historical record of musculoskeletal, cardiometabolic, and pulmonary morbidities. The level of motor impairment was determined by the Gross Motor Function Classification System (GMFCS) and stratified by less vs more severe motor impairment (GMFCS I–III vs IV–V). Logistic regression was used to determine the odds of NCD morbidity and multimorbidity in adults with CP compared to adults without CP, and for GMFCS IV–V compared to GMFCS I–III in those with CP, after adjusting for age, sex, body mass index, and smoking. Results: Adults with CP had a higher prevalence of osteopenia, osteoporosis, hypertension, myocardial infarction, hyperlipidemia, asthma, and multimorbidity compared to adults without CP, and higher odds of musculoskeletal (odds ratio [OR]: 6.97) and cardiometabolic morbidity (OR: 1.98), and multimorbidity (OR: 2.67). Adults with CP with GMFCS levels IV–V had a higher prevalence of osteopenia/osteoporosis, osteoarthritis, hypertension, other cardiovascular conditions, pulmonary embolism, and multimorbidity, and higher odds of musculoskeletal (OR: 3.41), cardiometabolic (OR: 2.05), pulmonary morbidity (OR: 1.42), and multimorbidity (OR: 3.45) compared to GMFCS I–III. Conclusion: Young adults with CP have a higher prevalence of chronic NCDs and multimorbidity compared to young adults without CP, which is pronounced in those with more severe motor impairment. These findings reiterate the importance of early screening for prevention of NCDs in CPNational Institutes of Health (NIH) and the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR

Memantine reduces consumption of highly palatable food in a rat model of binge eating

Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. Since the glutamatergic system has recently emerged as a viable target for binge-eating medication development, we compared the effects of subchronic treatment with glutamatergic receptor antagonists to the effects of a reference appetite-suppressing agent sibutramine on highly palatable food (lard) and normal chow intake. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. Generalized estimating equations analysis demonstrated that sibutramine (7.5 mg/kg, PO) significantly decreased lard consumption, with a concurrent increase in chow consumption. Sibutramine effects disappeared after treatment discontinuation. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation. The effects of the mGluR5 antagonist MTEP (7.5 mg/kg, IP) on food consumption were in the same direction as seen with memantine, but the observed differences were not significant. In an additional control experiment, sibutramine and memantine reduced unlimited (24 h) chow intake during the treatment phase. Present results provide evidence that glutamatergic neurotransmission might be involved in the regulation of excessive consumption of highly palatable foods, and suggest that NMDA receptor may be an attractive target for developing obesity and disordered eating pharmacotherapies

SCUBA divers as oceanographic samplers: The potential of dive computers to augment aquatic temperature monitoring

Monitoring temperature of aquatic waters is of great importance, with modelled, satellite and in-situ data providing invaluable insights into long-term environmental change. However, there is often a lack of depth-resolved temperature measurements. Recreational dive computers routinely record temperature and depth, so could provide an alternate and highly novel source of oceanographic information to fill this data gap. In this study, a citizen science approach was used to obtain over 7,000 scuba diver temperature profiles. The accuracy, offset and lag of temperature records was assessed by comparing dive computers with scientific conductivity-temperature-depth instruments and existing surface temperature data. Our results show that, with processing, dive computers can provide a useful and novel tool with which to augment existing monitoring systems all over the globe, but especially in under-sampled or highly changeable coastal environments

Temporary migration programmes: the cause or antidote for migrant worker exploitation in UK agriculture

The referendum result in Britain in 2016 and the potential loss of EU labour in the advent of a “hard Brexit” has raised pressing questions for sectors that rely on EU labour, such as agriculture. Coupled with the closure of the long-standing Seasonal Agricultural Scheme in 2013, policymakers are grappling with how to satisfy one the one hand employer demands for mobility schemes, and on the other public demands for restrictive immigration policies. Labour shortages in agriculture transcend the immigration debate, raising questions for food security, the future of automation and ultimately what labour market the UK hopes to build. Temporary Migration programmes have been heralded as achieving a triple win, yet they are rightly criticized for breeding bonded labour and exploitation. In lieu of a dedicated EU labour force agricultural employers are calling for the establishment of a new seasonal scheme. In this paper we explore whether the absence of a temporary migration programme resolves the potential exploitation of migrant workers. We argue that the absence of a TMP is not an antidote to migrant exploitation, and that a socially just TMP which is built around migrant agency may be the most palpable solution

Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom

\ua9 The Author(s) 2024.Background: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. Methods: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. Results: 132 pts were included. Median age was 56 years (28–91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5–6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. Conclusion: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience

Haplotype Reconstruction Error as a Classical Misclassification Problem: Introducing Sensitivity and Specificity as Error Measures

BACKGROUND: Statistically reconstructing haplotypes from single nucleotide polymorphism (SNP) genotypes, can lead to falsely classified haplotypes. This can be an issue when interpreting haplotype association results or when selecting subjects with certain haplotypes for subsequent functional studies. It was our aim to quantify haplotype reconstruction error and to provide tools for it. METHODS AND RESULTS: By numerous simulation scenarios, we systematically investigated several error measures, including discrepancy, error rate, and R(2), and introduced the sensitivity and specificity to this context. We exemplified several measures in the KORA study, a large population-based study from Southern Germany. We find that the specificity is slightly reduced only for common haplotypes, while the sensitivity was decreased for some, but not all rare haplotypes. The overall error rate was generally increasing with increasing number of loci, increasing minor allele frequency of SNPs, decreasing correlation between the alleles and increasing ambiguity. CONCLUSIONS: We conclude that, with the analytical approach presented here, haplotype-specific error measures can be computed to gain insight into the haplotype uncertainty. This method provides the information, if a specific risk haplotype can be expected to be reconstructed with rather no or high misclassification and thus on the magnitude of expected bias in association estimates. We also illustrate that sensitivity and specificity separate two dimensions of the haplotype reconstruction error, which completely describe the misclassification matrix and thus provide the prerequisite for methods accounting for misclassification