Assessing the Viability of the EQ-5D as Part of a Battery of Outcomes in Elderly Total Knee Arthroplasty Patients: A Comparison of Generic, Condition-Specific, and Preference-Based Patient-Reported Outcome Measures

Background In the current economic climate it has become increasingly important to evaluate the effectiveness of expensive procedures such as total knee arthroplasties (TKAs). Patient-reported outcome measures, such as generic and condition-specific profile measures, are popular ways of determining outcomes. However, these cannot be used reliably for the purpose of economic evaluations. The EQ-5D, designed for cost-utility analysis, could offer potential advantages to outcome measurement; however, little is known about the viability and performance of this measure in more elderly (_ 75 years) patient cohorts. Aims The aim of this study was to assess the viability of the EQ-5D for use in the evaluation of TKA and to provide justification for its continued inclusion in the clinical audit of patients undergoing arthroplasty in a large general hospital. Methods Seven-hundred and seventy-nine consecutive patients undergoing TKA participated in this study. Self-report audit questionnaire booklets were administered at baseline (during a pre-admission clinic appointment) and six months post-operatively (postally). Booklets comprised of the Oxford Knee Scale (OKS;), 12-dimension Short Form (SF-12;), and the EQ-5D (). Results Two-hundred and forty-six subjects completed both the baseline and follow-up audit surveys. Correlations were strongest between the EQ-5D and OKS instruments (baseline: Tb=-0.58; p0.01; follow-up: Tb=-0.41; p0.01),.. The EQ-5D displayed large effect sizes (d=0.94) and was able to detect clinically important HRQoL improvements (ROC P-value=0.65; CI0.08; p0.001), discriminate those patients who were experiencing poorer pre-operative health (p0.001), and detect those who deteriorated post-operatively (p0.001). Adequate reliability (Cronbach's =0.79) of the EQ-5D instrument was seen post-operatively as well. Conclusions Results from this study reveal that the EQ-5D instrument shows good responsiveness to health changes in elderly TKA patients post-operatively. Its correlations with the OKS, detection of poorer pre-operative health, and detection of deterioration post-operatively also suggest good validity for the EQ-5D in this cohort. Finally, the relatively large reliability statistic post-operatively supports the use of the EQ-5D in audits. Together, these findings support the continued use of the EQ-5D instrument in future arthroplasty audits and provide evidence that it is viable for the use in cost-utility analysis.sch_phyunpub2424unpu

Physical function following TKA compared to age matched healthy controls

Purpose: to explore whether physical and functional impairments exist in those who have undergone primary TKA compared to age matched healthy controls. Relevance: Many studies have suggested that although function generally improves following TKA, patients continue to experience significant functional limitations. Most of these studies however have assessed function using self-reported measures despite recommendations that both self-report and performance based measures are required to capture the full spectrum of functional ability. Furthermore, there have been no recent studies that have comprehensively compared outcomes in TKA with those who have no knee related pathology. Therefore, the evidence to suggest that functional limitations persist cannot be considered as robust. Participants: A group of patients (n = 15) were recruited who had undergone primary TKA for osteoarthritis between 10 and 14 months previously (median age = 71 years). A group of age matched health controls (n = 12, median age = 69.5 years) were recruited from local community groups. Methods: Self reported function (0-100 scale where 0 is best), timed-up-and-go, stair ascent/descent, walking speed, leg extensor power and range of motion were compared between groups. Analysis: Mann-Whitney U-tests were used to detect inter-group differences. The alpha level was set at 0.05. Results: Maximum flexion in the TKA group (median = 110o) was significantly less (p = 0.002) than the control group (median = 120o). The TKA group reported significantly worse function (median scores TKA = 10.0, control = 0.00, p = 0.028). No significant differences (p >0.05) however were found between groups in any of the performance based measures of function (timed up and go, timed stair ascent/descent, walking speed) or in knee extensor strength. Conclusions: although individuals with TKA perceived their functional ability to be significantly worse than their healthy counterparts, there was no evidence to suggest that significant functional impairments existed in this small group. Implications: expectations of outcome in TKA have been shown to be an important factor in overall patient satisfaction with their surgery. The results of this study could help to provide improved information regarding functional ability following TKA.sch_phyunpub2310unpu

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio

Direct Phenotypical and Functional Dysregulation of Primary Human B Cells by Human Immunodeficiency Virus (HIV) Type 1 In Vitro

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) induces a general dysregulation of immune system. Dysregulation of B cell compartment is generally thought to be induced by HIV-related immune activation and lymphopenia. However, a direct influence of HIV-1 particles on B cells was recently proposed as the third pathway of B cells dysregulation. METHODS/PRINCIPAL FINDINGS: We evaluated the direct and specific consequences of HIV-1 contact on activation, survival, proliferation and phenotype of primary B cells in vitro. Moreover, we examined expression of activation-induced cytidine deaminase (AID) mRNA that is responsible for class switch recombination (CSR) and somatic hypermutation (SHM). Here, we report that changes observed in cellular proliferation, phenotypes and activation of B cells could be caused by direct contact between HIV-1 particles and primary B cells in vitro. Finally, direct HIV-1-derived B cells activation led to the increase of AID mRNA expression and its subsequent CSR function was detected in vitro. CONCLUSION/SIGNIFICANCE: We showed that HIV-1 could directly induce primary B cells dysregulation triggering phenotypical and functional abilities of B cells in vitro that could explain in some extent early B-cell abnormalities in HIV disease

Promoting advance planning for health care and research among older adults: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Family members are often required to act as substitute decision-makers when health care or research participation decisions must be made for an incapacitated relative. Yet most families are unable to accurately predict older adult preferences regarding future health care and willingness to engage in research studies. Discussion and documentation of preferences could improve proxies' abilities to decide for their loved ones. This trial assesses the efficacy of an advance planning intervention in improving the accuracy of substitute decision-making and increasing the frequency of documented preferences for health care and research. It also investigates the financial impact on the healthcare system of improving substitute decision-making.</p> <p>Methods/Design</p> <p>Dyads (<it>n </it>= 240) comprising an older adult and his/her self-selected proxy are randomly allocated to the experimental or control group, after stratification for type of designated proxy and self-report of prior documentation of healthcare preferences. At baseline, clinical and research vignettes are used to elicit older adult preferences and assess the ability of their proxy to predict those preferences. Responses are elicited under four health states, ranging from the subject's current health state to severe dementia. For each state, we estimated the public costs of the healthcare services that would typically be provided to a patient under these scenarios. Experimental dyads are visited at home, twice, by a specially trained facilitator who communicates the dyad-specific results of the concordance assessment, helps older adults convey their wishes to their proxies, and offers assistance in completing a guide entitled <it>My Preferences </it>that we designed specifically for that purpose. In between these meetings, experimental dyads attend a group information session about <it>My Preferences</it>. Control dyads attend three monthly workshops aimed at promoting healthy behaviors. Concordance assessments are repeated at the end of the intervention and 6 months later to assess improvement in predictive accuracy and cost savings, if any. Copies of completed guides are made at the time of these assessments.</p> <p>Discussion</p> <p>This study will determine whether the tested intervention guides proxies in making decisions that concur with those of older adults, motivates the latter to record their wishes in writing, and yields savings for the healthcare system.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN89993391">ISRCTN89993391</a></p

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification