Mapping the Insomnia Severity Index instrument to EQ-5D health state utilities: a United Kingdom perspective

Objective: This study aimed to map the Insomnia Severity Index (ISI) to the EQ-5D-3L utility values from a UK perspective. Methods: Source data were derived from the 2020 National Health and Wellness Survey (NHWS) for France, Germany, Italy, Spain, the UK and the US. Ordinary least squares regression, generalised linear model (GLM), censored least absolute deviation, and adjusted limited dependent variable mixture model (ALDVMM) were employed to explore the relationship between ISI total summary score and EQ-5D utility while accounting for adjustment covariates derived from the NHWS. Fitting performance was assessed using standard metrics, including mean-squared error (MSE) and coefficient of determination (R2). Results: A total of 17,955 respondent observations were included, with a mean ISI score of 12.12 ± 5.32 and a mean EQ-5D-3L utility (UK tariff) of 0.71 ± 0.23. GLM gamma-log and ALDVMM were the two best performing models. The ALDVMM had better fitting performance (R2 = 0.320, MSE 0.0347) than the GLM gamma-log (R2 = 0.303, MSE 0.0353); in train-test split-sample validation, ALDVMM also slightly outperformed the GLM gamma-log model, with an MSE of 0.0351 versus 0.0355. Based on fitting performance, ALDVMM and GLM gamma-log were the preferred models. Conclusions: In the absence of preference-based measures, this study provides an updated mapping algorithm for estimating EQ-5D-3L utilities from the ISI summary total score. This new mapping not only draws its strengths from the use of a large international dataset but also the incorporation of adjustment variables (including sociodemographic and general health characteristics) to reduce the effects of confounders

Spatial clustering of food insecurity and its association with depression: a geospatial analysis of nationally representative South African data, 2008-2015.

While food insecurity is a persistent public health challenge, its long-term association with depression at a national level is unknown. We investigated the spatial heterogeneity of food insecurity and its association with depression in South Africa (SA), using nationally-representative panel data from the South African National Income Dynamics Study (years 2008-2015). Geographical clusters ("hotpots") of food insecurity were identified using Kulldorff spatial scan statistic in SaTScan. Regression models were fitted to assess association between residing in food insecure hotspot communities and depression. Surprisingly, we found food insecurity hotspots (p < 0.001) in high-suitability agricultural crop and livestock production areas with reliable rainfall and fertile soils. At baseline (N = 15,630), we found greater likelihood of depression in individuals residing in food insecure hotspot communities [adjusted relative risk (aRR) = 1.13, 95% CI:1.01-1.27] using a generalized linear regression model. When the panel analysis was limited to 8,801 participants who were depression free at baseline, residing in a food insecure hotspot community was significantly associated with higher subsequent incidence of depression (aRR = 1.11, 95% CI:1.01-1.22) using a generalized estimating equation regression model. The association persisted even after controlling for multiple socioeconomic factors and household food insecurity. We identified spatial heterogeneity of food insecurity at a national scale in SA, with a demonstrated greater risk of incident depression in hotspots. More importantly, our finding points to the "Food Security Paradox", food insecurity in areas with high food-producing potential. There is a need for place-based policy interventions that target communities vulnerable to food insecurity, to reduce the burden of depression

Randomised controlled trial of population screening for atrial fibrillation in people aged 70 years and over to reduce stroke: protocol for the SAFER trial

Introduction: There is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk. Methods and analysis: Approximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis. Ethics and dissemination: The London—Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee. Trial registration number: ISRCTN72104369

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

Impact of pre-existing depression and food insecurity on the trajectory of depressive symptomatology during the COVID-19 pandemic outbreak in South Africa: A panel analysis of nationally representative South African data.

We investigated the trajectory of depressive symptoms ("depression") from the start of the COVID-19 pandemic in South Africa (March 2020) until 2021, between individuals with and without pre-pandemic depression, specifically regarding the role of food security. Our investigation used publicly available panel data (N = 6,930) from the South African National Income Dynamics Study Coronavirus Rapid Mobile Survey (SA-NIDS-CRAM from 2020-2021) on those who had also participated in the pre-pandemic South African National Income Dynamics Study (SA-NIDS, 2017) depression interview. We investigated trends in depressive symptomatology (based on a 2-item Patient Health Questionnaire) at SA-NIDS-CRAM Wave 2 (July 2020), Wave 3 (February 2021) and Wave 5 (May 2021). Generalized estimating equations (GEE) with post-estimation linear combinations of estimators were fitted to investigate the roles of pre-pandemic depression (based on 2017 SA-NIDS data) and food insecurity during the pandemic on depressive symptomatology. During the pandemic, the highest levels of depression were observed consistently among those with pre-pandemic depression and food insecurity; and were lowest among those without pre-pandemic depression and food security. Depressive symptomatology rose in nearly equal magnitude during the early phases of the pandemic in two groups: those without pre-pandemic depression but food insecure during the pandemic; as well as those with pre-pandemic depression but food secure during the pandemic. However, this dynamic changed later in the pandemic, when higher depressive symptomatology was observed in the group with both pre-pandemic depression and food insecurity, widening the gap between them from Wave 3 (adj β = 0.63, p < 0.01) to Wave 5 (adj β = 0.79, p < 0.01). Our results highlight the importance of addressing both population mental health and food insecurity, particularly at the early stages of a crisis/disaster. As we showed that mental health impact is linked to food insecurity during a pandemic, strengthening social protection measures, especially around food and nutrition, would help build resilience to crises in the long term

Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients' selection

Cellular Growth Kinetics Distinguish a Cyclophilin Inhibitor from an HSP90 Inhibitor as a Selective Inhibitor of Hepatitis C Virus

During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA) and heat-shock protein 90 (HSP90) which have each been reported to inhibit replication of hepatitis C virus (HCV). By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA), exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth

No Differences in Soil Carbon Stocks Across the Tree Line in the Peruvian Andes

ABSTRACT Reliable soil organic carbon (SOC) stock measurements of all major ecosystems are essential for predicting the influence of global warming on global soil carbon pools, but hardly any detailed soil survey data are available for tropical montane cloud forests (TMCF) and adjacent high elevation grasslands above (puna). TMCF are among the most threatened of ecosystems under current predicted global warming scenarios. We conducted an intensive soil sampling campaign extending 40 km along the tree line in the Peruvian Andes between 2994 and 3860 m asl to quantify SOC stocks of TMCF, puna grassland, and shrubland sites in the transition zone between the two habitats. SOC stocks from the soil surface down to the bedrock averaged (±standard error SE) 11.8 (±1.5, N = 24) kg C/m 2 in TMCF, 14.7 (±1.4, N = 9) kg C/m 2 in the shrublands and 11.9 (±0.8, N = 35) kg C/m 2 in the grasslands and were not significantly different (P &gt; 0.05 for all comparisons). However, soil profile analysis revealed distinct differences, with TMCF profiles showing a uniform SOC distribution with depth, shrublands a linear decrease, and puna sites an exponential decrease in SOC densities with soil depth. Organic soil layer thickness reached a maximum ($70 cm) at the upper limit of the TMCF and declined with increasing altitude toward puna sites. Within TMCF, no significant increase in SOC stocks with increasing altitude was observed, probably because of the large variations among SOC stocks at different sites, which in turn were correlated with spatial variation in soil depth

Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text