Risk factors for fibrosis progression in non-alcoholic steatohepatitis: Analysis of the European cohort in the real-world GAIN study.

OBJECTIVE: To better understand drivers of disease progression in non-alcoholic steatohepatitis (NASH), we assessed clinical and sociodemographic markers of fibrosis progression in adults with NASH. PATIENTS AND METHODS: Physician-reported patient demographics and clinical characteristics were utilised from the real-world Global Assessment of the Impact of NASH (GAIN) study. Factors associated with likelihood of fibrosis progression since NASH diagnosis were identified using a logistic regression model. RESULTS: Overall, 2349 patients in Europe from the GAIN study were included; mean age was 54.6 years and 41% were women. Significant covariates included age, years since diagnosis, employment status, fibrosis stage at diagnosis, type 2 diabetes mellitus, hypertension, liver transplant and liver biopsy at diagnosis. Risk of progression was 1.16 (95% confidence interval 1.12-1.20; p<0.001) times higher for each additional year since NASH diagnosis and 5.43 (2.68-11.37; p<0.001) times higher when physicians proposed a liver transplant at diagnosis. Compared with full-time employed patients, risk of progression was 1.77 (1.19-2.60; p=0.004) times higher for unemployed patients and 3.16 (1.30-7.63; p=0.010) times higher for those unable to work due to NASH. CONCLUSIONS: Disease duration, NASH severity and presence of other metabolic comorbidities could help to assess risk of progression in patients with NASH.

Health state utilities for beta-thalassemia: a time trade-off study.

BACKGROUND: Beta-thalassemia (BT) is an inherited blood disorder characterized by reduced levels of functional hemoglobin resulting in phenotypes ranging from clinically asymptomatic to severely anemic. Patients with BT may require lifelong regular blood transfusions supported by appropriate iron chelation therapy (ICT). This study aimed to determine how the UK general population values BT health states associated with differing transfusion burden and ICT. METHODS: Composite time trade-off (cTTO) methodology was employed to elicit health state utilities in BT. Relevant BT literature related to symptom and quality-of-life impact, including physical, functional, and emotional well-being, and safety profiles of BT treatments were considered when drafting health state descriptions. Eleven health state descriptions were developed and validated by hematologists and patient advocates for clinical accuracy and completeness. 200 individuals from the UK general population participated in the cTTO interviews. RESULTS: The mean age of participants was 41.50 years (SD 16.01, range 18-81); 88 (46.8%) were female. Utility values ranged from 0.78 (SD 0.34) for non-transfusion dependent BT with oral ICT to 0.37 (SD 0.50) for high transfusion burden with subcutaneous ICT in transfusion-dependent BT. CONCLUSIONS: This study provides health utilities for a range of BT health states from the UK general population perspective. Importantly, lower transfusion burden and lower burden of anemia were associated with higher utilities. To a lesser extent, differential modes of ICT were found to impact utility valuations in patients with BT. The utilities obtained in this study can be employed as inputs in cost-effectiveness analyses of BT therapies.

Association of factor expression levels with annual bleeding rate in people with haemophilia B.

INTRODUCTION: Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. AIM: We evaluated the association between FEL and ABR in PwHB. METHODS: This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. RESULTS: The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05). CONCLUSION: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.

Examining the impact of haemophilia treatment on health-related quality of life.

INTRODUCTION: Haemophilia has substantial SD effects on health-related quality of life (HRQoL), particularly for people with severe haemophilia. How certain aspects of haemophilia influence HRQoL is not well understood. AIM: To develop predictive models of variables influencing HRQoL in people with severe haemophilia A or B. METHODS: We used data from 514 participants with haemophilia A or B who provided EQ-5D-3L responses in the 2015 CHESS study. Treatment was categorized as always been on-demand (POD), previously on prophylaxis and moved to on-demand regimen (SOD), on prophylaxis from diagnosis (PX), and prophylaxis, previously on-demand (PXOD). Target joints were defined as 'locations of chronic synovitis' as reported by the treating physician. Regression models were evaluated to assess the impact of demographic and clinical covariates on HRQoL scores. RESULTS: Significant covariates were generally consistent across models, with number of target joints, number of hospital admissions, and any haemophilia treatment regimen other than PX all independently negatively impacting estimated EQ-5D score. Higher level of treatment adherence (high vs. low/medium) and use of a prophylaxis treatment regimen had positive effects on estimated EQ-5D scores. Target joints were associated with a 0.04 decrement in EQ-5D score, and high versus low/medium adherence was associated with a 0.06 increment. PXOD, POD, and SOD treatment regimens were associated with decrements in predicted scores of 0.07, 0.09, and 0.08, respectively, versus PX. CONCLUSION: This study provides a model to estimate the impact of haemophilia interventions on HRQoL, to help assess the relative impact on patient-centric outcomes for this lifelong condition.

Association of factor expression levels with health-related quality of life and direct medical costs for people with haemophilia B.

AIMS: Gene therapy trials aim to provide a functional cure for patients with haemophilia B (HB), and treatment impact is analyzed by factor IX expression levels (FELs). We investigated the relationship of FELs with health-related quality of life (HRQoL) and costs. MATERIALS AND METHODS: This was a retrospective cross-sectional analysis of the European (CHESS I-II) and US (CHESS-US) CHESS population studies. Physicians recruited consecutive patients and extracted information from the medical records; patients completed questionnaires between 2014 and 2015 (CHESS-I), 2018-2019 (CHESS-II) and 2019 (CHESS US). Patients with inhibitors were excluded. HRQoL was assessed using the EQ-5D-5L. Twelve-month haemophilia-related direct medical costs included office visits and hospitalizations based on country-level unit costs. A Tobit model was used to analyze FELs and HRQoL and generalized linear models for direct medical costs. RESULTS: A total of 191 men with HB completed the EQ-5D questionnaire; the mean age was 36.8 years, with a mean FEL of 10.1 IU/dL (median, 4.0). Mean EQ-5D was 0.77 (SD, 0.23). The Tobit model adjusting for age, body mass index and blood-borne viruses showed every 1% increase in FEL was associated with +0.006 points in the mean EQ-5D score (p = .003). Mean haemophilia-related direct medical costs excluding factor replacement therapy were €2,028/year (median, €919) in CHESS I-II (EU, n = 226), and $7,171/year (median, $586) in CHESS US (n = 181). Adjusted EU and US models showed every 1% increase in FEL was associated with a decrease in haemophilia-related direct medical costs of €108/year and $529/year, respectively. LIMITATIONS: Direct medical costs were based on physician extraction of encounters from medical records, potentially underestimating costs of care. The voluntary nature of participation may have introduced selection biases. CONCLUSIONS: We observed a significant association of increases in FEL with increased HRQoL and decreased costs in Europe and the United States among men with HB and no inhibitors.

Clinical and sociodemographic determinants of disease progression in patients with nonalcoholic steatohepatitis in the United States.

ABSTRACT: One fifth of patients with nonalcoholic fatty liver disease (NAFLD) may progress to nonalcoholic steatohepatitis (NASH), which can increase the risk of cirrhosis, cancer, and death. To date, reported predictors of NASH progression have been heterogeneous.We identified determinants of fibrosis progression in patients with NASH in the United States using physician-reported data from the real-world Global Assessment of the Impact of NASH (GAIN) study, including demographics and clinical characteristics, NASH diagnostic information, fibrosis stage, comorbidities, and treatment. We developed a logistic regression model to assess the likelihood of fibrosis progression since diagnosis, controlling for sociodemographic and clinical variables. An iterative nested model selection approach using likelihood ratio test determined the final model.A total of 989 patients from the GAIN US cohort were included; 46% were women, 58% had biopsy-proven NAFLD, and 74% had fibrosis stage F0-F2 at diagnosis. The final multivariable model included age, years since diagnosis, sex, employment status, smoking status, obesity, fibrosis stage, diagnostic biopsy, Vitamin E, and liver transplant proposed at diagnosis. Odds of progression were 17% higher (odds ratio, 1.17 [95% CI: 1.11-1.23]; P < .001) with each year since NASH diagnosis, 41% lower (0.59 [0.38-0.90]; P = .016) for women than men, 131% higher (2.31 [1.30-4.03]; P = .004) for smokers versus non-smokers, and 89% higher (1.89 [1.26-2.86]; P = .002) with obesity. Odds of progression were also higher with part-time, retired, unemployed, and unable to work due to NASH status versus full-time employment, and when a liver transplant was proposed at diagnosis.Disease duration and severity, obesity, smoking, and lack of full-time employment were significant determinants of fibrosis progression. These findings can support clinical and health-policy decisions to improve NASH management in the US.

Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize.

Circulating tumor cell (CTC) clusters may represent one of the key mechanisms initiating the metastasis process. However, the series of pathophysiologic events by which CTC clusters originate, enter the circulation, and reach the distant sites remain to be identified. The cellular and molecular mechanisms that provide survival advantage for CTC clusters during the transit in the blood stream are also still largely unknown. Understanding the biology of CTC clusters is critical to assess this unified scheme employed by cancer and to device strategies to overcome key pathways responsible for their improved metastatic potential. CTC clusters remain an underdeveloped area of research begging the attention of multidisciplinary cancer research teams. Here, we provide insight on existing preclinical evidence on the potential mechanisms leading to CTC cluster formation and dissemination and on processes that may offer survival advantage. We also offer our perspective on future directions to delineate the role of CTC clusters in metastatic cascade and discuss their clinical significance. Cancer Res; 78(4); 845-52. ©2018 AACR.

Association of psychological distress, quality of life and costs with carpal tunnel syndrome severity: a cross-sectional analysis of the PALMS cohort.

OBJECTIVES: The Prediciting factors for response to treatment in carpal tunnel syndrome (PALMS) study is designed to identify prognostic factors for outcome from corticosteroid injection and surgical decompression for carpal tunnel syndrome (CTS) and predictors of cost over 2 years. The aim of this paper is to explore the cross-sectional association of baseline patient-reported and clinical severity with anxiety, depression, health-related quality of life and costs of CTS in patients referred to secondary care. METHODS: Prospective, multicentre cohort study initiated in 2013. We collected baseline data on patient-reported symptom severity (CTS-6), psychological status (Hospital Anxiety and Depression Scale), hand function (Michigan Hand Questionnaire) comorbidities, EQ-5D-3L (3-level version of EuroQol-5 dimension) and sociodemographic variables. Nerve conduction tests classified patients into five severity grades (mild to very severe). Data were analysed using a general linear model. RESULTS: 753 patients with CTS provided complete baseline data. Multivariable linear regression adjusting for age, sex, ethnicity, duration of CTS, smoking status, alcohol consumption, employment status, body mass index and comorbidities showed a highly statistically significant relationship between CTS-6 and anxiety, depression and the EQ-5D (p<0.0001 in each case). Likewise, a significant relationship was observed between electrodiagnostic severity and anxiety (p=0.027) but not with depression (p=0.986) or the EQ-5D (p=0.257). National Health Service (NHS) and societal costs in the 3 months prior to enrolment were significantly associated with self-reported severity (p<0.0001) but not with electrodiagnostic severity. CONCLUSIONS: Patient-reported symptom severity in CTS is significantly and positively associated with anxiety, depression, health-related quality of life, and NHS and societal costs even when adjusting for age, gender, body mass index, comorbidities, smoking, drinking and occupational status. In contrast, there is little or no evidence of any relationship with objectively derived CTS severity. Future research is needed to understand the impact of approaches and treatments that address psychosocial stressors as well as biomedical factors on relief of symptoms from carpal tunnel syndrome.

Reasons for patient's delay in diagnosis of breast carcinoma in Pakistan.

BACKGROUND: Delay in diagnosis of breast cancer is associated with a poorer survival and a pivotal contribution to this delayed diagnosis comes from patient delay in presenting at a clinic. Reasons involved must be evaluated in order to decrease this reducible delay. OBJECTIVES: i) To evaluate the reasons for patient delay in diagnosis of breast cancer; ii) to investigate any association with other variables. MATERIALS AND METHODS: A 6 month cross sectional study (from July 2012 to Dec 2012), was carried out in Surgical and Oncology Units of Civil Hospital, Karachi. A total of 100 females diagnosed with breast cancer of any histological type were interviewed after informed consent and relevant data were collected. Due ethical clearance was obtained. RESULTS: Mean age was 47.5±12.1 years with a range from 25-77 years. Mean duration of delay was 5.13±4.8 months, from shortest 1 month to longest 36 months. Duration of delay was observed to be no delay (<1 month) in 28%, short delay (1-3 months) in 30% and long delay (>3 months) in 42% of patients. Considering the symptoms as "harmless" (39%) was the most frequent reason of delay followed by "temporary" (20%) and the "use of traditional methods" (12%). Most common reason for later approaches was an increase in the size of the lump (41%). Statistically significant association (p-value <0.05) of longer patient delay was obtained with being single, being illiterate, painless breast lump as the first symptom, negative family history of breast cancer and vague attribution of the symptoms. CONCLUSIONS: Significant delay in approach to health care facility was observed in our study due to variable reasons given by women. Sufficient awareness regarding breast cancer, its symptoms and favorable effects of a timely diagnosis on prognosis must be imparted to our general population.