Head and neck cancer predictive risk estimator to determine control and therapeutic outcomes of radiotherapy (HNC-PREDICTOR):development, international multi-institutional validation, and web implementation of clinic-ready model-based risk stratification for head and neck cancer

Background: Personalised radiotherapy can improve treatment outcomes of patients with head and neck cancer (HNC), where currently a ‘one-dose-fits-all’ approach is the standard. The aim was to establish individualised outcome prediction based on multi-institutional international ‘big-data’ to facilitate risk-based stratification of patients with HNC. Methods: The data of 4611 HNC radiotherapy patients from three academic cancer centres were split into four cohorts: a training (n = 2241), independent test (n = 786), and external validation cohorts 1 (n = 1087) and 2 (n = 497). Tumour- and patient-related clinical variables were considered in a machine learning pipeline to predict overall survival (primary end-point) and local and regional tumour control (secondary end-points); serially, imaging features were considered for optional model improvement. Finally, patients were stratified into high-, intermediate-, and low-risk groups. Results: Performance score, AJCC8th stage, pack-years, and Age were identified as predictors for overall survival, demonstrating good performance in both the training cohort (c-index = 0.72 [95% CI, 0.66–0.77]) and in all three validation cohorts (c-indices: 0.76 [0.69–0.83], 0.73 [0.68–0.77], and 0.75 [0.68–0.80]). Excellent stratification of patients with HNC into high, intermediate, and low mortality risk was achieved; with 5-year overall survival rates of 17–46% for the high-risk group compared to 92–98% for the low-risk group. The addition of morphological image feature further improved the performance (c-index = 0.73 [0.64–0.81]). These models are integrated in a clinic-ready interactive web interface: https://uic-evl.github.io/hnc-predictor/ Conclusions: Robust model-based prediction was able to stratify patients with HNC in distinct high, intermediate, and low mortality risk groups. This can effectively be capitalised for personalised radiotherapy, e.g., for tumour radiation dose escalation/de-escalation

Models for Prediction of Factor VIII Half-Life in Severe Haemophiliacs: Distinct Approaches for Blood Group O and Non-O Patients

BACKGROUND: Von Willebrand factor (VWF) is critical for the in vivo survival of factor VIII (FVIII). Since FVIII half-life correlates with VWF-antigen pre-infusion levels, we hypothesized that VWF levels are useful to predict FVIII half-life. METHODOLOGY: Standardized half-life studies and analysis of pre-infusion VWF and VWF-propeptide levels were performed in a cohort of 38 patients with severe haemophilia A (FVIII <1 IU/ml), aged 15-44 years. Nineteen patients had blood-group O. Using multivariate linear regression-analysis (MVLR-analysis), the association of VWF-antigen, VWF-propeptide, age and body-weight with FVIII half-life was evaluated. PRINCIPAL FINDINGS: FVIII half-life was shorter in blood-group O-patients compared to non-O-patients (11.5+/-2.6 h versus 14.3+/-3.0 h; p = 0.004). VWF-antigen levels correlated with FVIII half-life considerably better in patients with blood-group non-O than O (Pearson-rank = 0.70 and 0.47, respectively). Separate prediction models evolved from MVLR-analysis for blood-group O and non-O patients, based on VWF-antigen and VWF/propeptide ratio. Predicted half-lives deviated less than 3 h of observed half-life in 34/38 patients (89%) or less than 20% in 31/38 patients (82%). CONCLUSION: Our approach may identify patients with shorter FVIII half-lives, and adapt treatment protocols when half-life studies are unavailable. In addition, our data indicate that survival of FVIII is determined by survival of endogenous VWF rather than VWF levels per se

Human platelet lysate as a fetal bovine serum substitute improves human adipose-derived stromal cell culture for future cardiac repair applications

Adipose-derived stromal cells (ASC) are promising candidates for cell therapy, for example to treat myocardial infarction. Commonly, fetal bovine serum (FBS) is used in ASC culturing. However, FBS has several disadvantages. Its effects differ between batches and, when applied clinically, transmission of pathogens and antibody development against FBS are possible. In this study, we investigated whether FBS can be substituted by human platelet lysate (PL) in ASC culture, without affecting functional capacities particularly important for cardiac repair application of ASC. We found that PL-cultured ASC had a significant 3-fold increased proliferation rate and a significantly higher attachment to tissue culture plastic as well as to endothelial cells compared with FBS-cultured ASC. PL-cultured ASC remained a significant 25% smaller than FBS-cultured ASC. Both showed a comparable surface marker profile, with the exception of significantly higher levels of CD73, CD90, and CD166 on PL-cultured ASC. PL-cultured ASC showed a significantly higher migration rate compared with FBS-cultured ASC in a transwell assay. Finally, FBS- and PL-cultured ASC had a similar high capacity to differentiate towards cardiomyocytes. In conclusion, this study showed that culturing ASC is more favorable in PL-supplemented medium compared with FBS-supplemented medium

Is new drug prescribing in primary care specialist induced?

<p>Abstract</p> <p>Background</p> <p>Medical specialists are often seen as the first prescribers of new drugs. However, the extent to which specialists influence new drug prescribing in primary care is largely unknown.</p> <p>Methods</p> <p>This study estimates the influence of medical specialists on new drug prescribing in primary care shortly after market introduction. The influence of medical specialists on prescribing of five new drugs was measured in a cohort of 103 GPs, working in 59 practices, over the period 1999 until 2003. The influence of medical specialists on new drug prescribing in primary care was assessed using three outcome measures. Firstly, the proportion of patients receiving their first prescription for a new or reference drug from a specialist. Secondly, the proportion of GPs prescribing new drugs before any specialist prescribes to their patients. Thirdly, we compared the time until the GP's first own prescribing between GPs who waited for prescriptions from specialists and those who did not.</p> <p>Results</p> <p>The influence of specialists showed considerable differences among the new drugs studied. The proportion of patients receiving their first prescription from a specialist was greatest for the combination salmeterol/fluticasone (60.2%), and lowest for rofecoxib (23.0%). The proportion of GPs prescribing new drugs before waiting for prescriptions from medical specialists ranged from 21.1% in the case of esomeprazole to 32.9% for rofecoxib. Prescribing new drugs by specialists did not shorten the GP's own time to prescribing.</p> <p>Conclusion</p> <p>This study shows that the influence of medical specialists is clearly visible for all new drugs and often greater than for the existing older drugs, but the rapid uptake of new drugs in primary care does not seem specialist induced in all cases. GPs are responsible for a substantial amount of all early prescriptions for new drugs and for a subpopulation specialist endorsement is not a requisite to initiate in new drug prescribing. This contradicts with the idea that the diffusion of newly marketed drugs always follows a two-step model, with medical specialists as the innovators and GPs as the followers.</p

Patient risk profiles and practice variation in nonadherence to antidepressants, antihypertensives and oral hypoglycemics

BACKGROUND: Many patients experience difficulties in following treatment recommendations. This study's objective is to identify nonadherence risk profiles regarding medication (antidepressants, antihypertensives, and oral hypoglycemics) from a combination of patients' socio-demographic characteristics, morbidity presented within general practice and medication characteristics. An additional objective is to explore differences in nonadherence among patients from different general practices. METHODS: Data were obtained by linkage of a Dutch general practice registration database to a dispensing registration database from the year 2001. Subjects included in the analyses were users of antidepressants (n = 4,877), antihypertensives (n = 14,219), or oral hypoglycemics (n = 2,428) and their GPs. Outcome variables were: 1) early dropout i.e., a maximum of two prescriptions and 2) refill nonadherence (in patients with 3+ prescriptions); refill adherence < 80% was considered as nonadherence. Multilevel modeling was used for analyses. RESULTS: Both early dropout and refill nonadherence were highest for antidepressants, followed by antihypertensives. Risk factors appeared medication specific and included: 1) non-western immigrants being more vulnerable for nonadherence to antihypertensives and antidepressants; 2) type of medication influencing nonadherence in both antihypertensives and antidepressants, 3) GP consultations contributing positively to adherence to antihypertensives and 4) somatic co-morbidity influencing adherence to antidepressants negatively. There was a considerable range between general practices in the proportion of patients who were nonadherent. CONCLUSION: No clear risk profiles for nonadherence could be constructed. Characteristics that are correlated with nonadherence vary across different types of medication. Moreover, both patient and prescriber influence adherence. Especially non-western immigrants need more attention with regard to nonadherence, for example by better monitoring or communication. Since it is not clear which prescriber characteristics influence adherence levels of their patients, there is need for further research into the role of the prescriber

SDOCT Imaging to Identify Macular Pathology in Patients Diagnosed with Diabetic Maculopathy by a Digital Photographic Retinal Screening Programme

INTRODUCTION: Diabetic macular edema (DME) is an important cause of vision loss. England has a national systematic photographic retinal screening programme to identify patients with diabetic eye disease. Grading retinal photographs according to this national protocol identifies surrogate markers for DME. We audited a care pathway using a spectral-domain optical coherence tomography (SDOCT) clinic to identify macular pathology in this subset of patients. METHODS: A prospective audit was performed of patients referred from screening with mild to moderate non-proliferative diabetic retinopathy (R1) and surrogate markers for diabetic macular edema (M1) attending an SDOCT clinic. The SDOCT images were graded by an ophthalmologist as SDOCT positive, borderline or negative. SDOCT positive patients were referred to the medical retina clinic. SDOCT negative and borderline patients were further reviewed in the SDOCT clinic in 6 months. RESULTS: From a registered screening population of 17 551 patients with diabetes mellitus, 311 patients met the inclusion criteria between (March 2008 and September 2009). We analyzed images from 311 patients' SDOCT clinic episodes. There were 131 SDOCT negative and 12 borderline patients booked for revisit in the OCT clinic. Twenty-four were referred back to photographic screening for a variety of reasons. A total of 144 were referred to ophthalmology with OCT evidence of definite macular pathology requiring review by an ophthalmologist. DISCUSSION: This analysis shows that patients with diabetes, mild to moderate non-proliferative diabetic retinopathy (R1) and evidence of diabetic maculopathy on non-stereoscopic retinal photographs (M1) have a 42.1% chance of having no macular edema on SDOCT imaging as defined by standard OCT definitions of DME when graded by a retinal specialist. SDOCT imaging is a useful adjunct to colour fundus photography in screening for referable diabetic maculopathy in our screening population

Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives

<p>Abstract</p> <p>Background</p> <p>Women from families with a high risk of breast or ovarian cancer in which genetic testing for mutations in the <it>BRCA1/2 </it>genes is inconclusive are a vulnerable and understudied group. Furthermore, there are no studies of the professional specialists who treat them - geneticists, genetic counsellors/nurses, oncologists, gynaecologists and breast surgeons.</p> <p>Methods</p> <p>We conducted a small qualitative study that investigated women who had developed breast cancer under the age of 45 and who had an inconclusive <it>BRCA1/2 </it>genetic diagnostic test (where no mutations or unclassified variants were identified). We arranged three focus groups for affected women and their close female relatives - 13 women took part. We also interviewed 12 health professionals who were involved in the care of these women.</p> <p>Results</p> <p>The majority of the women had a good grasp of the meaning of their own or a family member's inconclusive result, but a few indicated some misunderstanding. Most of the women in this study underwent the test for the benefit of others in the family and none mentioned that they were having the test purely for themselves. A difficult issue for sisters of affected women was whether or not to undertake prophylactic breast surgery. The professionals were sensitive to the difficulties in explaining an inconclusive result. Some felt frustrated that technology had not as yet provided them with a better tool for prediction of risk.</p> <p>Conclusions</p> <p>Some of the women were left with the dilemma of what decision to make regarding medical management of their cancer risk. For the most part, the professionals believed that the women should be supported in whatever management decisions they considered best, provided these decisions were based on a complete and accurate understanding of the genetic test that had taken place in the family.</p

Effectiveness of a stepped-care intervention to prevent major depression in patients with type 2 diabetes mellitus and/or coronary heart disease and subthreshold depression: A pragmatic cluster randomized controlled trial

Purpose Given the public health significance of poorly treatable co-morbid major depressive disorders (MDD) among patients with type 2 diabetes mellitus (DM2) and coronary heart disease (CHD), we need to investigate whether strategies to prevent the development of major depression could reduce its burden of disease. We therefore evaluated the effectiveness of a stepped-care program for subthreshold depression in comparison with usual care in patients with DM2 and/or CHD. Methods A cluster randomized controlled trial, with 27 primary care centers serving as clusters. A total of 236 DM2 and/or CHD patients with subthreshold depression (nine item Patient Health Questionnaire (PHQ-9) score ≥ 6, no current MDD according to DSM-IV criteria) were allocated to the intervention group (N = 96) or usual care group (n = 140). The stepped-care program was delivered by trained practice nurses during one year and consisted of four sequential treatment steps: watchful waiting, guided self-help, problem solving treatment and referral to the general practitioner. The primary outcome was the 12-month cumulative incidence of MDD as measured with the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included severity of depression (measured by PHQ-9) at 3, 6, 9 and 12 months. Results Of 236 patients (mean age, 67,5 (SD 10) years; 54.7% men), 210 (89%) completed the MINI at 12 months. The cumulative incidence of MDD was 9 of 89 (10.1%) participants in the intervention group and 12 of 121 (9.9%) participants in the usual care group. We found no statistically significant overall effect of the intervention (OR = 1.21; 95% confidence interval (0.12 to 12.41)) and there were no statistically significant differences in the course or severity of depressive symptoms between the two groups. Conclusions This study suggest that Step-Dep was not more effective in preventing MDD than usual care in a primary care population with DM2 and/or CHD and subthreshold depression

Moderately overweight and obese patients in general practice: a population based survey

BACKGROUND: Obesity is a main threat to public health in the Western world and is associated with diseases such as diabetes mellitus and coronary heart diseases. Up to now a minority of research studied the relation between obesity and the use of primary health care. In the Netherlands the general practitioner (GP) is the main primary health care provider. The objective of this article is to evaluate GP consultation and prescription of drugs in moderate and severely overweight (obese) persons in the Netherlands. METHODS: Data were used from a representative survey of morbidity in Dutch general practice in 2001. Our study sample consisted of 8,944 adult respondents (18+ years) who participated in an extensive health interview. Interview data were linked to morbidity and prescription registration data from 95 general practices where respondents were listed. Body mass index (BMI) was calculated using self-reported height and weight. Analyses were controlled for clustering within practices as well as for socio-demographic and life style characteristics. RESULTS: Obesity (BMI ≥ 30 kg/m2) was observed in 8.9% of men and 12.4% of women; for moderate overweight (BMI 25-<30 kg/m2) these percentages were 42.2% and 30.4% respectively. Obese men and women were more likely to consult their GP than persons without overweight. This especially holds for diseases of the endocrine system, the cardiovascular system, the musculoskeletal system, the gastro-intestinal system, and skin problems. Related to this, obese men and women were more likely to receive drugs for the cardiovascular system, the musculoskeletal system, alimentary tract and metabolism (including, for example, antidiabetics), and dermatologicals, but also antibiotics and drugs for the respiratory system. For moderately overweight men and women (BMI 25-<30 kg/m2) smaller but significant differences were found for diseases of the endocrine system, the cardiovascular system, and the musculoskeletal system. CONCLUSION: Obesity increases the workload of Dutch general practitioners and the use of prescribed medication. The current increase in the prevalence of obesity will further increase the use of health care and related costs. Since a large majority of Dutch persons visit their GP over the course of one year, GPs' potential role in effective prevention strategies cannot be denied