The whole truth and nothing but the truth, but what is the truth?

The moral aspects of genetic counselling are explored in situations where the outcome of a DNA test does not lead to certain knowledge. The most frequent type of interaction between counsellor and counsellee is when factual information is given, but sometimes "factual" information is difficult to obtain. How do counsellors deal with "uncertain" knowledge in genetics? Arguments and assumptions are presented and the finding of a 27 CAG repeat in the Huntington gene is used as an example. However, the questions "how far does the duty to inform reach?" and "to what extent is the doctor responsible?" are important in the whole field of genetics, and will be even more important in the future. The aims of science and clinical practice are discussed; we conclude that counsellors run the risk of taking on an infinite responsibility

Dilemmas in counselling females with the fragile X syndrome

The dilemmas in counselling a mildly retarded female with the fragile X syndrome and her retarded partner are presented. The fragile X syndrome is an X linked mental retardation disorder that affects males and, often less severely, females. Affected females have an increased risk of having affected offspring. The counselling of this couple was complicated by their impaired comprehension which subsequently impaired their thinking on the different options. The woman became pregnant and underwent CVS, which showed an affected male fetus. The pregnancy was terminated. Whether nondirective counselling for this couple was the appropriate method is discussed and the importance of a system oriented approach, through involving relatives, is stressed

Heritability of Ambulatory Heart Rate Variability.

Background - Reduced heart rate variability (HRV) is a prognostic factor for cardiac disease and cardiac mortality. Understanding the sources of individual differences in HRV may increase its diagnostic use and provide new angles for preventive therapy. To date, the contribution of genetic and environmental factors to the variance in HRV has not been investigated during prolonged periods of ambulatory monitoring in a naturalistic setting. Methods and Results - In 772 healthy twins and singleton siblings, ambulatory ECG was recorded during 24 hours. Two time domain measures of HRV were used: the standard deviations of all normal-to-normal intervals across 5-minute segments (SDNN index) and the root mean square of successive differences between adjacent normal RR intervals (RMSSD). Multivariate genetic analyses across 4 periods of day (morning, afternoon, evening, night) yielded significant estimates for genetic contribution to the mean ambulatory SDNN index (ranging from 35% to 47%) and the mean ambulatory RMSSD (ranging from 40% to 48%). Conclusions - Ambulatory HRV measures are highly heritable traits that can be used to support genetic association and linkage studies in their search for genetic variation influencing cardiovascular disease risk

Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up

Dietary patterns within educational groups and their association with CHD and stroke in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort

Higher-educated people often have healthier diets, but it is unclear whether specific dietary patterns exist within educational groups. We therefore aimed to derive dietary patterns in the total population and by educational level and to investigate whether these patterns differed in their composition and associations with the incidence of fatal and non-fatal CHD and stroke. Patterns were derived using principal components analysis in 36 418 participants of the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. Self-reported educational level was used to create three educational groups. Dietary intake was estimated using a validated semi-quantitative FFQ. Hazard ratios were estimated using Cox Proportional Hazard analysis after a mean follow-up of 16 years. In the three educational groups, similar 'Western', 'prudent' and 'traditional' patterns were derived as in the total population. However, with higher educational level a lower population-derived score for the 'Western' and 'traditional' patterns and a higher score on the 'prudent' pattern were observed. These differences in distribution of the factor scores illustrate the association between education and food consumption. After adjustments, no differences in associations between population-derived dietary patterns and the incidence of CHD or stroke were found between the educational groups (P interaction between 0·21 and 0·98). In conclusion, although in general population and educational groups-derived dietary patterns did not differ, small differences between educational groups existed in the consumption of food groups in participants considered adherent to the population-derived patterns (Q4). This did not result in different associations with incident CHD or stroke between educational groups

Exploring changes in dietary intake, physical activity and body weight during chemotherapy in women with breast cancer : A Mixed-Methods Study

Background: The present study aimed (i) to assess changes in dietary intake (DI), physical activity (PA) and body weight (BW) in breast cancer patients during chemotherapy; (ii) to describe how women explained, experienced and dealt with these potential changes; and (iii) to eventually develop lifestyle intervention strategies tailored to the women's personal needs during chemotherapy. Methods: A longitudinal parallel mixed-method design was used with quantitative assessment of changes in dietary intake (24-h recall, Appetite, Hunger, Sensory Perception questionnaire), physical activity (Short Questionnaire to Assess Health-enhancing physical activity, Multidimensional Fatigue Inventory) and BW (dual-energy X-ray absorptiometry), in addition to qualitative interviews with 25 women about these potential changes during chemotherapy. Results: Most women who perceived eating less healthily with low energy intake (EI) and being less active before diagnosis continued to do so during chemotherapy, according to quantitative measurements. They struggled to maintain sufficient energy intake. Despite a lower than average reported EI, they unexpectedly gained weight and explained that fatigue made them even more inactive during chemotherapy. Active women usually managed to stay active because exercise was very important to them and made them feel good, although they also suffered from the side-effects of chemotherapy. They found more ways to deal with taste, smell and appetite problems than women with a lower energy intake. Conclusions: The combination of the quantitative and qualitative data provided more insight into the changes in dietary intake, physical activity and BW during chemotherapy. The women's explanations showed why some women remain active and others need support to deal with changes in lifestyle factors such as healthy nutrition and fatigue.</p

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines

Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model. Methods and results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75). Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

Background Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. Methods In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. Results A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. Conclusions In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab