An audit of consent refusals in clinical research at a tertiary care center in India

Background and Rationale:

Ensuring research participants’ autonomy is one of the core ethical obligations of researchers. This fundamental principle confers on every participant the right to refuse to take part in clinical research, and the measure of the number of consent refusals could be an important metric to evaluate the quality of the informed consent process. This audit examined consent refusals among Indian participants in clinical studies done at our center.

Materials and Methods:

The number of consent refusals and their reasons in 10 studies done at our center over a 5-year period were assessed. The studies were classified by the authors according to the type of participant (healthy vs patients), type of sponsor (investigator-initiated vs pharmaceutical industry), type of study (observational vs interventional), level of risk [based on the Indian Council of Medical Research (ICMR) “Ethical Guidelines for Biomedical Research on Human Participants”], available knowledge of the intervention being studied, and each patient''s disease condition.

Results:

The overall consent refusal rate was 21%. This rate was higher among patient participants [23.8% vs. healthy people (14.9%); P = 0.002], in interventional studies [33.6% vs observational studies (7.5%); P < 0.0001], in pharmaceutical industry-sponsored studies [34.7% vs investigator-initiated studies (7.2%); P < 0.0001], and in studies with greater risk (P < 0.0001). The most common reasons for consent refusals were multiple blood collections (28%), inability to comply with the study protocol (20%), and the risks involved (20%).

Conclusion:

Our audit suggests the adequacy and reasonable quality of the informed consent process using consent refusals as a metric.KEY WORDS: Autonomy, consent, India, reason, refusal, risk     

Family history in the Finnish Prostate Cancer Screening Trial

Family history (FH) is one of the few known risk factors for prostate cancer (PC). There is also new evidence about mortality reduction in screening of PC with prostate‐specific antigen (PSA). Therefore, we conducted a prospective study in the Finnish Prostate Cancer Screening Trial to evaluate the impact of FH on outcomes of PC screening. Of the 80,144 men enrolled, 31,866 men were randomized to the screening arm and were invited for screening with PSA test (cut‐off 4 ng/ml) every 4 years. At the time of each invitation, FH of PC (FH) was assessed through a questionnaire. The analysis covered a follow‐up of 12 years from randomization for all men with data on FH. Of the 23,702 (74.3%) invited men attending screening, 22,756 (96.0%) provided information of their FH. Altogether 1,723 (7.3%) men reported at least one first‐degree relative diagnosed with PC and of them 235 (13.6%) were diagnosed with PC. Men with a first‐degree FH had increased risk for PC (risk ratio (RR) 1.31, p < 0.001) and the risk was especially elevated for interval cancer (RR 1.65, 95% CI 1.27–2.15). Risk for low‐grade (Gleason 2–6) tumors was increased (RR 1.46, 95% CI 1.15–1.69), but it was decreased for Gleason 8–10 tumors (RR 0.48, 95% CI 0.25–0.95). PSA test performance (sensitivity and specificity) was slightly inferior for FH positives. No difference in PC mortality was observed in terms of FH. Our findings provide no support for selective PSA screening targeting men with FH of PC.     

Clinical and histopathological characteristics of familial prostate cancer in Finland

Study Type – Aetiology (cohort) Level of Evidence 2b

OBJECTIVE

? To describe clinical and histopathological characteristics of Finnish familial prostate cancer (PCa) through a detailed analysis of cases in families.

PATIENTS AND METHODS

? In total, 202 Finnish families with 617 histopathologically confirmed PCa cases of confirmed genealogy were collected. ? Complete clinical data, including age and prostate‐specific antigen (PSA) at diagnosis, stage, grade and primary treatment, were gathered. The mean (range) number of affected men per family was 3 (2–8). ? All the available diagnostic biopsy samples (n= 323) were collected and regraded by the same uropathologist. ? A population‐based cohort of 3011 hospital district Pirkanmaa PCa patients was used as a control group.

RESULTS

? The mean (range) year of diagnosis of PCa was 1993 (1962–2006) and the mean (range) age at diagnosis was 68 (43–98 years). ? The median (range) primary PSA level was 12.0 (0.8–11 000) ng/mL. After regrading, the Gleason score was ≤6 in 38%, 7 in 37% and ≥8 in 25% of men. ? The subset of familial PCa men diagnosed after 1995 had higher PSA levels (P= 9.9 × 10^?6) and an earlier age of onset (P= 1.7 × 10^?6) than men in the control group, although there were no differences in cancer‐specific survival.

CONCLUSIONS

? We observed an earlier age of onset and higher PSA in familial PCa. ? However, differences between sporadic and familial or hereditary PCa cannot be truly solved until genetic testing of high‐risk genes in addition to family history is used to define PCa families. ? We also emphasize that, when histological samples are collected over a longer study period, reanalysis of the samples by the same experienced uropathologist should be considered. What’s known on the subject? and What does the study add? Previous hospital‐ or population‐based cross‐sectional studies comparing the clinical and histopathological features of hereditary, familial and sporadic PCa either reported weak trends or no differences in features measured except the age of onset. In present study we observed higher PSA and earlier age of onset in the subset of 257 familial PCa menin Finnish PCa families.     

Motives for and barriers to physical activity in twin pairs discordant for leisure time physical activity for 30 years

Long-term persistent physical activity is important in the prevention of chronic diseases, but a large number of people do not participate in physical activity to obtain health benefits. The purpose of this study was to examine the motives and perceived barriers to long-term engagement in leisure time physical activity. Same-sex twin pairs (N=16, mean age 60) discordant for physical activity over 30 years were identified from the Finnish Twin Cohort. We evaluated participants' physical activity motivation with the 73-item Recreational Exercise Motivation Measure and assessed barriers to physical activity with a 25-item questionnaire. The characteristics of physical activity motivation and perceived barriers between the active and inactive co-twins were analysed using paired tests. Motives related to the sub-dimensions of enjoyment and physical fitness and psychological state were the most important reasons for participation in physical activity among all the twin individuals analysed. The sub-dimensions mastery (p=0.018, Cohen's d=0.76), physical fitness (p=0.029, Cohen's d=0.69), and psychological state (p=0.039, Cohen's d=0.65) differed significantly between active and inactive co-twins. More than half of the participants reported no reasons for not being physically active. If reasons existed, participation in physical activity was deterred mostly by pain and various health problems. This study found no differences in perceived barriers between active and inactive co-twins. We conclude from our results that the main factors promoting persistent leisure time physical activity were participants' wish to improve or maintain their physical skills or techniques, a feeling that exercise would improve their mental and physical health and that they found the activity enjoyable. This study helps us understand the importance of the role of motives and the minor role of perceived barriers for engagement in persistent physical activity.     

Airborne transmission of tularemia in farmers

In a tularemia epidemic during 1982 in northern Finland, 53 patients showed no peripheral portal of entry for infection or associated lymphadenopathy. Respiratory symptoms were observed in 72% of the patients. 26/38 cases had abnormal chest films. Hilar adenopathy was the most common finding (36%). Four patients did not receive antibiotics; 43 received tetracyclines, 5 streptomycin and 1 cefuroxime and amoxycillin. All patients recovered. 50 patients acquired the infection during common farming activities, such as making fresh hay with a hay-cutter, handling dry hay, threshing, etc. Thus, airborne transmission may be an important source of infection in normal farming activities in endemic areas of tularemia.     

Dynamic imaging of coherent sources: Studying neural interactions in the human brain

Functional connectivity between cortical areas may appear as correlated time behavior of neural activity. It has been suggested that merging of separate features into a single percept ("binding") is associated with coherent gamma band activity across the cortical areas involved. Therefore, it would be of utmost interest to image cortico-cortical coherence in the working human brain. The frequency specificity and transient nature of these interactions requires time-sensitive tools such as magneto- or electroencephalography (MEG/EEG). Coherence between signals of sensors covering different scalp areas is commonly taken as a measure of functional coupling. However, this approach provides vague information on the actual cortical areas involved, owing to the complex relation between the active brain areas and the sensor recordings. We propose a solution to the crucial issue of proceeding beyond the MEG sensor level to estimate coherences between cortical areas. Dynamic imaging of coherent sources (DICS) uses a spatial filter to localize coherent brain regions and provides the time courses of their activity. Reference points for the computation of neural coupling may be based on brain areas of maximum power or other physiologically meaningful information, or they may be estimated starting from sensor coherences. The performance of DICS is evaluated with simulated data and illustrated with recordings of spontaneous activity in a healthy subject and a parkinsonian patient. Methods for estimating functional connectivities between brain areas will facilitate characterization of cortical networks involved in sensory, motor, or cognitive tasks and will allow investigation of pathological connectivities in neurological disorders.     

Human parvovirus B19-induced epidemic acute red cell aplasia in patients with hereditary hemolytic anemia

From March to August 1984, 26 patients with hereditary hemolytic anemia in northeastern Ohio developed acute, profound red cell aplasia. The patients included 14 males and 12 females 2 to 23 years old, with sickle cell anemia (20 cases), hemoglobin SC-disease (4 cases), sickle- beta-thalassemia (1 case), or hereditary spherocytosis (1 case). All had an acute onset of severe reticulocytopenia and anemia and prodromal symptoms of illness including fever, abdominal symptoms, headache, and arthralgias. Twenty-two received transfusions. Reticulocytosis occurred spontaneously within 2 to 14 days of presentation. In five acute-phase sera, 10(8) to 10(12) viral particles/mL were detected by electron microscopy. Human parvovirus B19 DNA was demonstrated in high concentration by hybridization in the same five acute-phase sera and in low concentration in sera of eight additional patients. The five highly viremic sera inhibited erythroid colony formation in vitro. B19- specific IgM was detected in sera of 24/26 patients, and B19-specific IgG in 21 of 22 patients tested. Our results indicate that human parvovirus B19 was the etiologic agent in this large epidemic of life- threatening acute red cell aplasia in patients with hereditary hemolytic anemia.