An overview of effective and potential new conservative interventions in patients with frozen shoulder.

Frozen shoulder (FS) is a pathology that is difficult to understand and difficult to manage. Over the last ten years, contradictory and new evidence is provided regarding the recovery and its natural course. This narrative review provides new information about the diagnosis and conservative treatment of patients with FS and ongoing research hypotheses that might provide new insights in the pathology and treatment options. FS has a characteristic course. People with Diabetes Mellitus and thyroid disorders have a higher risk of developing a FS. The diagnosis FS is based on pattern recognition and physical examination. Additionally, 'rule-in' and 'rule-out' criteria can be used to increase the likelihood of the frozen shoulder diagnosis. Recommended and most common physical therapy interventions are mobilization techniques and exercises, in which tissue irritability can guide its intensity. In addition, physical therapy is often complementary with patient education and pharmacotherapy. The latest evidence-based practice related to FS is proprioceptive neuromuscular facilitation and mirror therapy. In addition, interventions like pain neuroscience education, high-intensity interval training and lifestyle changes are still hypothetical. Finally, better insight in the involvement of biochemical processes, function of myofibroblasts and matrix metalloproteinases can provide better understanding in the pathophysiology and will be addressed in current review.

Children's Preferences for Oral Dosage Forms and Their Involvement in Formulation Research via EPTRI (European Paediatric Translational Research Infrastructure).

The paucity of evidence-based data on formulation characteristics preferred by the children is known to limit the design of tailored paediatric dosage forms. The European Paediatric Translational Research Infrastructure (EPTRI) commissioned a study to evaluate children's dosage forms perceived preferences in some European countries and explore the feasibility of using the young persons advisory groups (YPAGs) to involve children in formulation research. An online, age-adapted survey was developed and translated into six languages. The survey link was disseminated across seven European countries: Albania, Italy, the Netherlands, and Dutch-speaking part of Belgium, Romania, Spain, and the United Kingdom. Respondents' (n = 1172) perceived preferences for oral dosage forms primarily differed based on age, health status, and experience. Conventional dosage forms, i.e., liquid (35%), tablets (19%), and capsules (14%), were the most selected. Liquid was widely selected by children less than 12 years and by those healthy and taking medicines rarely. Monolithic solid forms were mostly chosen by adolescents and by children with a chronic disease taking medicines frequently. There was a clear lack of familiarity with more novel dosage forms (e.g., orodispersible films and granules). Noteworthy, granules were not appreciated, particularly by adolescents (52.8%). To rationalise the creation of paediatric formulations, it is important to involve children as active stakeholders and to apply tools assessing children's perspectives on medicines to inform acceptable dosage form development from the start.

Informed consent for neonatal trials: practical points to consider and a check list.

Obtaining informed consent from parents of critically ill neonates can be challenging. The parental decision-making process is influenced by the severity of the child's condition, the benefit-risk balance, their emotional state and the quality of the relationship with the clinical team. Independent of local legislation, parents may prefer that consent is sought from both. Misconceptions about the absence of risks or unrealistic expectations about benefits should be openly addressed to avoid misunderstandings which may harm the relationship with the clinical team. Continuous consent can be sought where it is unclear whether the free choice of parental consent has been compromised. Obtaining informed consent is a dynamic process building on trusting relationships. It should include open and honest discussions about benefits and risks. Investigators may benefit from training in effective communication. Finally, involving parents in neonatal research including the development of the informed consent form and the process of obtaining consent should be considered standard practice.

Participation of Parents of Hospitalized Children in Medical Rounds: A Qualitative Study on Contributory Factors.

PURPOSE: Factors that promote parents' participation during medical rounds on their hospitalized child have not been fully addressed. The aim of this study was to identify factors that promote the participation of family members during medical rounds. DESIGN AND METHODS: This was a descriptive qualitative study using elements of analysis from the grounded theory method. Semi-structured interviews and non-participant observations were performed from December 2015 until June 2016 and took place on a general academic pediatric ward where the age of children did not exceed 12 months. RESULTS: In total 20 participants were interviewed: 10 pediatric nurses, 4 pediatricians and 6 parents. In addition, five medical rounds were videotaped. Five themes emerged from the analyses of the interviews and videotapes: "conditions", "structure of medical rounds", "cast", "adaptive professionals" and "parents' participation as a process". CONCLUSION: Contextual factors, such as the room and seating arrangement, as well as the willingness of healthcare professionals to work together with the parents are important in enabling parents' participation. To promote active participation, professionals have to communicate in layman's terms and information given by parents has to be taken seriously. Support and coaching of parents during the medical rounds and evaluating the rounds are meaningful factors. PRACTICE IMPLICATIONS: These findings help healthcare professionals to restructure the traditional medical rounds to enable parents' participation. The identified communication skills and attitudes can enhance the competencies of nurses and doctors as communicators and collaborators. This urge the need for more specific education for professionals to promote parents' participation.

Recall and Retention of Consent Procedure Contents and Decisions: Results of a Randomized Controlled Trial.

BACKGROUND: Residual tissue samples, i.e., samples excised for diagnosis or during treatment, are commonly used for medical research. In the Netherlands, they can be used provided the patient did not opt out of this use. Previous research has shown that recall of the informed consent procedure for tissue use is poor. Here, we investigate recall of three consent procedures: informed consent, opt-out, and opt-out plus (an opt-out procedure with an information procedure similar to that of informed consent). METHODS: Patients (n = 1,319) with a variety of diseases were randomized into three trial arms: informed consent, opt-out plus, and opt-out. Questionnaires were administered 6 weeks and 6 months after randomization. RESULTS: Six hundred and seventy-three and 553 patients returned the 6-week and 6-month questionnaire, respectively. In the informed consent arm, recall of having received a brochure (55.3%) or oral information (69.4%) was similar to that in the opt-out plus arm (48.5 and 71.6%, respectively), at the 6-week assessment. Significantly more respondents in the informed consent and the opt-out plus arms versus the opt-out arm recalled that they had been informed about being able to control tissue use and which consent procedure they had experienced (6-week questionnaire range 53.2-75.8 vs. 13.9-16.1%; 6-month questionnaire range 43.5-84.2 vs. 3.2-35.4%). There were no significant differences between the informed consent and opt-out plus arms in this regard. CONCLUSIONS: Recall of the consent procedure was similar in opt-out plus and informed consent procedures. Overall, recall was moderate, indicating that there is room for improvement in the quality of information provision.

Rare disease registries: potential applications towards impact on development of new drug treatments.

BACKGROUND: Low prevalence, lack of knowledge about the disease course, and phenotype heterogeneity hamper the development of drugs for rare diseases. Rare disease registries (RDRs) can be helpful by playing a role in understanding the course of the disease, and providing information necessary for clinical trial design, if designed and maintained properly. We describe the potential applications of a RDR and what type of information should be incorporated to support the design of clinical trials in the process of drug development, based on a broad inventory of registry experience. We evaluated two existing RDRs in more detail to check the completeness of these RDRs for trial design. RESULTS: Before and during the application for regulatory approval a RDR can improve the efficiency and quality in clinical trial design by informing the sample size calculation and expected disease course. In exceptional circumstances information from RDRs has been used as historical controls for a one-armed clinical trial, and high quality RDRs may be used for registry-based randomized controlled trials. In the post marketing phase of (conditional) drug approval a disease-specific RDR is likely to provide more relevant information than a product-specific registry. CONCLUSIONS: A RDR can be very helpful to improve the efficiency and quality of clinical trial design in several ways. To enable the applicability and optimal use of a RDR longitudinal data collection is indispensable, and specific data collection, prepared for repeated measurement, is needed. The developed checklist can help to define the appropriate variables to include. Attention should be paid to the inclusion of patient-relevant outcome measures in the RDR from the start. More research and experience is needed on the possibilities and limitations of combining RDR information with clinical trial data to maximize the availability of relevant evidence for regulatory decisions in rare diseases.

Patients' Attitudes Towards the Return of Incidental Findings After Research with Residual Tissue: A Mixed Methods Study.

AIMS: To investigate the attitudes of patients toward the return of individual research results from scientific research with residual tissue. METHODS AND FINDINGS: We recruited 1319 patients from 6 Dutch hospitals. In total, 673 patients (51% response rate) completed the questionnaire and 146 were interviewed. Based on the questionnaire data, the majority of respondents (92%) wanted to be informed of incidental findings about both a curable (92%) and an incurable (76%) disease. Respondents' wishes to be informed about incidental findings did not vary significantly as a function of patient demographics or type of disease. The interview data show that respondents wished to be informed about incidental findings because they considered it to be normal practice; they expected the information to be of benefit for their health. Information should be provided by their physician. Yet, most respondents (84%) would consent to research even if they would not be informed about incidental findings, primarily because they recognized that there might be practical problems in providing such information, and because they valued scientific research highly. CONCLUSIONS: We conclude that, while the majority of patients want to be informed about incidental findings, they also recognize that this may be difficult.

How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians.

OBJECTIVES: In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. METHODS: Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies. KEY FINDINGS: The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose-ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose-finding study. CONCLUSIONS: The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.

[Biobanks and the return of results to donors]. / Biobanken en de terugkoppeling van onderzoeksbevindingen aan donoren.

Biobanks should return clinically significant and actionable research findings to donors who have given physical material to the biobank. Because the clinical significance of a research finding is hard to determine for the individual donor, a procedure to decide on clinical significance should be incorporated into a structure for the actual feedback of research results. Most published studies show that donors expect return of individual research results, but there is almost no experience with it. Explorative questionnaire-based research among Dutch biobanks from the BioBanking Medical Research Infrastructure (BBMRI.NL) shows that a substantial group of biobanks can return individual research findings from data analysis. On the basis of these experiences a return of results policy may be drafted that answers to the interests of donors and the possibilities of biobanks.

Public attitudes towards preventive genomics and personal interest in genetic testing to prevent disease: a survey study.

BACKGROUND: Genetic testing and family history assessment can be used as an aid in the prevention of common chronic diseases. The aim of this study was to determine public attitudes and interests towards offering genetic testing and family history-based risk assessment for common chronic disease prevention. METHODS: Cross-sectional questionnaire survey of a consumer panel representative for the Dutch population. The questionnaire was sent to 1399 panel members, aged ≥ 18 years. RESULTS: The response was 70% (978/1399). About half of the respondents expressed an interest in genetic testing to prevent specific diseases (cancer, cardiovascular disease, diabetes or dementia), with lower-educated respondents showing more interest than higher-educated respondents. Few respondents (24%) agreed that people should be preventively tested for all kinds of diseases. According to the respondents, genetic testing should be performed in the hospital (66%) and be directed to curable (57%) or preventable diseases (69%). Half of the respondents believed that family history assessment could help prevent disease, but only 21% thought it should be offered to everyone, as this could cause people to be worried. A minority (12%) reported that their family history had been assessed, whereas 59% did not have it assessed and did not think this would be necessary. Respondents have differentiated interests in preventive genomics, which varies depending on sex, age and level of education. CONCLUSIONS: Members of the public are interested in genetic testing for preventable and curable diseases, but they are ambivalent about family history risk assessment to prevent disease.

Developing a policy for paediatric biobanks: principles for good practice.

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions.

Public attitudes towards genetic testing revisited: comparing opinions between 2002 and 2010.

Ten years after the Human Genome Project, medicine is still waiting for many of the promised benefits, and experts have tempered their high expectations. Public opinion on genetic testing has generally been favourable but is this still the case? The aim of this study is to compare public experiences, beliefs and expectations concerning genetic testing over the years (2002 vs 2010). A cross-sectional questionnaire survey was conducted using the Dutch Health Care Consumer Panel in 2002 and 2010. Responses to questions in identical wording were compared. In 2002 and 2010, 817 (63%) and 978 (70%) members responded, respectively. Awareness and reported use of genetic tests remained stable over time. In 2010, more respondents expected genetic testing to become more widely applied, believed that knowledge about the genetic background of disease helps people live longer, and that testing should be promoted more intensively. In 2010, they were also more interested in their own genetic make-up. On the one hand, the concern that a dichotomy would emerge between people with 'good genes' and 'bad genes' was higher. On the other hand, respondents thought that insurance companies would be less likely to demand a genetic test in order to calculate health insurance premiums. In conclusion, the results suggest that in 8 years, expectations of benefits and potential use of genetic testing have been raised among the public, resulting in more positive opinions. Worries on inequity remain, although worries about premium differentiation by insurance companies have decreased.

Why do participants enroll in population biobank studies? A systematic literature review.

Therapeutic misconception has been extensively studied and addressed within clinical trials. An equivalent in the genetic research context has been identified as diagnostic misconception. There is not much data on this phenomenon in population-based biobank studies. Since misconceptions may generate undue motives to enroll, the authors aimed at reviewing studies addressing the reasons to participate in biobank studies. The main databases were searched using relevant keywords. Studies were included if peer-reviewed, in English and describing the reasons to enroll was provided by actual and apparently healthy donors. Although the 13 studies retrieved were heterogeneous, a scheme summarizing the main aspects involved in the decision-making process was developed. Expectation of personal benefit through health-related information was found in eight studies. Three of them discussed whether this expectation could be considered a form of therapeutic misconception. The magnitude of this phenomenon is an important ethical concern and ought to be further studied.

The changing landscape of genetic testing and its impact on clinical and laboratory services and research in Europe.

The arrival of new genetic technologies that allow efficient examination of the whole human genome (microarray, next-generation sequencing) will impact upon both laboratories (cytogenetic and molecular genetics in the first instance) and clinical/medical genetic services. The interpretation of analytical results in terms of their clinical relevance and the predicted health status poses a challenge to both laboratory and clinical geneticists, due to the wealth and complexity of the information obtained. There is a need to discuss how to best restructure the genetic services logistically and to determine the clinical utility of genetic testing so that patients can receive appropriate advice and genetic testing. To weigh up the questions and challenges of the new genetic technologies, the European Society of Human Genetics (ESHG) held a series of workshops on 10 June 2010 in Gothenburg. This was part of an ESHG satellite symposium on the 'Changing landscape of genetic testing', co-organized by the ESHG Genetic Services Quality and Public and Professional Policy Committees. The audience consisted of a mix of geneticists, ethicists, social scientists and lawyers. In this paper, we summarize the discussions during the workshops and present some of the identified ways forward to improve and adapt the genetic services so that patients receive accurate and relevant information. This paper covers ethics, clinical utility, primary care, genetic services and the blurring boundaries between healthcare and research.

Regulatory aspects of genetic research with residual human tissue: effective and efficient data coding.

In a large retrospective cohort of breast cancer patients, BRCA1 and BRCA2 germline mutations were analysed in DNA isolated from residual paraffin-embedded tissue samples. Because it was not feasible to ask individual for informed consent, a data and DNA coding protocol, based on the Dutch 'Code of Conduct', was developed. The corner stone of the protocol is that a trusted third party, in our case a notary, keeps the coding keys of clinical data and DNA. Because (re)linkage of the combined coded clinical and genotyping data (BRCA1/2) is only possible through the notary's keys, these can be considered to be comparable to anonymised data at the level of the researcher. Issues around retrospective genotyping of allegedly high-risk mutations and the coding procedure itself are discussed. Our protocol is an appropriate solution to safeguard the privacy of patients when using residual tissue or DNA of patients. Importantly, the coding procedure also allows re-linkage of new genotyping data or extended patient follow-up data to the valuable coded dataset.

Obtaining 'fresh' consent for genetic research with biological samples archived 10 years ago.

OBJECTIVE: To obtain consent from breast cancer survivors to use residual tissue for a study on carriership of germ line mutations in the BRCA 1 and 2 genes. To investigate which consent regimen patients prefer for research with archived tissue. PARTICIPANTS: One hundred and thirty-two patients surgically treated for breast cancer between 1995 and 1997 in the Netherlands Cancer Institute were mailed a consent form and a questionnaire. RESULTS: A consent form was obtained from 90%; 3% withheld consent for the use of archived tissue. A completed questionnaire was returned by 84%. 'One-time general consent' was considered to be the best procedure for consenting to research with stored tissue by 56%, 23% favoured the current 'opt-out' procedure; 21% did not know or had no preference. CONCLUSION: Obtaining fresh consent for genetic research with stored tissue is possible at the cost of time and effort. Most patients give consent for research with residual tissue.

[Secondary use of human tissue: consent and better information required]. / Nader gebruik van lichaamsmateriaal: zeggenschap en betere informatie nodig.

Human tissue remaining after diagnostic procedures is important for use in scientific research. This 'secondary use' of tissue is regulated by the Dutch Medical Treatment Contracts Act and the Code of Conduct for Proper Secondary Use of Human Tissue of the Dutch Federation of Biomedical Scientific Societies. Patients have the right to opt-out of further use of their residual tissue, but the procedures for objection and the provision of information involved are not regulated by statute. Dutch patients have a positive attitude to further use of human tissue for other purposes. They prefer, however, a procedure in which they are informed verbally by their health professional about research with residual tissue. The information can be brief and is best provided early in the treatment. Administrative and technical modifications of the current registration systems are necessary to support the opting-out procedure in practice. By taking the preferences of patients into account, trust in medical practice can be maintained.

Synthesis and initial evaluation of [11C](R)-RWAY in monkey-a new, simply labeled antagonist radioligand for imaging brain 5-HT1A receptors with PET.

PURPOSE: We aimed to fulfill a need for a radioligand that may be simply labeled with carbon-11 for effective positron emission tomography (PET) imaging of brain 5-HT(1A) receptors. METHODS: Racemic RWAY (2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylbutyryl]-1H-azepine) has high affinity for 5-HT(1A) receptors. The enantiomers of RWAY and O-desmethyl-RWAY, synthesized from commercially available materials, were each labeled with carbon-11 by treating the respective O-desmethyl precursor with [(11)C]iodomethane, and injected into rhesus monkey for measurement of regional brain uptake. The 5-HT(1A) selectivity of (R)-[(11)C]RWAY was checked by administering WAY-100635, before and after radioligand administration. Radiometabolites of (R)-[(11)C]RWAY in blood and urine were analyzed by HPLC with partial elucidation of their structures by LC-MS-MS. RESULTS: (R)-[(11)C]RWAY was a 5-HT(1A) receptor antagonist exhibiting high brain uptake with regional distribution consistent with specific binding to 5-HT(1A) receptors. The similar affinity, (S)-[(11)C]RWAY was a weak partial agonist at 5-HT(1A) receptors exhibiting similar brain peak uptake with much less 5-HT(1A) receptor-specific binding. The maximal ratio in receptor-rich cingulate gyrus to receptor-devoid cerebellum reached 6.4 at 87.5 min after injection of (R)-[(11)C]RWAY. After treatment with WAY-100635 before or after (R)-[(11)C]RWAY administration, radioactivity levels in 5-HT(1A) receptor-rich regions were reduced almost to that in cerebellum. Blood and urine radiometabolites were less lipophilic than parent and were not due to hydrolysis but to ring hydroxylations, oxidation, and dephenylation. CONCLUSION: (R)-[(11)C]RWAY is simply prepared and an effective antagonist for imaging brain 5-HT(1A) receptors. This radioligand resists hydrolysis in vivo, gives less lipophilic radiometabolites, and warrants further PET studies in human subjects.