Five Year Follow-up of a Randomized Controlled Trial of Laparoscopic Repair of Very Large Hiatus Hernia With Sutures Versus Absorbable Versus Nonabsorbable Mesh.

OBJECTIVE: To determine whether absorbable or nonabsorbable mesh repair of large hiatus hernias is followed by less recurrences at late follow-up compared to sutured repair. SUMMARY OF BACKGROUND DATA: Radiological recurrences have been reported in up to 30% of patients after repair of large hiatus hernias, and mesh repair has been proposed as a solution. Earlier trials have revealed mixed outcomes and early outcomes from a trial reported previously revealed no short-term advantages for mesh repair. METHODS: Multicentre prospective double-blind randomized controlled trial of 3 methods of hiatus hernia repair; sutures versus absorbable mesh versus nonabsorbable mesh. Primary outcome - hernia recurrence assessed by barium meal X-ray and endoscopy at 3-4 years. Secondary outcomes - clinical symptom scores at 2, 3, and 5 years. RESULTS: 126 patients were enrolled - 43 sutures, 41 absorbable mesh, and 42 nonabsorbable mesh. Clinical outcomes were obtained at 5 years in 89.9%, and objective follow-up was obtained in 72.3%. A recurrent hernia (any size) was identified in 39.3% after suture repair, 56.7% - absorbable mesh, and 42.9% - nonabsorbable mesh (P = 0.371). Clinical outcomes were similar at 5 years, except chest pain, diarrhea, and bloat symptoms which were more common after repair with absorbable mesh. CONCLUSIONS: No advantages were demonstrated for mesh repair at up to 5 years follow-up, and symptom outcomes were worse after repair with absorbable mesh. The longer-term results from this trial do not support mesh repair for large hiatus hernias.

Laparoscopic repair of very large hiatus hernia with sutures versus absorbable mesh versus nonabsorbable mesh: a randomized controlled trial.

OBJECTIVE: Determine whether absorbable or nonabsorbable mesh in repair of large hiatus hernias reduces the risk of recurrence, compared with suture repair. BACKGROUND: Repair of large hiatus hernia is associated with radiological recurrence rates of up to 30%, and to improve outcomes mesh repair has been recommended. Previous trials have shown less short-term recurrence with mesh, but adverse outcomes limit mesh use. METHODS: Multicentre prospective double blind randomized controlled trial of 3 methods of repair: sutures versus absorbable mesh versus nonabsorbable mesh. Primary outcome-hernia recurrence assessed by barium meal radiology and endoscopy at 6 months. Secondary outcomes-clinical symptom scores at 1, 3, 6, and 12 months. RESULTS: A total of 126 patients enrolled: 43 sutures, 41 absorbable mesh, and 42 nonabsorbable mesh. Among them, 96.0% were followed up to 12 months, with objective follow-up data in 92.9%. A recurrent hernia (any size) was identified in 23.1% after suture repair, 30.8% after absorbable mesh, and 12.8% after nonabsorbable mesh (P = 0.161). Clinical outcomes were similar, except less heartburn at 3 and 6 months and less bloating at 12 months with nonabsorbable mesh; more heartburn at 3 months, odynophagia at 1 month, nausea at 3 and 12 months, wheezing at 6 months; and inability to belch at 12 months after absorbable mesh. The magnitudes of the clinical differences were small. CONCLUSIONS: No significant differences were seen for recurrent hiatus hernia, and the clinical differences were unlikely to be clinically significant. Overall outcomes after sutured repair were similar to mesh repair.

Quality of Life Following Repair of Large Hiatal Hernia is Improved but not Influenced by Use of Mesh: Results From a Randomized Controlled Trial.

INTRODUCTION: Laparoscopic surgery is the treatment of choice for repair of large hiatus hernia, but can be followed by recurrence. Repair with prosthetic mesh has been recommended to prevent recurrence, although complications following mesh repair have generated disagreement about whether or not mesh should be used. The early objective and clinical results of a randomized trial of repair with mesh versus sutures have been reported, and revealed few differences. In the current study, we evaluated quality of life outcomes within this trial at follow-up to 2 years. METHODS: In a multicenter prospective double-blind randomized trial three methods for repair of large hiatus hernia were compared: sutures versus repair with absorbable mesh (Surgisis) versus non-absorbable (Timesh). Quality of life assessment using the Short-Form 36 (SF-36) questionnaire was undertaken at 3, 6, 12 and 24 months after surgery. SF-36 outcomes (8 individual scales and 2 composite scales) were determined for each group, and compared between groups, and across different follow-up points. RESULTS: 126 patients were enrolled-43 sutures, 41 absorbable mesh and 42 non-absorbable mesh. 115 (91.3%) completed a preoperative questionnaire, and 113 (89.7%) completed the post-operative questionnaire at 3 months, 116 (92.1%) at 6 months, 114 (90.5%) at 12 months, and 91 (72.2%) at 24 months. The SF-36 Physical and Mental Component Scores (PCS and MCS) improved significantly following surgery, and this improvement was sustained across 24 months follow-up (p < 0.001 for PCS and MCS at each follow-up point). There were no significant differences between the groups for the component scores or the eight SF-36 subscale scores at each follow-up time. 29 individuals had a recurrence at 6 months follow-up, of which 9 were symptomatic. The PCS were higher in patients with recurrence versus without (p < 0.01), and in patients with a symptomatic recurrence versus asymptomatic recurrence versus no recurrence (p = 0.001). CONCLUSION: SF-36 measured quality of life improved significantly after repair of large hiatal hernia at up to 2 years follow-up, and there were no differences in outcome for the different repair techniques. The use of mesh versus no mesh in repair of large hiatal hernia did not influence quality of life.

Therapeutic misconception: hope, trust and misconception in paediatric research.

Although the therapeutic misconception (TM) has been well described over a period of approximately 20 years, there has been disagreement about its implications for informed consent to research. In this paper we review some of the history and debate over the ethical implications of TM but also bring a new perspective to those debates. Drawing upon our experience of working in the context of translational research for rare childhood diseases such as Duchenne muscular dystrophy, we consider the ethical and legal implications of the TM for parental consent to research. In this situation, it is potentially the parent who is vulnerable to TM. In our analysis we not only consider the context of informed consent for research but also the wider environment in which the value of research is promoted, more broadly through the media but also more specifically through the communication strategies of patient organizations. All dissemination about developments in research for health runs the risk of portraying an overly optimistic view of the promise of biotechnological solutions and has the potential to encourage a 'collective' TM. In this paper we consider the challenge that TM presents to parents as well as explore the ethical and legal responsibilities of researchers to ensure an appropriately informed consent: compatible with a hopeful disposition of parents who consent for the their children whilst avoiding a blind and misleading optimism.

Disputing the ethics of research: the challenge from bioethics and patient activism to the interpretation of the Declaration of Helsinki in clinical trials.

In this paper we argue that the consensus around normative standards for the ethics of research in clinical trials, strongly influenced by the Declaration of Helsinki, is perceived from various quarters as too conservative and potentially restrictive of research that is seen as urgent and necessary. We examine this problem from the perspective of various challengers who argue for alternative approaches to what ought or ought not to be permitted. Key themes within this analysis will examine these claims and argue they have implications for the interests of the research subject, research governance and regulation. Using our work with TREAT-NMD, the neuromuscular clinical trials network, we posit that there is a place for advancing the discourse of moral rights and moral duties in the context of research, especially from the perspective of patients and their families, and for including the politics of patient activism and empowerment. At the same time we remain vigilant to the danger that the therapeutic misconception and other serious vulnerabilities for the patient population in clinical trials, are at risk of being overlooked.

Versioning biological cells for trustworthy cell engineering.

"Full-stack" biotechnology platforms for cell line (re)programming are on the horizon, thanks mostly to (a) advances in gene synthesis and editing techniques as well as (b) the growing integration of life science research with informatics, the internet of things and automation. These emerging platforms will accelerate the production and consumption of biological products. Hence, traceability, transparency, and-ultimately-trustworthiness is required from cradle to grave for engineered cell lines and their engineering processes. Here we report a cloud-based version control system for biotechnology that (a) keeps track and organizes the digital data produced during cell engineering and (b) molecularly links that data to the associated living samples. Barcoding protocols, based on standard genetic engineering methods, to molecularly link to the cloud-based version control system six species, including gram-negative and gram-positive bacteria as well as eukaryote cells, are shown. We argue that version control for cell engineering marks a significant step toward more open, reproducible, easier to trace and share, and more trustworthy engineering biology.

Managing childhood cancer pain into survivorship: recognition and emerging principles.

PURPOSE OF REVIEW: Continual refinement and further stratification of childhood cancer treatment has led to increased survivorship with recognized improvements in many long-term health outcomes. Despite this progress, persisting pain prevalence in childhood cancer survivors is increasing and emerging as a significant long-term health concern. RECENT FINDINGS: Currently, there is no guidance on how to approach and manage persisting pain in survivors of childhood cancer. SUMMARY: Clinicians should work with children and young people to optimize the management of pain and other symptoms on treatment. Focusing on an early post treatment screening for pain and other symptoms (including sleep and fatigue), and the role of on-going analgesic use. Follow-up should offer a multidisciplinary approach, aimed at lessening reliance on pharmacological approaches to pain management, addressing psychological concerns and promoting increased physical activity. The onus is on clinicians to mitigate the long-term risk of pharmacological reliance, particularly opioid dependency, in patients leaving their care and heading into adulthood. In this article, we highlight the emerging evidence of persisting pain in survivors of childhood cancer as a significant long-term health outcome and consider some initial principles of management.

Commentary 1: The Role of Ethical Reflexivity in Conducting Ethically Challenging Qualitative Research.

This paper is a commentary on Herzog et al.'s vignette drawn from their experience of conducting ethically challenging qualitative research. They describe an encounter with a family in which an older child has acted as a sibling donor to a sick younger sibling. It is evident that the process has taken its toll on the well-being of the older child and has created tensions within the family. What then are the ethical boundaries and responsibilities of researchers who enter the private domain of the family? This commentary responds with a model of "ethical reflexivity" which shows how a reflexive researcher can incorporate moral reflection at the different stages of the research process. Reflexivity works differently at different points, upstream it allows for anticipation and planning, incorporating ethical strategies into the methodology. Midstream reflexivity allows for evaluation, reflection and strategic response as the research unfolds and downstream it allows for a critical evaluation of how the research played out. Although it is a vital resource for any society to allow a wide degree of freedom for social scientists to research the social life, this freedom also brings responsibilities. Participation in research both creates and reveals the vulnerabilities of participants and since the researcher is entangled in these complexities they must also be prepared to respond and act. At times it may be necessary to step out of the role of researcher in order to offer support or take more decisive action especially when the well-being of vulnerable participants is at stake.

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics.

This is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease.

Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2.

New Recommendation on Biological Materials Could Hamper Muscular Dystrophy Research.

The new 'Recommendation of the Committee of Ministers to member States on research on biological materials of human origin', adopted in Europe in May 2016 is confusing and lacks specificity on the research use of biomaterials taken from persons not able to consent. It is possible to interpret the relevant clauses in a restrictive manner and doing so would hamper biobank research, by requiring researchers or biobank curators to examine individual records in detail, to check they are adhering to the Recommendation. This would be particularly problematic for muscular dystrophy and other rare disease research, the progress of which relies increasingly on the sharing of biomaterials and data internationally, as it will add complexity to the logistics of biomaterials and data sharing and introduce barriers for researchers preparing biomaterials for sharing. Such barriers are contradictory to EC policies on promoting and funding rare disease research and removing barriers to better care and treatment. Such policies work in concert with international progress in rare disease research, in particular the NIH's Rare Diseases Clinical Research Network and Genetic and Rare Diseases Information Centre. The rare disease community has in recent years worked to create a common framework of harmonised approaches to enable the responsible, voluntary, and secure sharing of biomaterials and data. These efforts are supported by the European Commission in such moves as FP7 funding to advance rare disease research and the introduction of National Plans for rare disease; and are bolstered by similar efforts in the USA via the Clinical and Translational Science Awards Program and the NIH/NCATS Patient Registry developments. Introducing Recommendations from the Committee of Ministers, containing clauses which are incompatible to the efforts to advance rare disease research, seems counter-productive.

'You should at least ask'. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research.

Within the myriad articles about participants' opinions of genomics research, the views of a distinct group - people with a rare disease (RD) - are unknown. It is important to understand if their opinions differ from the general public by dint of having a rare disease and vulnerabilities inherent in this. Here we document RD patients' attitudes to participation in genomics research, particularly around large-scale, international data and biosample sharing. This work is unique in exploring the views of people with a range of rare disorders from many different countries. The authors work within an international, multidisciplinary consortium, RD-Connect, which has developed an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for RD research. Focus groups were conducted with 52 RD patients from 16 countries. Using a scenario-based approach, participants were encouraged to raise topics relevant to their own experiences, rather than these being determined by the researcher. Issues include wide data sharing, and consent for new uses of historic samples and for children. Focus group members are positively disposed towards research and towards allowing data and biosamples to be shared internationally. Expressions of trust and attitudes to risk are often affected by the nature of the RD which they have experience of, as well as regulatory and cultural practices in their home country. Participants are concerned about data security and misuse. There is an acute recognition of the vulnerability inherent in having a RD and the possibility that open knowledge of this could lead to discrimination.

Improving the informed consent process in international collaborative rare disease research: effective consent for effective research.

The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.

The risk of re-identification versus the need to identify individuals in rare disease research.

There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.

Biofumigation with Brassica juncea, Raphanus sativus and Eruca sativa for the management of field populations of the potato cyst nematode Globodera pallida.

BACKGROUND: The viability of potato cyst nematode (PCN) populations (Globodera pallida) was evaluated in three field experiments using Brassica juncea, Raphanus sativus and Eruca sativa amendments. These species were summer cultivated and autumn incorporated in experiment 1; in experiment 2, overwintered brassicaceous cover crops were spring incorporated. Experiment 3 involved determination of effects of metconazole application on biomass/glucosinolate production by B. juncea and R. sativus and on PCN pre- and post-incorporation. Glucosinolate contents were determined before incorporation. Following cover crop incorporation, field plots were planted with susceptible potatoes to evaluate the biofumigation effects on PCN reproduction. RESULTS: In experiment 1, PCN population post-potato harvest was reduced (P = 0.03) in B. juncea-treated plots, while R. sativus prevented further multiplication, but in experiment 2 there were no significant effects on PCN reproduction. In experiment 3, B. juncea or R. sativus either untreated or treated with metconazole reduced PCN populations. Glucosinolate concentrations varied significantly between different plant regions and cultivation seasons. Metconazole application increased the sinigrin concentration in B. juncea tissues. Glucosinolate concentrations correlated positively with PCN mortality for summer-cultivated brassicaceous plants. CONCLUSION: The results demonstrated that B. juncea and R. sativus green manures can play an important role in PCN management, particularly if included in an integrated pest management scheme.

International Charter of principles for sharing bio-specimens and data.

There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues.

Laparoscopic gastric banding: safe and modestly successful.

BACKGROUND: Obesity is an increasing problem in Australia. It is defined as a body mass index (BMI) >30 kg/m(2). It is associated with a number of significant medical conditions, as well as psychological morbidity related to poor body image and the social stigma of obesity. Conservative management is rarely successful in patients with morbid obesity and bariatric surgery is an alternative more likely to produce sustained results. METHODS: To compare the initial results of the Lap-Band (Inamed Health, Santa Barbara, CA, USA) procedure when performed by experienced general laparoscopic surgeons, new to the procedure and those achieved by dedicated bariatric practitioners. RESULTS: The results of the present study showed forty-seven per cent excess weight lost at 2 years, 49% excess BMI lost at 2 years. Reoperation rate for band removal, prolapse/slippage was 25.3%. CONCLUSIONS: Acceptable results with Lap-Band are technically achievable by experienced laparoscopic surgeons with a low morbidity and mortality. The results of the present study are inferior to those reported by dedicated bariatric practices who have performed large numbers of this operation. The rate of band slippage was unacceptably high and there was a significant problem with patients being lost to follow up. Possible reasons for this are discussed.

Autonomy and audit--striking the balance.

The Data Protection Act 1998 purports to implement European legislation which aims to protect the privacy of individuals. There were such concerns about the implications of the Act for certain research and audit that it became necessary to enact further legislation to enable such essential activities to continue. Although this empowers the Secretary of State for Health to approve proposals for these purposes, there should still be a requirement that the use of identifiable personal information without consent must be justified on compelling public interest grounds. It is this that can confound those seeking to rely on such justification. There can either be too cavalier an approach to the issue, and/or there is little sense of what considerations should come into play. This paper attempts to highlight some of the difficulties that are theoretically raised by some audit activities and set out the legal framework within which they must operate. However, the key focus is on how ethical considerations might inform the public interest argument.

Guidance in social and ethical issues related to clinical, diagnostic care and novel therapies for hereditary neuromuscular rare diseases: "translating" the translational.

Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a wider resource for any concerned parent, patient, or clinician to ask a question of ethical concern. Issues raised range from science related ethical issues, issues related to hereditary neuromuscular diseases and the new therapeutic approaches and questions concerning patients rights in the context of patient registries and bio-banks. We conclude by recommending the PEC as a model for similar research contexts in rare diseases.