Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

How well do the public understand palliative care? A mixed methods study

Background: International research suggests that the general public appear to be confused about what palliative care is and who provides it.1 2 An understanding of public views is needed in order to target education and policy campaigns and to manage future needs, expectations and resourcing of care.

Aim: The aim of this study was to establish the current levels of awareness and perceptions of palliative care among the general public in Northern Ireland.

Methods: A mixed methods study comprising two phases was undertaken. A community-based cross-sectional survey with a population of 3,557 individuals aged over 17 years was performed. Information was collected using a structured questionnaire consisting of 17 items. Open questions were subject to content analysis; closed questions were subject to descriptive statistics with inferential testing as appropriate. This was followed by semi structured telephone interviews (n=50).

Results: Responses indicated limited knowledge about palliative care. Respondents who worked in healthcare themselves or who had a close relative or friend who had used a palliative care service were more aware of palliative care and the availability of different palliative care services. The main barriers to raising awareness were fear, lack of interaction with health services and perception of lack of resources. A key aspect identified for promoting palliative care was the development of understanding and use of the term itself and targeted educational strategies.

Conclusions: Public awareness of the concept of palliative care and of service availability remains insufficient. An increased awareness of palliative care is needed, in order to improve knowledge of and access to services when required, empower individuals, involve communities and ultimately to improve the delivery of palliative and end-of-life care.

Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Background: Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.

Methods: COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.

Findings: We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).

Interpretation: Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.

Nurses' experiences providing palliative care to individuals living in rural communities aspects of the physical residential setting

Introduction: Efforts are needed to improve palliative care in rural communities, given the unique characteristics and inherent challenges with respect to working within the physical aspects of residential settings. Nurses who work in rural communities play a key role in the delivery of palliative care services. Hence, the purpose of this study was to explore nurses’ experiences of providing palliative care in rural communities, with a particular focus on the impact of the physical residential setting.

Methods: This study was grounded in a qualitative approach utilizing an exploratory descriptive design. Individual telephone interviews were conducted with 21 community nurses. Data were analyzed by thematic content analysis.

Results: Nurses described the characteristics of working in a rural community and how it influences their perception of their role, highlighting the strong sense of community that exists but how system changes over the past decade have changed the way they provide care. They also described the key role that they play, which was often termed a ‘jack of all trades’, but focused on providing emotional, physical, and spiritual care while trying to manage many challenges related to transitioning and working with other healthcare providers. Finally, nurses described how the challenges of working within the physical constraints of a rural residential setting impeded their care provision to clients who are dying in the community, specifically related to the long distances that they travel while dealing with bad weather.

Management and diagnosis of psychogenic cough, habit cough, and tic cough: A systematic review

BACKGROUND: Several pharmacologic and nonpharmacologic therapeutic options have been used to treat cough that is not associated with a pulmonary or extrapulmonary etiology.

METHODS: We conducted a systematic review to summarize the evidence supporting different cough management options in adults and children with psychogenic, tic, and habit cough. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched from the earliest inception of each database to September 2013. Content experts were contacted, and we searched bibliographies of included studies to identify additional references.

RESULTS: A total of 18 uncontrolled studies were identified, enrolling 223 patients (46% male subjects, 96% children and adolescents). Psychogenic cough was the most common descriptive term used (90% of the studies). Most of the patients (95%) had no cough during sleep; barking or honking quality of cough was described in only eight studies. Hypnosis (three studies), suggestion therapy (four studies), and counseling and reassurance (seven studies) were the most commonly used interventions. Hypnosis was effective in resolving cough in 78% of the patients and improving it in another 5%. Suggestion therapy resolved cough successfully in 96% of the patients. The greatest majority of improvements noted with these forms of therapy occurred in the pediatric age group. The quality of evidence is low due to the lack of control groups, the retrospective nature of all the studies, heterogeneity of definitions and diagnostic criteria, and the high likelihood of reporting bias.

CONCLUSIONS: Only low-quality evidence exists to support a particular strategy to define and treat psychogenic, habit, and tic cough. Patient values, preferences, and availability of potential therapies should guide treatment choice.

A Comparison of Support Needs Between Rural and Urban Family Caregivers Providing Palliative Care

The present study examined the support needs for urban and rural family caregivers of a palliative family member using a cross-sectional telephone survey in northeastern Ontario, Canada (n = 140; 70 urban, 70 rural). Support needs identified as most important by both the groups were informational. Rural caregivers reported greater unmet needs in tangible support (P =.01). No differences were observed between the groups for emotional or informational support needs (P =.25 and P =.35, respectively). Rural and urban caregivers perceived care for care recipients as accessible (mean accessibility score 1.9, standard deviation [SD] = 0.09 and 1.7, SD = 0.7, respectively, P =.20); the majority indicated that when needed, services were easily and quickly obtained. Although there are similarities in the formal care experiences, rural caregivers experience greater unmet needs in receiving support for instrumental activities. © The Author(s) 2013.

Comparing the experiences of rural and urban family caregivers of the terminally ill

Introduction: There are many challenges in delivering rural health services; this is particularly true for the delivery of palliative care. Previous work has identified consistent themes around end-of-life care, including caregiver burden in providing care, the importance of informal care networks and barriers imposed by geography. Despite these well-known barriers, few studies have explored the experience of palliative care in rural settings. The purpose of the present study was to compare the experiences of rural family caregivers actively providing end-of-life care to the experiences of their urban counterparts. Methods: Caregivers' perceived health status, the experience of burden in caregiving, assessment of social supports and the pattern of formal care used by the terminally ill were explored using a consistent and standardized measurement approach. A cross-sectional survey study was conducted with 100 informal caregivers (44 rural, 56 urban) actively providing care to a terminally ill patient recruited from a publicly funded community agency located in northeastern Ontario, Canada. The telephone-based survey included questions assessing: (i) caregiver perceived burden (14-item instrument based on the Caregiver's Burden Scale in End-of-Life Care [CBS-EOLC]); (ii) perceived social support (modified version of the Multidimensional Scale of Perceived Social Support [MSPSS] consisting of 12 items); and (iii) functional status of the care recipient (assessed using the Eastern Collaborative Oncology Group performance scale). Results: Rural and urban caregivers were providing care to recipients with similar functional status; the majority of care recipients were either capable of all self-care or experiencing some limitation in self-care. No group differences were observed for caregiver perceived burden: both rural and urban caregivers reported low levels of burden (CBS-EOLC score of 26.5 [SD=8.1] and 25.0 [SD=9.2], respectively; p=0.41). Urban and rural caregivers also reported similarly high levels of social support (mean MSPSS total score of 4.3 [SD=0.7] and 4.1 [SD=0.8], respectively; p=0.40). Although caregivers across both settings reported using a comparable number of services (rural 4.8 [SD=1.9] vs urban 4.5 [SD=1.8]; p=0.39), the types of services used differed. Rural caregivers reported greater use of family physicians (65.1% vs 40.7%; p=0.02), emergency room visits (31.8% vs 13.0%; p=0.02) and pharmacy services (95.3% vs 70.4%; p=0.002), while urban caregivers reported greater use of caregiver respite services (29.6% vs 11.6%; p=0.03). Conclusion: Through the use of standardized tools, this study explored the experiences of rural informal family caregivers providing palliative care in contrast to the experiences of their urban counterparts. The results of the present study suggest that while there are commonalities to the caregiving experience regardless of setting, key differences also exist. Thus, location is a factor to be considered when implementing palliative care programs and services. © K Brazil, S Kaasalainen, A Williams, C Rodriguez, 2013.

Patient safety and communication: A new assessment for doctors trained in countries where language differs from that of the host country: Results of a pilot using a domain-based assessment

Objective

Global migration of healthcare workers places responsibility on employers to comply with legal employment rights whilst ensuring patient safety remains the central goal. We describe the pilot of a communication assessment designed for doctors who trained and communicated with patients and colleagues in a different language from that of the host country. It is unique in assessing clinical communication without assessing knowledge.

A 14-station OSCE was developed using a domain-based marking scheme, covering professional communication and English language skills (speaking, listening, reading and writing) in routine, acute and emotionally challenging contexts, with patients, carers and healthcare teams. Candidates (n = 43), non-UK trained volunteers applying to the UK Foundation Programme, were provided with relevant station information prior to the exam.

The criteria for passing the test included achieving the pass score and passing 10 or more of the 14 stations. Of the 43 candidates, nine failed on the station criteria. Two failed the pass score and also the station criteria. The Cronbach's alpha coefficient was 0.866.

This pilot tested ‘proof of concept’ of a new domain-based communication assessment for non-UK trained doctors.

The test would enable employers and regulators to verify communication competence and safety in clinical contexts, independent of clinical knowledge, for doctors who trained in a language different from that of the host country.

Next-generation sequencing-based molecular diagnosis of 82 retinitis pigmentosa probands from Northern Ireland

Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.

Understanding the practice nurse’s role in the cancer care tapestry

Background: The are currently 2 million people in the UK living with or
after cancer, and this number is expected to double by 2030 (Maddams et
al, 2012). However, many report unmet physical and psychological needs.

Aim: To determine the learning needs of practice nurses to take on an
enhanced role with people affected by cancer, particularly after primary
treatment, and to develop a course to meet these needs.

Method: The Macmillan Steering Group designed and developed a course for practice
nurses to identify their learning needs, enabling participating practice
nurses to work collaboratively with each other and the course facilitator.
There was strong patient involvement throughout. The course was
evaluated by self-assessment of knowledge, skills and confidence, patient
satisfaction questionnaires and in-depth, qualitative telephone interviews
with the participants and their supporting GPs.

Results: The practice nurses reported changed practice, with increased confidence in discussing
issues relating to cancer and its treatment with patients and relatives.
They understood the importance of supported self-management and were
able to signpost patients to appropriate sources of information and
support. Many of the practice nurses started initiating and undertaking
Cancer Care Reviews, both as planned appointments and opportunistically.
Over the past year, a further nine pilots have been completed throughout
the UK, demonstrating that these results are reproducible in other settings.

Conclusions: With appropriate support and training and protected time
to include cancer care into their everyday work, practice nurses can take
on an important role in the support and care of people affected by cancer

Implant-retained overdentures did not have a significant improvement in dietary intake

DESIGN: Randomised controlled trial.

INTERVENTION: Patients aged 65 or above edentate for a minimum of five years, with sufficient bone for two implants in the anterior mandible, were recruited. Those with systemic disease that contraindicated implants or had a low mini-mental state evaluation score were excluded. Patients in both groups had a standard maxillary complete denture fabricated. Patients randomised to the treatment group received a two-implant mandibular overdenture while those in the control group received a standard mandibular complete denture. Three 24-hour dietary recalls were collected by telephone interviews at baseline and at 12 months.

RESULTS: 255 patients were randomised: 128 received a standard complete denture (CD) and 127 a two-implant mandibular overdenture (IOD). 127 patients were available at 12-month follow up, 114 in the CD group and 103 in the IOD group. No significant between-group differences were found.

CONCLUSIONS: Although there is much evidence supporting the adoption of two-implant mandibular overdenture (IOD) treatment as the standard of care for edentate patients, this evidence does not include an improvement in dietary intake at one year for medically healthy independent edentate elders when given no specific dietary counselling.

An analysis of the attitudes of dental patients attending general dental practice in Galway

AIM: To describe the patterns of dental attendance and attitudes towards tooth loss of general dental practice patients in Galway.

OBJECTIVES: 1. To determine the pattern of adult dental attendance in general practices in Galway; and, 2. To examine the oral health attitudes of these patients.

METHOD: Questionnaires were distributed to 311 consecutive adult patients in the waiting rooms of ten general dental practices in Galway, which were randomly selected from the telephone directory.

RESULTS: A total of 254 of the 311 questionnaires distributed were fully completed, returned and included in the results, giving a response rate of 81.7%. A total of 59% of dentate participants attended their dentist for annual or biannual examinations compared to 23% of edentate patients. Some 10.5% of medical card holders and 0.5% of non-medical card holders were edentulous.

CONCLUSIONS: The data from the survey indicated that medical card holders in Galway were more likely to be edentulous than nonmedical card holders. Edentate patients were less likely to be regular dental attenders than dentate patients.

An evaluation of a tiered interrelated intervention to address hazardous/ harmful drinking

In Northern Ireland, alcohol misuse impacts negatively on individual drinkers, families and communities. The ‘Alcohol and You Project’ in the South Eastern Health and Social Care Trust is a funded project providing a range of inter-related services with the Trust and alcohol/drug misuse charities. It includes a self-help interactive website, brief intervention drop in clinics and counseling services. Queen's University Belfast is evaluating the effectiveness of the project to reduce hazardous/ harmful drinking.

THE SAAF STUDY: evaluation of the Safeguarding Children Assessment and Analysis Framework (SAAF), compared with management as usual, for improving outcomes for children and young people who have experienced, or are at risk of, maltreatment: study protocol for a randomised controlled trial

Background: Serious case reviews and research studies have indicated weaknesses in risk assessments conducted by child protection social workers. Social workers are adept at gathering information but struggle with analysis and assessment of risk. The Department for Education wants to know if the use of a structured decision-making tool can improve child protection assessments of risk.

Methods/design: This multi-site, cluster-randomised trial will assess the effectiveness of the Safeguarding Children Assessment and Analysis Framework (SAAF). This structured decision-making tool aims to improve social workers' assessments of harm, of future risk and parents' capacity to change. The comparison is management as usual.

Inclusion criteria: Children's Services Departments (CSDs) in England willing to make relevant teams available to be randomised, and willing to meet the trial's training and data collection requirements.

Exclusion criteria: CSDs where there were concerns about performance; where a major organisational restructuring was planned or under way; or where other risk assessment tools were in use.

Six CSDs are participating in this study. Social workers in the experimental arm will receive 2 days training in SAAF together with a range of support materials, and access to limited telephone consultation post-training. The primary outcome is child maltreatment. This will be assessed using data collected nationally on two key performance indicators: the first is the number of children in a year who have been subject to a second Child Protection Plan (CPP); the second is the number of re-referrals of children because of related concerns about maltreatment. Secondary outcomes are: i) the quality of assessments judged against a schedule of quality criteria and ii) the relationship between the three assessments required by the structured decision-making tool (level of harm, risk of (re) abuse and prospects for successful intervention).

Discussion: This is the first study to examine the effectiveness of SAAF. It will contribute to a very limited literature on the contribution that structured decision-making tools can make to improving risk assessment and case planning in child protection and on what is involved in their effective implementation.

Parents’ and young people’s involvement in designing a trial of ventilator weaning

Consulting with users is considered best practice and is highly recommended in designing new trials. As part of our feasibility work, we undertook a consultation exercise with parents, ex-patients and young people prior to designing a trial of protocol-based ventilator weaning. Our aims were to (1) ascertain views on the relevance and importance of the trial; (2) determine the important parent/patient outcome measures; and (3) ascertain views on informed consent in a cluster randomized controlled trial. We conducted audio-recorded face-to-face, telephone and focus group interviews with parents and young people. Data were content analysed to generate information to address our specific consultation objectives. The setting was the north-western region of England. A total of 16 participants were interviewed: 2 parents of paediatric intensive care unit (PICU) survivors; 1 PICU survivor; and 13 young people from the former Medicines for Children Research Network. The trial objectives were deemed important and relevant, and participants considered the most important outcome measure to be the length of time on ventilation. Parents and young people did not consider written informed consent to be a necessary requirement in the context of this trial, rather awareness of unit participation in the trial was important with the opportunity of opting out of data collection. This consultation provided useful, pragmatic insights to inform trial design. We encountered significant challenges in recruiting parents and young people for this consultation exercise, and novel recruitment methods need to be considered for future work in this field. Patient and public involvement is essential to ensure that future trials answer parent-relevant questions and have meaningful outcome measures, as well as involving parents and young people in the general development of health care services.