Response to the editorial by Dr Geraghty.

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Exploring stories of occupational engagement in a regional secure unit.

This paper focuses on the occupational experiences of five men living within a forensic mental health unit over a year. This study used a descriptive qualitative case study methodology to explore the meaning and value placed on daily life (activities, occupations and routines), and how this changed over time. The men's stories showed a complex picture of their experiences of daily life. This study demonstrated the impact of the environment on the men and the ongoing challenge of the need to balance treatment/therapy with security demands and opportunities. Three interrelated themes were identified: (1) Power and Occupation; (2) Therapy or Punishment; (3) Occupational Opportunities within Restrictions. These findings serve as a reminder to clinical teams to reassess the value of occupations attributed by their patients and the impact of the secure environment, whilst also acknowledging the potential for occupations to have a negative impact on well-being.

The experience of meaning in circle dance.

Circle dance, which derives from the tradition of folk dances, is practised worldwide. This article explores the meanings participants attribute to it. In-depth interviews with 39 participants, teachers and coordinators of teacher training programmes from the circle dance network in the United Kingdom were undertaken. Applying a constructivist grounded theory approach, major categories, representing respectively the experiences of circle dance participants, teachers and coordinators, were developed. This article specifically focuses on the first major category, termed "I can't imagine life without it", which relates to the experience of 22 dancers. From an occupational perspective, the study reveals how participants realise a sense of meaning and satisfaction through engagement in circle dance and the potential contribution of this occupation to well-being.

Survey of UK sonographers on the prevention of work related muscular-skeletal disorder (WRMSD).

BACKGROUND: To establish whether the current training of student sonographers in both academic and clinical settings is sufficient for educating about the dangers of work-related musculoskeletal disorders (WRMSDs). METHODS: A dual method of data collection was undertaken. Initially, a focus group was set up, involving a small group of practicing sonographers from a hospital in the United Kingdom, with the results of that survey being used to design a postal survey questionnaire. The questionnaire focused on ergonomics, scanning technique, training in physical techniques, personal general health, risk, stress, and task management. It was sent to seven participating universities across the United Kingdom. Approvals were obtained from the local ethics committees, the hospital Trust, and the academic institution. RESULTS: The focus group highlighted several areas in which improvements could be made in educating sonographers on the reduction of WRMSDs. The questionnaire results indicated that students are being taught about certain aspects of WRMSD prevention by both their university and clinical mentors. Respondents received training on the prevention of WRMSDs: 97% in the university setting and 81% from clinical mentors. CONCLUSIONS: Improvements need to be made in terms of educating students to perform muscle-strengthening exercises during the workday; to have a system of reporting injury; to consider personal health, well-being, and stress management in the workplace; and to evaluate the ergonomics of computer workstations.

What is the current NHS service provision for patients severely affected by chronic fatigue syndrome/myalgic encephalomyelitis? A national scoping exercise.

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), in its most severe clinical presentation, can result in patients becoming housebound and bedbound so unable to access most available specialist services. This presents particular clinical risks and treatment needs for which the National Institute for Health and Care Excellence (NICE) advises specialist medical care and monitoring. The extent of National Health Service (NHS) specialist provision in England for severe CFS/ME is currently unknown. OBJECTIVES: To establish the current NHS provision for patients with severe CFS/ME in England. SETTING AND PARTICIPANTS: All 49 English NHS specialist CFS/ME adult services in England, in 2013. METHOD: Cross-sectional survey by email questionnaire. PRIMARY OUTCOME MEASURES: Adherence to NICE guidelines for severe CFS/ME. RESULTS: All 49 services replied (100%). 33% (16/49) of specialist CFS/ME services provided no service for housebound patients. 55% (27/49) services did treat patients with severe CFS/ME and their interventions followed the NICE guidelines. The remaining services (12%, 6/49) offered occasional or minimal support where funding allowed. There was one NHS unit providing specialist inpatient CFS/ME provision in England. CONCLUSIONS: Study findings highlight substantial variation in access to specialist care for patients with severe presentation of CFS/ME. Where treatment was provided, this appeared to comply with NICE recommendations for this patient group.

NPAS3 variants in schizophrenia: a neuroimaging study.

BACKGROUND: This research is a one-site neuroimaging component of a two-site genetic study involving patients with schizophrenia at early and later stages of illness. Studies support a role for the neuronal Per-Arnt-Sim 3 (NPAS3) gene in processes that are essential for normal brain development. Specific NPAS3 variants have been observed at an increased frequency in schizophrenia. In humans, NPAS3 protein was detected in the hippocampus from the first trimester of gestation. In addition, NPAS3 protein levels were reduced in the dorsolateral prefrontal cortex of some patients with schizophrenia. Npas3 knockout mice display behavioural, neuroanatomical and structural changes with associated severe reductions in neural precursor cell proliferation in the hippocampal dentate gyrus. This study will evaluate the hypothesis that the severe reductions in neural precursor cell proliferation in the dentate gyrus will be present to some degree in patients carrying schizophrenia-associated NPAS3 variants and less so in other patients. METHODS/DESIGN: Patients enrolled in the larger genetic study (n = 150) will be invited to participate in this neuroimaging arm. The genetic data will be used to ensure a sample size of 45 participants in each genetic subgroup of patients (with and without NPAS3 variants). In addition, we will recruit 60 healthy controls for acquisition of normative data. The following neuroimaging measures will be acquired from the medial temporal region: a) an index of the microcellular environment; b) a macro-structural volumetric measure of the hippocampus; and c) concentration levels of N-acetylaspartate, a marker of neuronal health. DISCUSSION: This study will help to establish the contribution of the NPAS3 gene and its variants to brain tissue abnormalities in schizophrenia. Given the genetic and phenotypic heterogeneity of the disorder and the large variation in outcomes, the identification of biological subgroups may in future support tailoring of treatment approaches in order to optimize recovery.

Experiences of daily activity in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and their implications for rehabilitation programmes.

PURPOSE: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME), has a significant impact upon daily functioning. Most recommended treatments aim to alter activity patterns based upon assumptions of activity avoidance. However, as there is limited research on the experience of activity and occupational beliefs in people with CFS/ME, this study took a qualitative approach to understand the meaning of activity in people with this disabling condition. METHOD: This study applied a social constructivist grounded theory methodology. Semi-structured interviews took place with 14 participants attending a Specialist CFS/ME Service in England. FINDINGS: The emergent themes described a premorbid state of constant action with difficulty stopping an activity once it had commenced. When this pattern was interrupted by illness, participants attempted to maintain their previous level of occupational engagement. Negative associations and emotions were described in response to the concept of doing nothing or limited activity. A recurring cycle was reported of increasing activity levels when symptoms improved, followed by post exertional symptoms. CONCLUSIONS: Consequently, participants' beliefs about concepts of both activity and inactivity need to be considered within the application of rehabilitation programmes for CFS/ME that aim to modify activity related behaviours. IMPLICATIONS FOR REHABILITATION: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is commonly treated in the UK using activity modification. In this small qualitative study, patients expressed negative feelings and beliefs towards the concept of doing nothing and therefore sought to push their activity levels when this was available, leading to recurring cycles of symptoms and activity. Rehabilitation programmes need to consider how people with CFS/ME engaged with activity and inactivity before the condition and how this may impact upon engagement with activity-based rehabilitation programmes.

Alphanumeric paging: a potential source of problems in patient care and communication.

PURPOSE: In recent years, the use of numeric paging in many medical centers has been largely replaced by 1-way alphanumeric paging. There is currently no research studying the potential for alphanumeric paging to lead to problems in communication. The purpose of this article is to determine whether the use of alphanumeric pagers may lead to potential problems in patient care and/or communication. METHODS: Alphanumeric pages sent to residents on 3 surgical services at the Medical College of Virginia Hospital were collected over a 3-month period. The pages were classified according to reason for the page, amount of information provided, and follow-up required. RESULTS: A total of 52,384 alphanumeric pages were sent to residents on the surgical services over a 3-month period. There were 1037 pages (2.0% of total) that contained patient laboratory results. 11,844 pages (22.6% of total) contained a callback number with no sender information and 6198 (11.8% of total) contained a callback number and sender information. Trauma pages totaled 10,312 (19.7% of total). There were 2636 pages (5.0% of total) that contained identifying information, potentially violating HIPAA regulations. CONCLUSIONS: The authors have observed a significant number of occurrences in which alphanumeric pages lack sufficient information, do not indicate the urgency of the page, and still require immediate callback by residents. This potentially interrupts patient care and educational activities.

Call for participation in the neurogenetics consortium within the Human Variome Project.

The rate of DNA variation discovery has accelerated the need to collate, store and interpret the data in a standardised coherent way and is becoming a critical step in maximising the impact of discovery on the understanding and treatment of human disease. This particularly applies to the field of neurology as neurological function is impaired in many human disorders. Furthermore, the field of neurogenetics has been proven to show remarkably complex genotype-to-phenotype relationships. To facilitate the collection of DNA sequence variation pertaining to neurogenetic disorders, we have initiated the "Neurogenetics Consortium" under the umbrella of the Human Variome Project. The Consortium's founding group consisted of basic researchers, clinicians, informaticians and database creators. This report outlines the strategic aims established at the preliminary meetings of the Neurogenetics Consortium and calls for the involvement of the wider neurogenetic community in enabling the development of this important resource.

Therapeutic videoconferencing interventions for the treatment of long-term conditions.

We conducted a systematic review of literature relating to videoconferencing in therapeutic interventions for chronic conditions. Two hundred articles were reviewed in detail, 35 of which were relevant to the study. Of these, eight were randomized controlled trials (RCTs) and the remainder were service evaluations, pilot studies and case studies. Two major themes emerged, relating specifically to videoconferencing: clinical outcomes and patient satisfaction. There were 14 studies which measured clinical outcomes of interventions for chronic conditions delivered by videoconferencing. A range of evidence, including four RCTs of high quality, indicates that interventions for a variety of conditions, including psychological and physical, delivered by videoconferencing produce similar outcomes to treatment delivered in-person. Evidence suggests that levels of patient satisfaction with telerehabilitation are high and that the formation of a good therapeutic alliance is possible. Several papers reported that clinical staff showed lower levels of satisfaction in using telerehabilitation than patients. It is feasible to use videoconferencing as a means of delivering therapeutic interventions for people with chronic conditions in rural communities.

Association of NPAS3 exonic variation with schizophrenia.

BACKGROUND: We previously identified the neuronal PAS3 (NPAS3) gene as a candidate gene for schizophrenia. A mother and daughter, both with schizophrenia, were carriers of a translocation, t(9;14)(q34;q13), that disrupts the NPAS3 gene. The gene is located at 14q13, a region implicated in schizophrenia and bipolar disorder in various linkage studies. NPAS3 belongs to the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) transcription factor family, involved in diverse processes including the regulation of cell differentiation and circadian rhythms, and the development and function of the nervous system. METHODS: The 12 exons encoding NPAS3 were sequenced in DNA from individuals with schizophrenia. NPAS3 variants were identified in exons 6 and 12, initially in 12 patients only. These two exons were then sequenced in 83 patients and 83 controls. RESULTS AND CONCLUSION: Three common variants of NPAS3, also found in controls, showed a positive association with schizophrenia (NM_001164749: rs12434716, c.1654G>C, p=0.009; rs10141940, c.2208C>T, p=0.01; rs10142034, c.2262C>G, p=0.01). The c.1654G>C variant, results in an p.Ala552Pro change and may affect NPAS3 protein function directly. Alternatively, the three SNPs may affect the splicing of NPAS3 transcripts, as they are each located within putative exonic splicing enhancer (ESE) motifs (ESEFinder). A c.726C>T variant, identified in three patients, is located in an ESE element and is predicted to reduce the function of the motif. Other variants, identified in controls, included c.2089G>A (p.Gly697Ser) and c.2097T>C. Our identification of potentially defective NPAS3 variants supports recent studies that implicate perturbations in NPAS3 pathways in impaired neurogenesis and psychosis.

Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B.

Wilson disease (WND) is an autosomal recessive disorder resulting from mutation of ATP7B. Transport of copper by ATP7B from the trans-Golgi of hepatocytes into apical membrane-trafficked vesicles for excretion in the bile is the major means of copper elimination from the body. Although copper is an essential nutrient, homeostasis must be carefully maintained. If homeostasis is disrupted, copper can accumulate within the liver, kidney, cornea, and/or brain. The range of organs affected leads to clinical heterogeneity and difficulty in WND diagnosis. Sequencing of ATP7B is an important adjunct for diagnosis but has led to the discovery of many novel missense variants. Although prediction programs are available, functional characterization is essential for determining the consequence of novel variants. We have tested 12 missense variants localized to the ATP loop of ATP7B and compared three predictive programs (SIFT, PolyPhen, and Align-GVGD). We found p.L1043P, p.G1000R, p.G1101R, p.I1102T, p.V1239G, and p.D1267V deleterious; p.G1176E and p.G1287S intermediate; p.E1173G temperature sensitive; p.T991M and p.I1148T mild; and p.R1228T functioning as wild type. We found that SIFT most often agreed with functional data (92%), compared with PolyPhen (83%) and Align-GVGD (67%). We conclude that variants found to negatively affect function likely contribute to the WND phenotype in patients.

A minigene approach for analysis of ATP7B splice variants in patients with Wilson disease.

Wilson disease (WND) is an autosomal recessive condition that results in accumulation of copper in the liver and brain when a membrane bound copper transporter, ATP7B, is defective. ATP7B is expressed in hepatic, brain and kidney cells, and a defect can lead to liver, neurological and renal damage in WND patients. Presentation is variable with a broad range of age of onset and symptoms, and not all biochemical signs used in diagnosis are found in every patient. Therefore, diagnosis by mutation analysis is particularly important. To date, there are approximately 380 probable disease-causing variants in ATP7B, 33 of which are splice site variants that are predicted to affect splicing, based on their location. Few of these splice site variants have been analyzed in vivo. Some exonic variations also have the potential to affect splicing. The aim of this project was to use minigenes for transcript analysis. We have chosen exon 8 as our focus and have cloned a wild-type three-exon minigene into a mammalian expression vector. After transfection, extracted RNA was analyzed by reverse transcription PCR and accurate splicing was detected. This minigene will facilitate the analysis of the numerous potential splice variants identified in exon 8 of ATP7B, with the advantage that patient cell lines are not required for each variant.

A child with terminal 14q deletion syndrome: consideration of genotype-phenotype correlations.

Patients with terminal deletions of chromosome 14 usually share a number of clinical features. The syndrome is thought not to be associated with multiple congenital anomalies. We report on a patient having a terminal deletion of about 3.2 Mb, with the breakpoint in 14q32.32. Multiple health problems led to his early death. By molecular techniques (array comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH)), we identified two previously reported patients with deletions in the terminal part of chromosome 14 of almost exactly the same size and compare the phenotypes of all three children. The phenotype of the current patient is much more severe than the phenotypes of the two patients reported previously. The patients also present different sets of dysmorphic features described previously as characteristic for 14q deletion syndrome. Molecular cytogenetic mapping showed that the breakpoints in all three patients were clustered within a 240 kb interval. The possibility of recurrent breakpoint location in terminal 14q deletion syndrome, as well as detailed characterization of the spectrum of phenotypes associated with the syndrome, will require the investigation of multiple patients with similar deletions in 14q.

New mutations in the Wilson disease gene, ATP7B: implications for molecular testing.

Wilson disease (WND), an autosomal recessive disorder of copper transport with a broad range of genotypic and phenotypic characteristics, results from mutations in the ATP7B gene. ATP7B encodes a copper transporting P-type ATPase involved in the transport of copper into the plasma protein ceruloplasmin, and for excretion of copper from the liver. Defects in ATP7B lead to copper storage in liver, brain and kidney. Mutation analysis was carried out on 300 WND patients of various origins, and new mutations not previously reported were identified: European white (p.L217X, c.918_931, c.1073delG, c.3082_3085delAAGAinsCG, p.V536A, p.S657R, p.A971V, p.T974M, p.Q1004P, p.D1164N, p.E1173G, p.I1230V, p.M1359I, c.2355+4A>G), Sephardic Jewish (p.Q286X), Filipino (p.G1149A), Lebanese (p.R1228T), Japanese (p.D1267V) and Taiwanese (p.A1328T). All but one missense variant have strong evidence for classification as disease-causing mutations. In the patients reported here, we also identified 20 nucleotide substitutions, six not previously reported, which cause silent amino acid changes or intronic changes. Documentation and characterization of all variants is essential for accurate DNA diagnosis in WND because of the wide range of clinical and biochemical variability.

Can the MELD score predict perioperative morbidity for patients with liver cirrhosis undergoing laparoscopic cholecystectomy?

The Model for End Stage Liver Disease (MELD) score is a mortality predictor in patients awaiting liver transplantation. We evaluated the MELD score's ability to predict morbidity for patients with cirrhosis undergoing laparoscopic cholecystectomy. From March 1991 to February 2004, data of all patients undergoing laparoscopic cholecystectomy were prospectively collected. Data of patients with liver cirrhosis were reviewed. The MELD and Child scores were correlated with outcome variables. Of 7859 patients undergoing laparoscopic cholecystectomy, 99 patients (1.3%) exhibited liver cirrhosis, 44 women and 55 men. The mean age was 55 years (range, 28 to 92 years). The mortality rate was 6.3 per cent, morbidity rate 18 per cent, and conversion rate 11 per cent. Laboratory values on 55 patients were available to calculate MELD scores. The mean MELD score was 11 (range, 6 to 23). There was no significant variation in MELD scores with gender (P = 0.61) or cirrhosis etiology, alcoholic and nonalcoholic (P = 0.52). MELD and Child's score correlated well (P < 0.001); however, the risk of complication was not related to the MELD (P = 0.94) or Child-Pugh-Turcotte score (P = 0.26). Morbidity for patients with liver cirrhosis undergoing laparoscopic cholecystectomy remains high. The MELD score is useful for transplant risk stratification for but requires further investigation regarding morbidity prediction for laparoscopic cholecystectomy.

Sequence variation in the ATP-binding domain of the Wilson disease transporter, ATP7B, affects copper transport in a yeast model system.

ATP7B is a copper transporting P-type ATPase defective in the autosomal recessive copper storage disorder, Wilson disease (WND). Functional assessment of variants helps to distinguish normal from disease-causing variants and provides information on important amino acid residues. A total of 11 missense variants of ATP7B, originally identified in WND patients, were examined for their capacity to functionally complement a yeast mutant strain in which the yeast gene ortholog, CCC2, was disrupted. Solution structures of ATP7B domains were used to predict the effects of each variant on ATP7B structure. Three variants lie within the copper-binding domain and eight within the ATP-binding domain of ATP7B. All three ATP7B variants within the copper-binding domain and four within the ATP-binding domain showed full complementation of the yeast ccc2 phenotype. For the remaining four located in the ATP-binding domain, p.Glu1064Lys and p.Val1106Asp were unable to complement the yeast ccc2 high-affinity iron uptake deficiency phenotype, apparently due to mislocalization and/or change in conformation of the variant protein. p.Leu1083Phe exhibited a temperature-sensitive phenotype with partial complementation at 30 degrees C and a severe deficit at 37 degrees C. p.Met1169Val only partially complemented the ccc2 phenotype at 30 degrees C and 37 degrees C. Therefore, four variant positions were identified as important for copper transport and as disease-causing changes. Since the yeast assay specifically evaluates copper transport function, variants with normal transport could be defective in some other aspect of ATP7B function, particularly trafficking in mammalian cells. Functional assessment is critical for reliable use of mutation analysis as an aid to diagnosis of this clinically variable condition.

A child with deletion (14)(q24.3q32.13) and auditory neuropathy.

An interstitial deletion in the middle and distal part of chromosome 14 is a rare chromosomal abnormality characterized by a wide spectrum of phenotypic manifestations. We present a patient with a nearly 20 Mb interstitial deletion of chromosome 14q24.3q32.13 determined by FISH, that is associated with minor dysmorphic features, developmental delay, absent speech and auditory neuropathy. The deleted region contains 130 known genes, among them 48 with reported function or association with human disease. The patient's phenotype is compared with interstitial deletions of the distal part of chromosome 14 reported previously. We hypothesize, that there is (are) a gene (genes) in the 14q32.11-q32.13 that is (are) important for the hearing process and for which haploinsufficiency can cause auditory neuropathy. Several genes in the region, among them calmodulin, chromogranin A, the goosecoid and FOXN3, can contribute to the observed phenotype. Detailed mapping in additional patients with 14q32 deletions and hearing loss could further define the candidate region.