Author Correction: Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cognitive behavioural therapy for insomnia (CBTi) as a treatment for tinnitus-related insomnia: protocol for a randomised controlled trial.

BACKGROUND: A significant proportion of patients with chronic tinnitus report clinical levels of sleep disturbance (insomnia). Despite the significant health and functioning implications of this, no rigorous trials have investigated treatments that target tinnitus-related insomnia. This is the first randomised controlled trial evaluating Cognitive Behavioural Therapy for insomnia (CBTi) in tinnitus compared with other psychological treatments. METHODS/DESIGN: The study will test the efficacy of group CBTi as a treatment for tinnitus-related insomnia in a single-centre randomised controlled trial. Participants will be 102 patients with chronic, clinically significant tinnitus and insomnia in the absence of organic sleep disorders. Participants will be randomised to one of three intervention arms: six sessions of CBTi or six sessions of sleep support group or two sessions of audiologically based care. The primary outcomes will be changes in sleep as measured on the Insomnia Severity Index and key outcomes on a 2-week sleep diary (sleep efficiency and total sleep time). Outcomes will be collected 3, 10, 14 and 34 weeks post-randomisation. Secondary measures include sleep quality, sleep beliefs, tinnitus severity, psychological distress and quality of life. A sub-sample of participants will provide two weeks of actigraphy data at the same time points. Data on satisfaction and treatment experience will be collected at 10 and 34 weeks post-randomisation from all participants. DISCUSSION: Findings from the study will be submitted to a peer-reviewed journal. It is anticipated that findings may inform future clinical practice in the treatment of tinnitus-related insomnia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03386123. Retrospectively registered on 29 December 2017.

Widespread prevalence of a CREBRF variant amongst Maori and Pacific children is associated with weight and height in early childhood.

OBJECTIVE: Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with body mass index in Samoans. METHODS: A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Maori, Pacific, European and Asian individuals in the cohort. RESULTS: We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Maori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129). CONCLUSIONS: We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.

A Feasibility Study of High-Strength Bi-2223 Conductor for High-Field Solenoids.

We performed a feasibility study on a high-strength Bi2-x Pb x Sr2Ca2Cu3O10-x (Bi-2223) tape conductor for high-field solenoid applications. The investigated conductor, DI-BSCCO Type HT-XX, is a pre-production version of Type HT-NX, which has recently become available from Sumitomo Electric Industries (SEI). It is based on their DI-BSCCO Type H tape, but laminated with a high-strength Ni-alloy. We used stress-strain characterizations, single- and double-bend tests, easy- and hard-way bent coil-turns at various radii, straight and helical samples in up to 31.2 T background field, and small 20-turn coils in up to 17 T background field to systematically determine the electro-mechanical limits in magnet-relevant conditions. In longitudinal tensile tests at 77 K, we found critical stress- and strain-levels of 516 MPa and 0.57%, respectively. In three decidedly different experiments we detected an amplification of the allowable strain with a combination of pure bending and Lorentz loading to ≥ 0.92% (calculated elastically at the outer tape edge). This significant strain level, and the fact that it is multi-filamentary conductor and available in the reacted and insulated state, makes DI-BSCCO HT-NX highly suitable for very high-field solenoids, for which high current densities and therefore high loads are required to retain manageable magnet dimensions.

Regulation of IL-12p40 by HIF controls Th1/Th17 responses to prevent mucosal inflammation.

Intestinal inflammatory lesions are inherently hypoxic, due to increased metabolic demands created by cellular infiltration and proliferation, and reduced oxygen supply due to vascular damage. Hypoxia stabilizes the transcription factor hypoxia-inducible factor-1α (HIF) leading to a coordinated induction of endogenously protective pathways. We identified IL12B as a HIF-regulated gene and aimed to define how the HIF-IL-12p40 axis influenced intestinal inflammation. Intestinal lamina propria lymphocytes (LPL) were characterized in wild-type and IL-12p40-/- murine colitis treated with vehicle or HIF-stabilizing prolyl-hydroxylase inhibitors (PHDi). IL12B promoter analysis was performed to examine hypoxia-responsive elements. Immunoblot analysis of murine and human LPL supernatants was performed to characterize the HIF/IL-12p40 signaling axis. We observed selective induction of IL-12p40 following PHDi-treatment, concurrent with suppression of Th1 and Th17 responses in murine colitis models. In the absence of IL-12p40, PHDi-treatment was ineffective. Analysis of the IL12B promoter identified canonical HIF-binding sites. HIF stabilization in LPLs resulted in production of IL-12p40 homodimer which was protective against colitis. The selective induction of IL-12p40 by HIF-1α leads to a suppression of mucosal Th1 and Th17 responses. This HIF-IL12p40 axis may represent an endogenously protective mechanism to limit the progression of chronic inflammation, shifting from pro-inflammatory IL-12p70 to an antagonistic IL-12p40 homodimer.

Thymosin ß4: Roles in Development, Repair, and Engineering of the Cardiovascular System.

The burden of cardiovascular disease is a growing worldwide issue that demands attention. While many clinical trials are ongoing to test therapies for treating the heart after myocardial infarction (MI) and heart failure, there are few options doctors able to currently give patients to repair the heart. This eventually leads to decreased ventricular contractility and increased systemic disease, including vascular disorders that could result in stroke. Small peptides such as thymosin ß4 (Tß4) are upregulated in the cardiovascular niche during fetal development and after injuries such as MI, providing increased neovasculogenesis and paracrine signals for endogenous stem cell recruitment to aid in wound repair. New research is looking into the effects of in vivo administration of Tß4 through injections and coatings on implants, as well as its effect on cell differentiation. Results so far demonstrate Tß4 administration leads to robust increases in angiogenesis and wound healing in the heart after MI and the brain after stroke, and can differentiate adult stem cells toward the cardiac lineage for implantation to the heart to increase contractility and survival. Future work, some of which is currently in clinical trials, will demonstrate the in vivo effect of these therapies on human patients, with the goal of helping the millions of people worldwide affected by cardiovascular disease.

Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model.

B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora.

A multidisciplinary, biopsychosocial treatment for non-cardiac chest pain.

BACKGROUND: Non-cardiac chest pain (NCCP) affects up to 80% of patients attending chest pain clinics, but its treatment is suboptimal. AIM: To describe the outcomes of a pilot, stepped care, biopsychosocial management programme in terms of improvements in chest pain, psychosocial scores and use of healthcare resources. METHODS: Of 198 referrals, 77 patients were suitable for the clinic and received a one hour biopsychosocial assessment. Stepped care consisted of assessment only, low intensity Cognitive Behaviour Therapy (CBT), or high intensity CBT. RESULTS: The proportion with pain occurring more than once monthly fell from 100% at baseline to 61% at 3 months (p < 0.001). Pain interference reduced significantly (p < 0.001) from 5.9 [SD 2.2] at baseline to 3.2 [SD 2.6] at 3 months. Depression scores improved from a mean 8.8 to 5.4 (p < 0.05) and anxiety from 6.9 to 4.6 (p < 0.05). Use of healthcare resources improved with a fall in consultations for chest pain over 6 months from a mean 2.6 to 0.1 (p < 0.05). The impact on work and social functioning reduced from 10.4 [SD 10.4] to 3.9 [SD 7.5]: [t (70) = 6.3, p < 0.001). Further improvements occurred at 6 months for chest pain frequency (which fell to 51%, p = 0.003), interference (2.6 [SD 2.1], p < 0.05) and avoidance of exercise (p = 0.03). Otherwise improvements were maintained between 3 and 6 months. CONCLUSION: A stepped-care biopsychosocial approach to NCCP is effective in reducing chest pain frequency and improving behaviour and wellbeing. It can be delivered in part by a nurse allowing integration into any chest pain clinic.

The rapid access chest pain clinic: unmet distress and disability.

AIMS: To determine the characteristics, clinical needs and level of health-care use of patients with non-cardiac (NCCP) and cardiac-chest pain (CCP) attending a Rapid Access Chest Pain Clinic in an inner-London Hospital. METHODS: A cross-sectional comparison of NCCP and CCP patients on measures of pain, mood, beliefs, somatic symptoms and use of services completed by patients attending the Rapid Access Chest Pain Clinic over an 18-month period. RESULTS: There were no significant differences between NCCP and CCP patients in terms of chest pain frequency, duration or severity or associated distress; however, NCCP were younger (53 vs. 60, OR = 1.05) and reported 'atypical' pain more frequently (82% vs. 50%, OR = 3.72). The NCCP group reported more panic-type beliefs about chest pain (5.8 vs. 4.3, P < 0.05) and lower 'illness coherence' (a patient's belief that the illness 'makes sense') (3.5 vs. 4.7, P < 0.05). Anxiety and depression scores were similar in both groups. Both groups had similar levels of health-care use but patients with NCCP saw more types of health-care worker (mean 1.7) than those with CCP (mean 1.4, P < 0.05). CONCLUSION: Patients with NCCP are as disabled and distressed as patients with CCP however current services fail to meet their needs. We suggest that a biopsychosocial approach should be explored.

[Clinical and electrophysiological and molecular genetic characteristics of the course of relapsing-remitting multiple sclerosis].

In order to study specific features of remitting multiple sclerosis patients with different genotypes of polymorphic loci rs1800629 gene TNFα, rs6074022 gene CD40, rs10492972 gene KIF1B, rs187238 IL-18 gene, conducted clinical and electrophysiological examination of 149 patients with relapsing-remitting multiple sclerosis. Found that the most common symptoms of rapidly progressive relapsing-remitting multiple sclerosis were cerebellar and sensory disorders. Severity of pyramidal and cerebellar, stem, pelvic disorders, and thus the value of EDSS score was significantly higher in the group of patients with recurrent exacerbations during the year. Intensity changes of latencies of peaks I, III of short-stem evoked potentials and central motor conduction time determined by the ball on a scale EDSS. Genotype C/C polymorphism rs187238 locus IL-18 gene associated with frequent exacerbations of relapsing-remitting multiple sclerosis, high speed of progression of the disease and is characterized by marked changes in latency of peak V ABR and VEP P100. With polymorphic locus allele rs187238 IL-18 is associated with more frequent exacerbations PPC (OR=1.714 (1.051-2.797); p=0.02), and increases the risk of rapidly progressive nature of the disease in a 2-fold (OR=2.040 (1.140-3.650) p=0.015).

Spinal cord intramedullary cavernoma: A case report.

BACKGROUND: Spinal Cord Intramedullary Cavernoma is a rare disease. It is a vascular disorder composed of capillary-liked vessels without intervening neurons within a spinal lesion. It may only be discovered incidentally or may be diagnosed after a neurologic deficit. Patients may present with weakness which could mimic other neurologic pathology. CASE: A case of a 65 year old with history of hypertension and diabetes mellitus. He had previous microdissectomy of the lumbar L4-L5 disc. He presented with progressive lower leg paresis, urinary retention and obstipation. An MRI revealed a cavernous angioma at the T5 level. CONCLUSION: A multitude of neurologic deficits could lead to a patient presenting with a Spinal Cord Cavernoma. Prompt imaging is warranted in cases presenting with the symptoms to allow appropriate diagnoses and treatment. The clinician must be aware of this rare, but debilitating disease complex.

Non-cardiac chest pain: time to extend the rapid access chest pain clinic?

Non-cardiac chest pain is common. It has a low risk of coronary events, but causes considerable physical and social disability and inappropriate health-care usage. It is a heterogeneous condition, which may be caused by or associated with gastro-oesophageal, musculoskeletal or psychiatric abnormalities and sustained by psychological factors including catastrophisation, avoidance behaviour and abnormal help-seeking. These may coexist and their relative contributions may vary in different patients or at different times in an individual patient. The absence of a unitary cause probably explains why treatment studies show only moderate success. An individualised biopsychosocial approach takes account of all causative and sustaining processes and has been shown to work in pain syndromes at other sites. We suggest that this approach should be tried for chest pain using a multidisciplinary clinic model including cardiologists, psychologists and nurses linked with a Rapid Access Chest Pain Clinic.

Intrusions in trauma and psychosis: information processing and phenomenology.

BACKGROUND: Intrusions are common symptoms of both post-traumatic stress disorder (PTSD) and schizophrenia. It has been suggested that an information processing style characterized by weak trait contextual integration renders psychotic individuals vulnerable to intrusive experiences. This 'contextual integration hypothesis' was tested in individuals reporting anomalous experiences in the absence of a need for care. METHOD: Twenty-six low schizotypes and 23 individuals reporting anomalous experiences were shown a traumatic film with and without a concurrent visuospatial task (VST). Participants rated post-traumatic intrusions for frequency and form, and completed self-report measures of information processing style. It was predicted that, because of their weaker trait contextual integration, the anomalous experiences (AE) group would (1) exhibit more intrusions following exposure to the trauma film, (2) display intrusions characterized by more PTSD qualities and (3) show a greater reduction of intrusions with the concurrent VST. RESULTS: As predicted, the AE group reported a lower level of trait contextual integration and more intrusions than the low schizotypes, both immediately after watching the film and during the following 7 days. Their post-traumatic intrusive memories were more PTSD-like (more intrusive, vivid and associated with emotion). The VST had no effect on the number of intrusions in either group. CONCLUSIONS: These findings provide some support for the proposal that weak trait contextual integration underlies the development of intrusions within both PTSD and psychosis.

Knowledge, attitudes and behaviours associated with the provision of hepatitis C care by Canadian family physicians.

The role of primary care physicians in providing care for hepatitis C virus (HCV) infection is increasingly emphasized, but many gaps and challenges remain. This study explores family physicians' knowledge, attitudes and practices associated with providing care for HCV infection. Seven hundred and forty-nine members of the College of Family Physicians of Canada (CFPC) completed a self-administered survey examining knowledge, attitudes and behaviours regarding HCV infection screening and care. Multivariate analyses were performed using the outcome, HCV care provision, and variables based on a conceptual model of practice guideline adherence. Family physicians providing basic-advanced HCV care were more likely to be older, practice in a rural setting, have injection drug users (IDU) in their practice and have higher levels of knowledge about the initial assessment (OR = 1.77; 95% CI = 1.23-2.54) and treatment of HCV (OR = 1.74; 95% CI = 1.24-2.43). They were also less likely to believe that family physicians do not have a role in HCV care (OR = 0.41; 95% CI = 0.30-0.58). Educational programmes should target physicians less likely to provide HCV care, namely family physicians practicing in urban areas and those who do not care for any IDU patients. Training and continuing medical education programmes that aim to shift family physicians' attitudes about the provision of HCV care by promoting their roles as integral to HCV care could contribute to easing the burden on consultant physicians and lead to improved access to treatment for HCV infection.

Acidification and urine calcium: is it a preanalytical necessity?

BACKGROUND: It has been suggested that for the accurate measurement of calcium in urine, samples must be collected into bottles containing acid. Acidification poses risks to both patients and laboratory staff. Here we reappraise whether acidification is a preanalytical necessity. METHODS: Twenty-four-hour urine samples were collected from 133 patients into bottles without acid or preservatives. In a subset of 29 patients, 10 mL aliquots were prepared to test the effect on urine calcium of 0.1, 1.0 and 5.0 mol/L hydrochloric acid (HCl). Calcium was then measured immediately after acidification, after 12 h and seven days storage at 4 degrees C. In a separate study, urine calcium concentrations in paired control (non-acidified) and acidified (with 5 mol/L HCl) samples were compared in 133 patients. When available, we recorded the time from start of urine collection to time of analysis. Calcium was measured using the cresolphthalein complexone colorimetric endpoint assay on the Roche Modular system. RESULTS: There was no significant difference in the calcium concentration in the 29 cases studied between the varying acid concentrations tested compared with non-acidified urine (P = 0.987). Overall, in 133 patients there was no difference between control and acidified samples (P = 0.888). We found no correlation between basal urine pH and urine calcium at all time points studied. CONCLUSIONS: Our results suggest that the acidification of urine samples is not a preanalytical necessity for the measurement of urine calcium.

Re-engineering the target specificity of Clostridial neurotoxins - a route to novel therapeutics.

The ability to chemically couple proteins to LH(N)-fragments of clostridial neurotoxins and create novel molecules with selectivity for cells other than the natural target cell of the native neurotoxin is well established. Such molecules are able to inhibit exocytosis in the target cell and have the potential to be therapeutically beneficial where secretion from a particular cell plays a causative role in a disease or medical condition. To date, these molecules have been produced by chemical coupling of the LH(N)-fragment and the targeting ligand. This is, however, not a suitable basis for producing pharmaceutical agents as the products are ill defined, difficult to control and heterogeneous. Also, the molecules described to date have targeted neuroendocrine cells that are susceptible to native neurotoxins, and therefore the benefit of creating a molecule with a novel targeting domain has been limited. In this paper, the production of a fully recombinant fusion protein from a recombinant gene encoding both the LH(N)-domain of a clostridial neurotoxin and a specific targeting domain is described, together with the ability of such recombinant fusion proteins to inhibit secretion from non-neuronal target cells. Specifically, a novel protein consisting of the LH(N)-domains of botulinum neurotoxin type C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

Defining scholarship at the Uniformed Services University of the Health Sciences School of Medicine: A study in cultures.

Medical schools' long-awaited recognition of the varied contributions of their faculty has caused active dialogue and debate. The discourse centers on the best approach for incorporating a broader definition of scholarship, including professional service, into the traditional promotion and tenure processes. At the School of Medicine of the Uniformed Services University of the Health Sciences (USUHS), the majority of the clinical faculty also serve as active-duty uniformed medical officers, and the subject of how to appropriately recognize their varied contributions has long been contended. Concerns have been raised from all constituent groups that broadening the definition of scholarship at the USUHS has the potential to lower the standards of the academy and thus devalue faculty positions. The USUHS has viewed this challenge as a study in the integration of cultures. Institutional cultures include those of the academy, the military, government, basic science, and clinical science, and all the resulting permutations. A nine-year review of scholarship, promotion, and tenure at the USUHS has resulted in a document that supports the diverse missions of the university and appropriately rewards the accomplishments of its faculty. The dialogue continues, as the new document is subject to continuing review and ongoing critical analysis.