A missense mutation in FIC1 is associated with greenland familial cholestasis

Greenland familial cholestasis is a severe form of intrahepatic cholestasis described among indigenous Inuit families in Greenland. Patients present with jaundice, pruritus, bleeding episodes, and steatorrhea, and die in childhood due to end-stage liver disease. We investigated the possibility that Greenland familial cholestasis is caused by a mutation in FIC1, the gene defective in patients with progressive familial intrahepatic cholestasis type 1 and many cases of benign recurrent intrahepatic cholestasis. Using single-strand conformation polymorphism analysis and sequencing of the FIC1 exons, a missense mutation, 1660 G-->A (D554N), was detected and was shown to segregate with the disease in Inuit patients from Greenland and Canada. Examination of liver specimens from 3 Inuit patients homozygous for this mutation revealed bland canalicular cholestasis and, on transmission electron microscopy, coarsely granular Byler bile, as previously described in patients with progressive familial intrahepatic cholestasis type 1. These data establish Greenland familial cholestasis as a form of progressive familial intrahepatic cholestasis type 1 and further underscore the importance of unimpeded FIC1 activity for normal bile formation.     

A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease

OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.     

Fludarabine-based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with Fanconi anaemia

Eighteen consecutive patients aged 5·5–24 years with Fanconi anaemia and diagnoses of aplastic anaemia ( n  = 8), myelodysplastic syndrome ( n  = 4), acute myeloid leukaemia ( n  = 6), received allogeneic haematopoietic stem cell transplants from alternative donors. All patients had been transfused, 13 had previously been treated with androgens and 14 had a history of infection. Donors were related human leucocyte antigen (HLA) mismatched for eight patients, unrelated HLA mismatched for seven patients and unrelated HLA matched for three patients. Cytoreduction included single dose total body irradiation (450 cGy), fludarabine (150 mg/m²) and cyclophosphamide (40 mg/kg). Immunosuppression included antithymocyte globulin and tacrolimus. Grafts were granulocyte colony-stimulating factor-mobilized, CD34⁺ T-cell-depleted peripheral blood stem cells in 15 patients and T-cell-depleted marrows in three. All 18 patients engrafted with 100% donor chimaerism; only one patient developed graft-versus-host disease (GVHD). With a median follow-up of 4·2 years, 13/18 patients were alive, 12 of these were disease-free. Five-year overall survival and disease-free survival were 72·2% and 66·6% respectively. Immune reconstitution was achieved at approximately 6 months post-transplant for most patients. These are encouraging results of T-cell-depleted transplants from alternative donors using fludarabine-based cytoreduction in 18 high-risk patients with Fanconi anaemia, with no evidence of rejection and minimal GVHD.     

Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts

OBJECTIVEWe evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes.RESEARCH DESIGN AND METHODSWe prospectively followed 76,530 women in the Nurses’ Health Study (NHS) (1986–2012), 81,569 women in NHS II (1991–2017), and 34,468 men in the Health Professionals Follow-up Study (1986–2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis.RESULTSWe documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12–23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7–9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0–35.6% of the associations between changes in PDI and hPDI and diabetes risk.CONCLUSIONSImproving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.     

How doctors move from generic goals to specific communicative behavior in real practice consultations

Objective

To understand how recommendations for communication can be brought into alignment with clinical communication routines, we explored how doctors select communicative actions during consultations.

Methods

We conducted stimulated recall interviews with 15 GPs (general practitioners), asking them to comment on recordings of two consultations. The data analysis was based on the principles of grounded theory.

Results

A model describing how doctors select communicative actions during consultations was developed. This model illustrates how GPs constantly adapt their selection of communicative actions to their evaluation of the situation. These evaluations culminate in the selection of situation-specific goals. These multiple and often dynamic goals require constant revision and adaptation of communication strategies, leading to constant readjustments of the selection of communicative actions. When selecting consultation goals GPs weigh patients’ needs and preferences as well as the medical situation and its consequences.

Conclusions

GPs’ selection of communicative actions during consultations is situational and goal driven.

Practice implications

To help doctors develop communicative competence tailored to the specific situation of each consultation, holistic communication training courses, which pay attention to the selection of consultation goals and matching communication strategies besides training specific communication skills, seem preferable to current generic communication skills training.     

“Many miles to go …”: a systematic review of the implementation of patient decision support interventions into routine clinical practice

Background

Two decades of research has established the positive effect of using patient-targeted decision support interventions: patients gain knowledge, greater understanding of probabilities and increased confidence in decisions. Yet, despite their efficacy, the effectiveness of these decision support interventions in routine practice has yet to be established; widespread adoption has not occurred. The aim of this review was to search for and analyze the findings of published peer-reviewed studies that investigated the success levels of strategies or methods where attempts were made to implement patient-targeted decision support interventions into routine clinical settings.

Methods

An electronic search strategy was devised and adapted for the following databases: ASSIA, CINAHL, Embase, HMIC, Medline, Medline-in-process, OpenSIGLE, PsycINFO, Scopus, Social Services Abstracts, and the Web of Science. In addition, we used snowballing techniques. Studies were included after dual independent assessment.

Results

After assessment, 5322 abstracts yielded 51 articles for consideration. After examining full-texts, 17 studies were included and subjected to data extraction. The approach used in all studies was one where clinicians and their staff used a referral model, asking eligible patients to use decision support. The results point to significant challenges to the implementation of patient decision support using this model, including indifference on the part of health care professionals. This indifference stemmed from a reported lack of confidence in the content of decision support interventions and concern about disruption to established workflows, ultimately contributing to organizational inertia regarding their adoption.

Conclusions

It seems too early to make firm recommendations about how best to implement patient decision support into routine practice because approaches that use a ‘referral model’ consistently report difficulties. We sense that the underlying issues that militate against the use of patient decision support and, more generally, limit the adoption of shared decision making, are under-investigated and under-specified. Future reports from implementation studies could be improved by following guidelines, for example the SQUIRE proposals, and by adopting methods that would be able to go beyond the ‘barriers’ and ‘facilitators’ approach to understand more about the nature of professional and organizational resistance to these tools. The lack of incentives that reward the use of these interventions needs to be considered as a significant impediment.

     

Imaging the Intracranial Atherosclerotic Vessel Wall Using 7T MRI: Initial Comparison with Histopathology

BACKGROUND AND PURPOSE:Several studies have attempted to characterize intracranial atherosclerotic plaques by using MR imaging sequences. However, dedicated validation of these sequences with histology has not yet been performed. The current study assessed the ability of ultra-high-resolution 7T MR imaging sequences with different image contrast weightings to image plaque components, by using histology as criterion standard.MATERIALS AND METHODS:Five specimens of the circle of Wills were imaged at 7T with 0.11 × 0.11 mm in-plane-resolution proton attenuation–, T1-, T2-, and T2*-weighted sequences (through-plane resolution, 0.11–1 mm). Tissue samples from 13 fiducial-marked locations (per specimen) on MR imaging underwent histologic processing and atherosclerotic plaque classification. Reconstructed MR images were matched with histologic sections at corresponding locations.RESULTS:Forty-four samples were available for subsequent evaluation of agreement or disagreement between plaque components and image contrast differences. Of samples, 52.3% (n = 23) showed no image contrast heterogeneity; this group comprised solely no lesions or early lesions. Of samples, 25.0% (n = 11, mostly advanced lesions) showed good correlation between the spatial organization of MR imaging heterogeneities and plaque components. Areas of foamy macrophages were generally seen as proton attenuation–, T2-, and T2*- hypointense areas, while areas of increased collagen content showed more ambiguous signal intensities. Five samples showed image-contrast heterogeneity without corresponding plaque components on histology; 5 other samples showed contrast heterogeneity based on intima-media artifacts.CONCLUSIONS:MR imaging at 7T has the image contrast capable of identifying both focal intracranial vessel wall thickening and distinguishing areas of different signal intensities spatially corresponding to plaque components within more advanced atherosclerotic plaques.

Intracranial atherosclerosis is emerging as one of the main causes of cerebral ischemic stroke and transient ischemic attack, with a high risk of recurrent ischemic events.¹ In recent years, several MR imaging sequences have been developed on 3T and 7T field strengths that specifically visualize the intracranial arterial vessel wall, enabling direct assessment of intracranial atherosclerotic plaques.^2–8 Similar to studies of carotid artery atherosclerosis almost a decade ago, several studies have recently attempted to characterize intracranial plaque components, such as intraplaque hemorrhage,^9,10 fibrous cap,¹¹ and lipid components, by using MR imaging.^12,13For the carotid arteries, much research has already been done validating image signal heterogeneity within the vessel wall with histology, the criterion standard.^14–20 Imaging carotid artery atherosclerosis has the advantage of easy access to ex vivo atherosclerotic plaque material for validation, using carotid endarterectomy specimens. It is now possible to image calcification, fibrous cap, intraplaque hemorrhage, and lipid-rich necrotic core in the carotid artery with moderate-to-good sensitivity and specificity by using multicontrast MR imaging.²⁰ Although 1 recent study showed promising preliminary results of plaque characterization by using a combined T1- and T2-weighted sequence²¹ compared with histology, dedicated validation with histology of intracranial vessel wall sequences with multiple image contrast weightings has not yet been performed. Therefore, whether MR imaging with multiple image contrast weightings has enough image contrast to also visualize various intracranial atherosclerotic plaque components remains a question.Validation of MR images with histology for intracranial atherosclerosis in vivo is much more cumbersome compared with carotid plaques, because no therapies (comparable with carotid endarterectomy) exist in which intracranial atherosclerotic plaques are removed. Furthermore, intracranial arteries are smaller than carotid (or other major peripheral) arteries,²² necessitating a high spatial resolution, and therefore high SNR, for plaque visualization. Because the SNR increases approximately linearly with field strength, 7T MR imaging might provide the spatial resolution necessary to image small atherosclerotic plaques.²² Furthermore, several dedicated intracranial vessel wall sequences at 7T have already shown promising results in the visualization of vessel wall lesions in vivo.In this feasibility study, ultra-high-resolution 7T MR imaging sequences with different image contrast weightings were developed and used in an ex vivo setting, to assess the ability (image contrast) of 7T MR imaging to image different intracranial atherosclerotic plaque components. For validation of our findings, results were compared with histology.     

Characterization of mutations in ATP8B1 associated with hereditary cholestasis

Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are clinically distinct hereditary disorders. PFIC patients suffer from chronic cholestasis and develop liver fibrosis. BRIC patients experience intermittent attacks of cholestasis that resolve spontaneously. Mutations in ATP8B1 (previously FIC1) may result in PFIC or BRIC. We report the genomic organization of ATP8B1 and mutation analyses of 180 families with PFIC or BRIC that identified 54 distinct disease mutations, including 10 mutations predicted to disrupt splicing, 6 nonsense mutations, 11 small insertion or deletion mutations predicted to induce frameshifts, 1 large genomic deletion, 2 small inframe deletions, and 24 missense mutations. Most mutations are rare, occurring in 1-3 families, or are limited to specific populations. Many patients are compound heterozygous for 2 mutations. Mutation type or location correlates overall with clinical severity: missense mutations are more common in BRIC (58% vs. 38% in PFIC), while nonsense, frameshifting, and large deletion mutations are more common in PFIC (41% vs. 16% in BRIC). Some mutations, however, lead to a wide range of phenotypes, from PFIC to BRIC or even no clinical disease. ATP8B1 mutations were detected in 30% and 41%, respectively, of the PFIC and BRIC patients screened.     

It's LiFe! Mobile and Web-Based Monitoring and Feedback Tool Embedded in Primary Care Increases Physical Activity: A Cluster Randomized Controlled Trial

BackgroundPhysical inactivity is a major public health problem. The It’s LiFe! monitoring and feedback tool embedded in the Self-Management Support Program (SSP) is an attempt to stimulate physical activity in people with chronic obstructive pulmonary disease or type 2 diabetes treated in primary care.ObjectiveOur aim was to evaluate whether the SSP combined with the use of the monitoring and feedback tool leads to more physical activity compared to usual care and to evaluate the additional effect of using this tool on top of the SSP.MethodsThis was a three-armed cluster randomised controlled trial. Twenty four family practices were randomly assigned to one of three groups in which participants received the tool + SSP (group 1), the SSP (group 2), or care as usual (group 3). The primary outcome measure was minutes of physical activity per day. The secondary outcomes were general and exercise self-efficacy and quality of life. Outcomes were measured at baseline after the intervention (4-6 months), and 3 months thereafter.ResultsThe group that received the entire intervention (tool + SSP) showed more physical activity directly after the intervention than Group 3 (mean difference 11.73, 95% CI 6.21-17.25; P<.001), and Group 2 (mean difference 7.86, 95% CI 2.18-13.54; P=.003). Three months after the intervention, this effect was still present and significant (compared to Group 3: mean difference 10.59, 95% CI 4.94-16.25; P<.001; compared to Group 2: mean difference 9.41, 95% CI 3.70-15.11; P<.001). There was no significant difference in effect between Groups 2 and 3 on both time points. There was no interaction effect for disease type.ConclusionsThe combination of counseling with the tool proved an effective way to stimulate physical activity. Counseling without the tool was not effective. Future research about the cost-effectiveness and application under more tailored conditions and in other target groups is recommended.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01867970","term_id":"NCT01867970"}}NCT01867970, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01867970","term_id":"NCT01867970"}}NCT01867970 (archived by WebCite at http://www.webcitation.org/6a2qR5BSr).