An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

Background: Our previous array, the Comparative Genomic Hybridisation design (CGH-array) for nemaline myopathy (NM), named the NM-CGH array, revealed pathogenic copy number variation (CNV) in the genes for nebulin (NEB) and tropomyosin 3 (TPM3), as well as recurrent CNVs in the segmental duplication (SD), i.e. triplicate, region of NEB (TRI, exons 82-89, 90-97, 98-105). In the light of this knowledge, we have designed and validated an extended CGH array, which includes a selection of 187 genes known to cause neuromuscular disorders (NMDs). Objective: Our aim was to develop a reliable method for CNV detection in genes related to neuromuscular disorders for routine mutation detection and analysis, as a much-needed complement to sequencing methods. Methods: We have developed a novel custom-made 4×180 k CGH array for the diagnostics of NMDs. It includes the same tiled ultra-high density coverage of the 12 known or putative NM genes as our 8×60 k NM-CGH-array but also comprises a selection of 175 additional genes associated with NMDs, including titin (TTN), at a high to very high coverage. The genes were divided into three coverage groups according to known and potential pathogenicity in neuromuscular disorders. Results: The array detected known and putative CNVs in all three gene coverage groups, including the repetitive regions of NEB and TTN. Conclusions: The targeted neuromuscular disorder 4×180 k array-CGH (NMD-CGH-array v1.0) design allows CNV detection for a broader spectrum of neuromuscular disorders at a high resolution. © 2018 - IOS Press and the authors. All rights reserved.Peer reviewe

An inventory of collaborative medication reviews for older adults-evolution of practices

Background Collaborative medication review (CMR) practices for older adults are evolving in many countries. Development has been under way in Finland for over a decade, but no inventory of evolved practices has been conducted. The aim of this study was to identify and describe CMR practices in Finland after 10 years of developement. Methods An inventory of CMR practices was conducted using a snowballing approach and an open call in the Finnish Medicines Agency's website in 2015. Data were quantitatively analysed using descriptive statistics and qualitatively by inductive thematic content analysis. Clyne et al's medication review typology was applied for evaluating comprehensiveness of the practices. Results In total, 43 practices were identified, of which 22 (51%) were designed for older adults in primary care. The majority (n = 30, 70%) of the practices were clinical CMRs, with 18 (42%) of them being in routine use. A checklist with criteria was used in 19 (44%) of the practices to identify patients with polypharmacy (n = 6), falls (n = 5), and renal dysfunction (n = 5) as the most common criteria for CMR. Patients were involved in 32 (74%) of the practices, mostly as a source of information via interview (n = 27, 63%). A medication care plan was discussed with the patient in 17 practices (40%), and it was established systematically as usual care to all or selected patient groups in 11 (26%) of the practices. All or selected patients' medication lists were reconciled in 15 practices (35%). Nearly half of the practices (n = 19, 44%) lacked explicit methods for following up effects of medication changes. When reported, the effects were followed up as a routine control (n = 9, 21%) or in a follow-up appointment (n = 6, 14%). Conclusions Different MRs in varying settings were available and in routine use, the majority being comprehensive CMRs designed for primary outpatient care and for older adults. Even though practices might benefit from national standardization, flexibility in their customization according to context, medical and patient needs, and available resources is important.Peer reviewe

Transverse myocutaneous gracilis flap reconstruction is feasible after pelvic exenteration : 12-year surgical and oncological results

Introduction: Pelvic exenteration (PE) is the only curative treatment for certain locally advanced intrapelvic malignancies. PE has high morbidity, and optimal reconstruction of the pelvic floor remains undetermined. Materials and methods: A retrospective chart review was performed at a tertiary university center to assess the surgical and oncological outcomes of 39 PE procedures over a 12-year period. The majority of patients (n = 25) underwent transverse musculocutaneous gracilis (TMG) flap reconstruction for pelvic floor reconstruction. Results: The 1- and 5-year overall survival (OS) was 72% (95%CI 58%-86%) and 48% (95%CI 31%-65%), respectively. In multivariate analysis, lymph node metastasis (HR 3.070, p = 0.024) and positive surgical margins (HR 3.928, p = 0.009) were risk factors for OS. In this population, 71.8% of the patients had at least one complication. The complication rate was 65.4% and 84.6% for patients with versus without flap reconstruction, respectively (p = 0.191). The length of stay was longer for patients with a major complication 16,0 +/- 5,9 days vs. 29,4 +/- 14,8 days, p = 0.001, but complications did not affect OS. Conclusion: For selected patients, PE is a curative option for locally advanced, residual, or recurrent intrapelvic tumors. Pelvic floor and vulvovaginal defects can reliably be reconstructed using TMG flaps. TMG flaps are favored in our institution over abdominal-based flaps because the donor site morbidity is reasonable and TMG does not interfere with enterostomy. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.Peer reviewe

Community Pharmacists' Contribution to Medication Reviews for Older Adults : A Systematic Review

ObjectivesTo identify medication review interventions for older adults that involve community pharmacists and evidence of outcomes of these interventions. DesignSystematic review. MeasurementsCinahl, MEDLINE (Ovid), Scopus, International Pharmaceutical Abstracts, and Cochrane Library were searched for articles published between January 2000 and February 2016. Articles involving community pharmacists in medication reviews for outpatients aged 65 and older were included. Evidence of economic, clinical, and humanistic outcomes of interventions was summarized. ResultsSixteen articles were found that described 12 medication review interventions, of which 6 were compliance and concordance reviews, 4 were clinical medication reviews, and 2 were prescription reviews according to a previously developed typology. Community pharmacists' contributions to reviewing medications varied from sending the dispensing history to other healthcare providers to comprehensive involvement in medication management. The most commonly assessed outcomes of the interventions were medication changes leading to reduction in actual or potential drug-related problems (n=12) and improved adherence (n=5). ConclusionRegardless of community pharmacists' contributions to interventions, medication review interventions seem to reduce drug-related problems and increase medication adherence. More well-designed, rigorous studies with more sensitive and specific outcomes measures need to be conducted to assess the effect of community pharmacists' contributions to reviewing medications and improving the health of older adults.Peer reviewe

Clinical results and quality of life after reconstruction following sacrectomy for primary bone malignancy

Background: Sacrectomy is a rare and demanding surgical procedure that results in major soft tissue defects and spinopelvic discontinuity. No consensus is available on the optimal reconstruction algorithm. Therefore, the present study evaluated the results of sacrectomy reconstruction and its impact on patients' quality of life (QOL). Methods: A retrospective chart review was conducted for 21 patients who underwent sacrectomy for a primary bone tumour. Patients were divided into groups based on the timing of reconstruction as follows: no reconstruction, immediate reconstruction or delayed reconstruction. QOL was measured using the EQ-5D instrument before and after surgery in patients treated in the intensive care unit. Results: The mean patient age was 57 (range 22-81) years. The most common reconstruction was gluteal muscle flap (n =9) and gluteal fasciocutaneous flap (n = 4). Four patients required free-tissue transfer, three latissimus dorsi flaps and one vascular fibula bone transfer. No free flap losses were noted. The need for unplanned re-operations did not differ between groups (p =0.397), and no significant differences were found for pre- and post-operative QOL or any of its dimensions. Discussion: Free flap surgery is reliable for reconstructing the largest sacrectomy defects. Even in the most complex cases, surgery can be safely staged, and final reconstruction can be carried out within 1 week of resection surgery without increasing peri-operative complications. Sacrectomy does not have an immoderate effect on the measured QOL. (C) 2018 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer

Peer reviewe

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

E-health: Determinants, opportunities, challenges and the way forward for countries in the WHO African Region

BACKGROUND: The implementation of the 58(th )World Health Assembly resolution on e-health will pose a major challenge for the Member States of the World Health Organization (WHO) African Region due to lack of information and communications technology (ICT) and mass Internet connectivity, compounded by a paucity of ICT-related knowledge and skills. The key objectives of this article are to: (i) explore the key determinants of personal computers (PCs), telephone mainline and cellular and Internet penetration/connectivity in the African Region; and (ii) to propose actions needed to create an enabling environment for e-health services growth and utilization in the Region. METHODS: The effects of school enrolment, per capita income and governance variables on the number of PCs, telephone mainlines, cellular phone subscribers and Internet users were estimated using a double-log regression model and cross-sectional data on various Member States in the African Region. The analysis was based on 45 of the 46 countries that comprise the Region. The data were obtained from the United Nations Development Programme (UNDP), the World Bank and the International Telecommunications Union (ITU) sources. RESULTS: There were a number of main findings: (i) the adult literacy and total number of Internet users had a statistically significant (at 5% level in a t-distribution test) positive effect on the number of PCs in a country; (ii) the combined school enrolment rate and per capita income had a statistically significant direct effect on the number of telephone mainlines and cellular telephone subscribers; (iii) the regulatory quality had statistically significant negative effect on the number of telephone mainlines; (iv) similarly, the combined school enrolment ratio and the number of telephone mainlines had a statistically significant positive relationship with Internet usage; and (v) there were major inequalities in ICT connectivity between upper-middle, lower-middle and low income countries in the Region. By focusing on the adoption of specific technologies we attempted to interpret correlates in terms of relationships instead of absolute "causals". CONCLUSION: In order to improve access to health care, especially for the majority of Africans living in remote rural areas, there is need to boost the availability and utilization of e-health services. Thus, universal access to e-health ought to be a vision for all countries in the African Region. Each country ought to develop a road map in a strategic e-health plan that will, over time, enable its citizens to realize that vision

Effect of standing posture during whole body vibration training on muscle morphology and function in older adults: A randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Whole body vibration (WBV) is a novel modality of exercise shown to improve musculoskeletal function. This study aims to examine the effects of standing posture during low magnitude WBV training on muscle function and muscle morphology in older adults.</p> <p>Methods</p> <p>Nineteen men and women (50-80 years) were recruited to a three month randomised controlled trial and allocated to one of three groups: WBV with flexed knees (FK), WBV with locked knees (LK), or sham WBV with flexed knees (CON). Exposure was intermittent (1 min WBV:1 min rest) for 20 min, three times per week for 13 weeks. Measurements were taken at baseline and at three months. Primary outcomes included upper and lower body muscle function (strength, power and velocity). Secondary outcomes were muscle morphology, balance, habitual and maximal gait velocity, stair climb power, and chair stand performance.</p> <p>Results</p> <p>Sixteen subjects completed the study. Relative (%) upper body contraction velocity improved significantly after WBV with FK compared to LK (FK 16.0%, LK -7.6%, CON 4.7, p = 0.01). Relative upper body strength (LK 15.1%, p = 0.02; FK 12.1%, p = 0.04; CON 4.7%) increased significantly following WBV compared to control. Absolute (p = 0.05) and relative (p = 0.03) lower leg strength significantly improved with both standing postures (LK 14.4%; FK 10.7%; CON 1.3%). Only the LK group differed significantly from CON in relative leg strength gains (p = 0.02). Potentially clinically meaningful but statistically non-significant improvements in lower leg muscle cross-sectional area (LK 3.7 cm², FK 2.4 cm², CON 2.2 cm²p = 0.13) were observed after WBV with LK compared to the other groups. No significant effects of WBV on any functional performance tests were observed.</p> <p>Conclusions</p> <p>Our results suggest that WBV may improve muscle strength and contraction velocity in some muscle groups in older adults. However, hypothesised differential adaptation to standing posture (FK > LK) was observed only for upper body contraction velocity, making recommendations regarding this prescriptive element inconclusive. The efficacy, mechanism of action and long term feasibility of WBV for musculoskeletal health in older adults warrants continued investigation in robustly designed, sufficiently powered future studies.</p> <p>Trial Registration</p> <p>ACTRN12609000353291.</p

Did cybercrime cause the crime drop?

Recent studies have hypothesised that the international crime drop was the result of the rise in cybercrime. We subject this ‘cybercrime hypothesis’ to critical assessment. We find significant evidence and argument indicating that cybercrime could not have caused the crime drop, and so we reject the cybercrime hypothesis