Correct positioning of the calcar screw leads to superior results in proximal humerus fractures treated with carbon-fibre-reinforced polyetheretherketone plate osteosynthesis with polyaxial locking screws

Background: Plate osteosynthesis with implants made of carbon-fibre-reinforced polyetheretherketone (CFR-PEEK) has recently been introduced for the treatment of fractures of the proximal humerus (PHFs). The advantages of the CFR-PEEK plate are considered to be its radiolucency, its favourable modulus of elasticity, and the polyaxial placement of the screws with high variability of the angle. The primary aim of this study is to investigate the influence of calcar screw positioning on the complication and revision rates after CFR-PEEK plating of PHFs. The secondary aim is to assess its influence on functional outcome. Material and methods: Patients were identified retrospectively. Minimum follow-up was 12 months. The cohort was divided into two groups depending on the distance of the calcar screw to the calcar (group I: &lt; 12 mm, group II: ≥ 12 mm). The range of motion (ROM), Subjective Shoulder Value Score (SSV) and Constant–Murley Score (CS) were analysed at follow-up examination. Subjective complaints, complications (e.g. humeral head necrosis, varus dislocation) and the revision rate were evaluated. Results: 51 patients (33 female, 18 male) with an average age of 68.6 years were included after a period of 26.6 months (group I: 32 patients, group II: 19 patients). Apart from the gender distribution, no significant differences were seen in the patient characteristics. The outcome scores showed significantly better clinical results in group I: SSV 83.4 vs 71.2, p = 0.007; CS 79.1 vs 67.8, p = 0.013. Complications were seen less frequently in group I (18.8 % vs 47.4 %, p = 0.030). Conclusion: This study shows that the positioning of the calcar screw is relevant for CFR-PEEK plate osteosynthesis in PHFs with a good reduction of the fracture. Optimal positioning of the calcar screw close to the calcar (&lt; 12 mm) is associated with a lower rate of complications, resulting in significantly superior functional outcomes.</p

Lateralising reverse shoulder arthroplasty using bony increased offset (BIO-RSA) or increasing glenoid component diameter:comparison of clinical, radiographic and patient reported outcomes in a matched cohort

Background: This study aims to compare the range of motion (ROM) of reverse shoulder arthroplasty lateralised by bony increased offset (BIO-RSA) using a standard 38-mm (mm) component to regular reverse shoulder arthroplasty (RSA) lateralised by using a 42-mm glenoid component. The secondary aims are to compare patient-reported and radiographic outcomes between the two groups. Materials and Methods: All patients with a BIO-RSA and size 38 glenosphere were retrospectively identified and matched to patients with a regular RSA and size 42 glenosphere. Matched patients were invited for a follow-up visit. ROM was assessed as well as radiographic outcomes (lateralisation, distalisation, inferior overhang, scapular notching, heterotopic bone formation, radiolucency, stress shielding, bone graft healing and viability and complications) and patient-reported outcomes (subjective shoulder value, Constant score, American Shoulder and Elbow Surgeons, activities of daily living which require internal rotation, activities of daily living which require external rotation and a visual analogue scale for pain). Outcomes were compared between the two groups. Results: In total, 38 BIO-RSAs with a size 38 glenosphere were matched to 38 regular RSAs with a size 42 glenosphere. Of the 76 matched patients, 74 could be contacted and 70 (95%) were included. At the final follow-up, there were no differences between the two groups in ROM, patient-reported outcomes or radiographic outcomes (p &gt; 0.485). Conclusions: Using a larger glenosphere is a feasible alternative to BIO-RSA for lateralising RSA, providing comparable ROM, patient-reported and radiographic results, while potentially decreasing costs, operative time and complication rates. Level of evidence III.</p

Specialist multidisciplinary input maximises rare disease diagnoses from whole genome sequencing

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk

Neuromuscular disease genetics in under-represented populations: increasing data diversity

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% ‘solved’ and ∼13% ‘possibly solved’ outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally

Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol

Vagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called “Microburst VNS”, in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

Abstract: TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics