A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor.

Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16-1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren's disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02-1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren's disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.

The use of intramedullary devices for adult radial head and neck fractures. A systematic review.

The management of isolated radial neck and head fractures is controversial. Plate fixation and tripod fixation are two commonly employed techniques but risk damage to soft tissues and implant-related complications. Intramedullary fixation is commonly used in pediatric cases and reduces the potential drawbacks of open fixation. This systematic review aimed to analyze outcomes of intramedullary fixation in adults in terms of function, union, and complication rates. A systematic review of the literature was conducted following the PRISMA guidelines using Medline and EMBASE's online databases. The review was registered on the PROSPERO database. Studies were appraised using the Methodological Index for non-randomized studies (MINORS) tool. Seven studies were deemed eligible for inclusion (n=55). Mean ages of patients ranged from 31.3 to 44.2 years, and mean follow-up ranged from 9 to 86 months. The Mayo Elbow Performance score (MEPs) was reported in five case series (mean scores 81.8 -97.9) and the prevalence of excellent results ranged from 71% and 83%. Although 100% of fractures united, the pooled complication rate was 24% (range 0-50%). The most common complications were elbow stiffness (7%), superficial radial nerve neuropraxia (7%), malunion (5%), and AVN (1.8%). No study reported any patients requiring revision surgery. Intramedullary fixation for radial head and neck fractures appears to provide a reliable alternative treatment option in terms of union, range of motion, and functional outcomes. Further robust trials direct comparing against open fixation techniques are required.

The use of the internal joint stabiliser for elbow instability Report of two cases and systematic review.

The management of elbow fracture-dislocations is challenging. The internal joint stabiliser (IJS) (Skeletal Dynamics, Miami, FL) has been advocated as an alternative to traditional techniques. This article shares our initial clinical experience and provide a systematic review analysing the ability of the IJS to maintain radiographic joint reduction and the associated complication profile. Two cases of elbow fracture-dislocations treated at our centre using the IJS are presented. A systematic review of the literature was conducted using the online databases Medline, Scopus and EMBASE. Clinical studies reporting the maintenance of joint reduction after the use of IJS in patients with acute or chronic elbow instability were included. The two cases reported remained radiographically concentric at 6 months follow up without complications. 5 studies met the inclusion criteria and were included in the systematic review (total n=65). Only two patients across the studies had ongoing radiological instability (3%) and both were associated with coronoid insufficiency. The mean flexion-extension arc ranged from 106° to 135° and pronation- supination arc ranged from 138° to 151°. The mean DASH scores ranged from 16 to 37.3 and the mean Broberg and Morrey Functional score from 68.2 to 93. Complication rates in the case series ranged from 21% to 40%, the commonest complications were heterotopic ossification, neuropathy and infections. Initial reports into the use of the Internal Joint Stabiliser for elbow instability have shown a low incidence of residual radiological joint incongruency.

A multiorganism pipeline for antiseizure drug discovery: Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant.

OBJECTIVE: Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS: We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS: Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm γ-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE: These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions.

Analyzing the public discourse on works of fiction - Detection and visualization of emotion in online coverage about HBO's Game of Thrones.

This paper presents a Web intelligence portal that captures and aggregates news and social media coverage about "Game of Thrones", an American drama television series created for the HBO television network based on George R.R. Martin's series of fantasy novels. The system collects content from the Web sites of Anglo-American news media as well as from four social media platforms: Twitter, Facebook, Google+ and YouTube. An interactive dashboard with trend charts and synchronized visual analytics components not only shows how often Game of Thrones events and characters are being mentioned by journalists and viewers, but also provides a real-time account of concepts that are being associated with the unfolding storyline and each new episode. Positive or negative sentiment is computed automatically, which sheds light on the perception of actors and new plot elements.

Improvement in low back pain following spinal decompression: observational study of 119 patients.

STUDY DESIGN: Prospective clinical observational study of low back pain (LBP) in patients undergoing laminectomy or laminotomy surgery for lumbar spinal stenosis (LSS). OBJECTIVES: To quantify any change in LBP following laminectomy or laminotomy spinal decompression surgery. PATIENTS AND METHODS: 119 patients with LSS completed Oswestry Disability Index questionnaire (ODI) and Visual Analogue Scale for back and leg pain, preoperatively, 6 weeks and 1 year postoperatively. RESULTS: There was significant (p < 0.0001) reduction in mean LBP from a baseline of 5.14/10 to 3.03/10 at 6 weeks. Similar results were seen at 1 year where mean LBP score was 3.07/10. There was a significant (p < 0.0001) reduction in the mean ODI at 6 weeks and 1 year postoperatively. Mean ODI fell from 44.82 to 25.13 at 6 weeks and 28.39 at 1 year. CONCLUSION: The aim of surgery in patients with LSS is to improve the resulting symptoms that include radicular leg pain and claudication. This observational study reports statistically significant improvement of LBP after LSS surgery. This provides frequency distribution data, which can be used to inform prospective patients of the expected outcomes of such surgery.

Ethics and responsible AI deployment.

As Artificial Intelligence (AI) becomes more prevalent, protecting personal privacy is a critical ethical issue that must be addressed. This article explores the need for ethical AI systems that safeguard individual privacy while complying with ethical standards. By taking a multidisciplinary approach, the research examines innovative algorithmic techniques such as differential privacy, homomorphic encryption, federated learning, international regulatory frameworks, and ethical guidelines. The study concludes that these algorithms effectively enhance privacy protection while balancing the utility of AI with the need to protect personal data. The article emphasises the importance of a comprehensive approach that combines technological innovation with ethical and regulatory strategies to harness the power of AI in a way that respects and protects individual privacy.

Type III open complete articular fractures of the distal humerus: case series outcomes after orthoplastic reconstruction.

Background: Open complete articular injuries of this distal humerus are rare injuries which are challenging to manage. The study unit aims to present a small case series of Gustilo-Anderson type III open complete articular fractures which have undergone a single-stage definitive fixation and soft-tissue coverage, presenting their functional outcomes. Methods: Retrospective case series identifying all type IIIB AO 13-C3 distal humeral fractures from the unit trauma database. The primary outcome was the Oxford Elbow Score. Secondary outcomes included deep infection, nonunion, and reoperation. Results: A total of six patients were identified, (four open type IIIA, 2 type IIIB). All patients underwent single-sitting definitive fixation and soft-tissue coverage. Mean range of motion arc was 90 degrees. The median Oxford Elbow Score was 35 (range 21-43), representative of mild to moderate arthritis. One patient (n = 1) developed deep infection at 24 months and required reoperation. All patients (n = 6) proceeded to union at the latest follow-up. We present a case report of a 59-years-old patient who sustained a type IIIB, AO 13-C3 distal humeral fracture who underwent single-sitting definitive fixation and flap coverage. Conclusion: This case series reports that positive functional outcomes representative of mild/moderate arthritis at short to midterm follow-up can be achieved after definitive fixation and soft-tissue coverage in a single sitting, including when the soft tissue is deficient. This is a rare injury which is under-reported in the literature.

Acute knee clinics are effective in reducing delay to diagnosis following anterior cruciate ligament injury.

BACKGROUND: Delays to diagnosis of anterior cruciate ligament (ACL) injury and specialist consultation continue to place patients at risk of early onset osteoarthritis. Incorporating acute knee clinics within a streamlined accident and emergency (A&E) pathway have shown potential in reducing delay but specific evaluative research is lacking. The aim of this service evaluation was to investigate the effectiveness of an acute knee clinic at one NHS Trust in the United Kingdom (UK), on reducing the delay to diagnosis of ACL injury and specialist consultation compared to a standard A&E pathway. METHODS: An uncontrolled before and after design was utilised for this service evaluation. Data were collected from historical electronic patient records over a 1-year period with analysed results compared against previously collected data from the same NHS Trust. RESULTS: 81 records met the criteria for the streamlined A&E pathway and were compared against 50 from the standard A&E pathway. For the streamlined A&E pathway median delay to diagnosis reduced from 97 to 14 days and delay to specialist consultation reduced from 158.5 to 45 days and were of statistical significance. The incorporation of an acute knee clinic was identified as the most influential factor on delay in addition to the location of presentation and mechanism of injury. CONCLUSIONS: Introducing an acute knee clinic within a streamlined A&E pathway has a clinically relevant effect on reducing delay to diagnosis and specialist consultation and allows findings to be extrapolated and implemented to all UK based NHS Trust A&E departments.

Should Kirschner wires for fixation of lateral humeral condyle fractures in children be buried or left exposed? A systematic review.

BACKGROUND: Displaced lateral humeral condyle fractures in children are usually treated with open reduction and internal fixation. When treated operatively with Kirschner wires, the bent cut near side wire ends are either buried in the subcutaneous tissue or are left exposed. It is believed that burying the wires allows them to remain in longer and hence facilitate better union. Leaving them exposed seems to necessitate earlier removal, especially to reduce the risk of wire tract infection. There is not a clear consensus in published literature whether subcutaneous wire burial is better or not. PATIENTS AND METHODS: A systematic review of literature was performed using online database EMBASE, Pubmed, Medline, CINAHL and Cochrane database. The inclusion criteria comprised only those studies that compared lateral humeral condyle fracture fixation in children with wires buried subcutaneously versus those left exposed to skin. RESULTS: Of the four studies identified, three reported that it was safe to leave the wires exposed and that there was no statistically significant advantage of burying the wires with regards to risk of infection. However, our meta-analysis of the four studies demonstrated on forest plot charts that there is an increased risk of infection when the wires are left exposed (odds ratio 0.538 CI 0.437-0.639), but the overall complication rate was less in the group treated with exposed wires. Treatment with exposed wires was also cost effective when compared to treatment with buried wires. DISCUSSION: Our review concluded that despite a higher risk of superficial infections, exposed wires are safe and an economical option when fixing lateral humeral condyle fractures in children. LEVEL OF EVIDENCE: II, systematic review.

Mapping the Human Kinome in Response to DNA Damage.

We provide a catalog for the effects of the human kinome on cell survival in response to DNA-damaging agents, covering all major DNA repair pathways. By treating 313 kinase-deficient cell lines with ten diverse DNA-damaging agents, including seven commonly used chemotherapeutics, we identified examples of vulnerability and resistance that are kinase specific. To investigate synthetic lethal interactions, we tested the response to carmustine for 25 cell lines by establishing a phenotypic fluorescence-activated cell sorting (FACS) assay designed to validate gene-drug interactions. We show apoptosis, cell cycle changes, and DNA damage and proliferation after alkylation- or crosslink-induced damage. In addition, we reconstitute the cellular sensitivity of DYRK4, EPHB6, MARK3, and PNCK as a proof of principle for our study. Furthermore, using global phosphoproteomics on cells lacking MARK3, we provide evidence for its role in the DNA damage response. Our data suggest that cancers with inactivating mutations in kinases, including MARK3, are particularly vulnerable to alkylating chemotherapeutic agents.

A Caenorhabditis elegans assay of seizure-like activity optimised for identifying antiepileptic drugs and their mechanisms of action.

BACKGROUND: Epilepsy affects around 1% of people, but existing antiepileptic drugs (AEDs) only offer symptomatic relief and are ineffective in approximately 30% of patients. Hence, new AEDs are sorely needed. However, a major bottleneck is the low-throughput nature of early-stage AED screens in conventional rodent models. This process could potentially be expedited by using simpler invertebrate systems, such as the nematode Caenorhabditis elegans. NEW METHOD: Head-bobbing convulsions were previously reported to be inducible by pentylenetetrazol (PTZ) in C. elegans with loss-of-function mutations in unc-49, which encodes a GABAA receptor. Given that epilepsy-linked mutations in human GABAA receptors are well documented, this could represent a clinically-relevant system for early-stage AED screens. However, the original agar plate-based assay is unsuited to large-scale screening and has not been validated for identifying AEDs. Therefore, we established an alternative streamlined, higher-throughput approach whereby mutants were treated with PTZ and AEDs via liquid-based incubation. RESULTS: Convulsions induced within minutes of PTZ exposure in unc-49 mutants were strongly inhibited by the established AED ethosuximide. This protective activity was independent of ethosuximide's suggested target, the T-type calcium channel, as a null mutation in the worm cca-1 ortholog did not affect ethosuximide's anticonvulsant action. COMPARISON WITH EXISTING METHOD: Our streamlined assay is AED-validated, feasible for higher throughput compound screens, and can facilitate insights into AED mechanisms of action. CONCLUSIONS: Based on an epilepsy-associated genetic background, this C. elegans unc-49 model of seizure-like activity presents an ethical, higher throughput alternative to conventional rodent seizure models for initial AED screens.

Radial Head Fractures.

BACKGROUND: Radial head fractures are common elbow injuries in adults and are frequently associated with additional soft tissue and bone injuries. METHODS: A literature search was performed and the authors' personal experiences are reported. RESULTS: Mason type I fractures are treated non-operatively with splinting and early mobilisation. The management of Mason type II injuries is less clear with evidence supporting both non-operative treatment and internal fixation. The degree of intra-articular displacement and angulation acceptable for non-operative management has yet to be conclusively defined. Similarly the treatment of type III and IV fractures remain controversial. Traditional radial head excision is associated with valgus instability and should be considered only for patients with low functional demands. Comparative studies have shown improved results from internal fixation over excision. Internal fixation should only be attempted when anatomic reduction and initiation of early motion can be achieved. Authors have reported that results from fixation are poorer and complication rates are higher if more than three fragments are present. Radial head arthroplasty aims to reconstruct the native head and is indicated when internal fixation is not feasible and in the presence of complex elbow injuries. Overstuffing of the radiocapitellar joint is a frequent technical fault and has significant adverse effects on elbow biomechanics. Modular design improves the surgeon's ability to reconstruct the native joint. Two randomised controlled trials have shown improved clinical outcomes and lower complication rate following arthroplasty when compared to internal fixation. CONCLUSION: We have presented details regarding the treatment of various types of radial head fractures - further evidence, however, is still required to provide clarity over the role of these different management strategies.

Complex Elbow Dislocations and the "Terrible Triad" Injury.

BACKGROUND: The elbow is the second most commonly dislocated joint in adults and up to 20% of dislocations are associated with a fracture. These injuries can be categorised into groups according to their mechanism and the structures injured. METHODS: This review includes a literature search of the current evidence and personal experiences of the authors in managing these injuries. RESULTS: All injuries are initially managed with closed reduction of the ulno-humeral joint and splinting before clinical examination and radiological evaluation. Dislocations with radial head fractures should be treated by restoring stability, with treatment choice depending on the type and size of radial head fracture. Terrible triad injuries necessitate operative treatment in almost all cases. Traditionally the LCL, MCL, coronoid and radial head were reconstructed, but there is recent evidence to support repairing of the coronoid and MCL only if the elbow is unstable after reconstruction of lateral structures. Surgical treatment of terrible triad injuries carries a high risk of complications with an average reoperation rate of 22%. Varus posteromedial rotational instability fracture-dislocations have only recently been described as having the potential to cause severe long-term problems. Cadaveric studies have reinforced the need to obtain post-reduction CT scans as the size of the coronoid fragment influences the long-term stability of the elbow. Anterior dislocation with olecranon fracture has the same treatment aims as other complex dislocations with the added need to restore the extensor mechanism. CONCLUSION: Complex elbow dislocations are injuries with significant risk of long-term disability. There are several case-series in the literature but few studies with sufficient patient numbers to provide evidence over level IV.

Decompensation of ocular torsion following malrotation of a toric intraocular lens.

Toric intraocular lenses (IOLs) are being increasingly used to correct corneal astigmatism in cataract surgery. A quarter of patients that undergo cataract surgery may benefit from a toric rather than a spherical IOL. However, these implants must be positioned accurately, because postoperative rotation of the toric IOL can have clinically significant consequences. We present the first documented case of a 78-year-old woman who presented with diplopia as a result of exacerbation of a preexisting torsion following toric lens implantation.

Botulinum toxin: a novel treatment for pediatric cyclic esotropia.

Cyclic esotropia is a rare entity in which an esotropia presents in a regular 48-96 hour cycle, typically described as a 24-hour period of orthotropia followed by a 24-hour period of esotropia. The underlying mechanism of this phenomenon is unknown. Treatment usually involves surgical correction of the manifest strabismus. We report the case of a 3-year-old girl whose cyclic esotropia was broken following injection of botulinum toxin to both medial rectus muscles. She has remained constantly esophoric for 1 year.