The Unique Demands of Playing Posture on Youth Violinists and Violists

The high prevalence of performing arts injuries is an acknowledged challenge facing the performing arts medicine community. The injuries seem to affect string players the most among orchestral musicians, specifically violinists and violists. The asymmetrical posture, head and neck displacement, and spinal displacement required by the posture to play violin and viola can lead to discomfort or injury in the performer. Performance related musculoskeletal disorders (PRMDs) can have an adverse impact on the life of a musician, preventing them from performing or making it uncomfortable. While there is a large body of research on PRMDs relating to adult musicians, there have been few investigations of the unique challenges faced by children playing violin or viola. The two instruments have similar posture, leading to similar potential risk factors. The muscular tissue, rapid bodily change and growth, general misfit between child and instrument, backpack use, and desk posture of children playing the violin and viola prevent unique risk factors that are not found in adults. Potential solutions to these risk factors include proper instrument sizing with a chin rest and shoulder rest and posture awareness with an emphasis on balance and pain treatment. The advancement of research into youth-related performing arts injuries could play a part in reducing the alarmingly high levels of performance related injury in adult violinists and violists

Quantum Circuit Cosmology: The Expansion of the Universe Since the First Qubit

We consider cosmological evolution from the perspective of quantum information. We present a quantum circuit model for the expansion of a comoving region of space, in which initially-unentangled ancilla qubits become entangled as expansion proceeds. We apply this model to the comoving region that now coincides with our Hubble volume, taking the number of entangled degrees of freedom in this region to be proportional to the de Sitter entropy. The quantum circuit model is applicable for at most 140 $e$-folds of inflationary and post-inflationary expansion: we argue that no geometric description was possible before the time $t_1$ when our comoving region was one Planck length across, and contained one pair of entangled degrees of freedom. This approach could provide a framework for modeling the initial state of inflationary perturbations.Comment: v2, minor correction

Zinc containing dental fixative causing copper deficiency myelopathy

A 62-year-old male, previously well, was referred to neurology clinic following 6 months history of worsening lower limbs instability, paraesthesia, pain and weakness rendering him housebound. Examination revealed upper motor neuron pattern of weakness of the lower limbs and loss of proprioception. Serum analysis revealed reduced caeruloplasmin and copper levels with raised zinc. Spinal imaging revealed subtle dorsal column intensity changes in C2-C7, confirmed with 3T MRI. A copper deficiency myeloneuropathy was diagnosed secondary to chronic use of a zinc-containing dental fixative paste. The paste was discontinued and a copper supplementation was started. Resolution of symptoms was not achieved with intensive physiotherapy. The patient remains a wheelchair user though progression of symptoms has halted. Prompt recognition and treatment of hyperzincaemia-induced hypocupraemia earlier in the disease course may have prevented any irreversible neurological deficit

Genetic overlap between autism, schizophrenia and bipolar disorder

There is strong evidence that genetic factors make substantial contributions to the etiology of autism, schizophrenia and bipolar disorders, with heritability estimates being at least 80% for each. These illnesses have complex inheritance, with multiple genetic and environmental factors influencing disease risk; however, in psychiatry, complex genetics is further compounded by phenotypic complexity. Autism, schizophrenia and bipolar disorder are effectively syndromic constellations of symptoms that define groups of patients with broadly similar outcomes and responses to treatment. As such the diagnostic categories are likely to be heterogeneous and the boundaries between them somewhat arbitrary. Recent applications of whole-genome technologies have discovered rare copy number variants and common single-nucleotide polymorphisms that are associated with risk of developing these disorders. Furthermore, these studies have shown an overlap between the genetic loci and even alleles that predispose to the different phenotypes. The findings have several implications. First, they show that copy number variations are likely to be important risk factors for autism and schizophrenia, whereas common single-nucleotide polymorphism alleles have a role in all disorders. Second, they imply that there are specific genetic loci and alleles that increase an individual's risk of developing any of these disorders. Finally, the findings suggest that some of the specific genetic loci implicated so far encode proteins, such as neurexins and neuroligins, that function in synaptic development and plasticity, and therefore may represent a common biological pathway for these disorders

Search for a schizophrenia susceptibility locus on chromosome 17

The search for genetic variants that alter the risk of developing schizophrenia has met with little success (Owen et al., 2005a) with the best example coming from a large multiply affected pedigree (Blackwood et al., 2001, Millar et al., 2000, St Clair et al., 1990). In this study a genome-wide significant schizophrenia linkage region in a single pedigree (Williams et al., 2003a) has been refined to an 11.7Mb region at 17q23-q24 where all 6 affected males share 21 consecutive microsatellite marker genotypes. Analysis of this region by oligonucleotide-array comparative genome hybridisation shows that no large deletions explain the linkage signal. High-density genotyping identified a region of homozygosity present in C702 affecteds that was not identified in 2709 individuals from the UK. This rare diplotype encompasses the 3' of the gene encoding Protein Kinase C Alpha (PRKCA), implicated in the pathogenesis of schizophrenia and related disorders (Mimics et al., 2001, Hahn and Friedman, 1999, Birnbaum et al., 2004). Mutation screening of PRKCA in the linked pedigree C702 identified an exonic haplotype with a minor allele frequency of 0.003, which is homozygous in affected individuals. The haplotype is associated in a UK case-control sample with major mental illness (p=0.05. OR=l .8) due to risk in males (p=0.005. OR=3.9). Also, the pedigree C702 genotype was not observed in -9000 Europeans. Association mapping of PRKCA using schizophrenia and psychosis case-control samples from Europe identified a common associated allele (rs3803821, meta analysis p=0.02, OR=l.l) that shows significant overtransmission in a trios sample (p=0.03). Therefore, PRKCA may represent the locus causing the pedigree C702 linkage signal and contains genetic variation associated with schizophrenia and related disorders

Cutaneous expression of growth-associated protein 43 is not a compelling marker for human nerve regeneration in carpal tunnel syndrome.

Growth-associated protein 43 (GAP-43) has long been used as a marker for nerve regeneration following nerve injury, with numerous in vitro and animal studies showing its upregulation in regenerating neurons. In humans, expression of GAP-43 has predominantly been examined in skin biopsies from patients with peripheral neuropathies; with several studies showing a reduction in GAP-43 immunoreactive cutaneous nerve fibres. However, it remains elusive whether cutaneous GAP-43 is a valid marker for human nerve regeneration. Here, we present a cohort of 22 patients with electrodiagnostically confirmed carpal tunnel syndrome (CTS), used as a model system for focal nerve injury and neural regeneration after decompression surgery. We evaluate GAP-43 immunoreactivity and RNA expression levels in finger skin biopsies taken before and 6 months after surgery, relative to healthy controls. We further classify patients as 'regenerators' or 'non-regenerators' based on post-surgical epidermal re-innervation. We demonstrate that patients with CTS have lower GAP-43 positive intra-epidermal nerve fibre density (IENFD) before surgery than healthy controls. However, this difference disappears when normalising for total IENFD. Of note, we found surgery did not change GAP-43 expression in IENF, with no differences both in patients who were classified as regenerators and non-regenerators. We also did not identify pre-post surgical differences in cutaneous GAP-43 gene expression or associations with regeneration. These findings suggest cutaneous GAP-43 may not be a compelling marker for nerve regeneration in humans

Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability

Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2 ) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2 mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability

Whole Genome Association Study in a Homogenous Population in Shandong Peninsula of China Reveals JARID2 as a Susceptibility Gene for Schizophrenia

DNA pooling can provide an economic and efficient way to detect susceptibility loci to complex diseases. We carried out a genome screen with 400 microsatellite markers spaced at approximately 10 cm in two DNA pools consisting of 119 schizophrenia (SZ) patients and 119 controls recruited from a homogenous population in the Chang Le area of the Shandong peninsula of China. Association of D6S289, a dinucleotide repeat polymorphism in the JARID2 gene with SZ, was found and confirmed by individual genotyping (X2 = 17.89; P = .047). In order to refine the signal, we genotyped 14 single nucleotide polymorphisms (SNPs) covering JARID2 and the neighboring gene, DNTBP1, in an extended sample of 309 cases and 309 controls from Shandong peninsula (including the samples from the pools). However, rs2235258 and rs9654600 in JARID2 showed association in allelic, genotypic and haplotypic tests with SZ patients from Chang Le area. This was not replicates in the extended sample, we conclude that JARID2 could be a susceptibility gene for SZ

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison

BACKGROUND Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival. METHODS In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses. RESULTS There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023). CONCLUSIONS These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS

Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data

Objective: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. Design: Cohort study emulating a comparative effectiveness trial (target trial). Setting: Linked primary care, hospital, and death data in England, 2015-21. Participants: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. Main outcome measures: Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. Results: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were −2.5 mmol/mol (95% confidence interval (CI) −3.7 to −1.3) for SGLT-2 inhibitors versus sulfonylureas and −3.2 mmol/mol (−4.6 to −1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking—the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). Conclusions: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints