Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly.

BACKGROUND: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. METHODS: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. RESULTS: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. CONCLUSION: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.

Reliable radical stabilization energies from diffusion Monte Carlo calculations.

We assess the performance of variational (VMC) and diffusion (DMC) quantum Monte Carlo methods for calculating the radical stabilization energies of a set of 43 carbon-centered radical species. Even using simple single-determinant trial wavefunctions, both methods perform exceptionally well, with mean absolute deviations from reference values well under the chemical accuracy standard of 1 kcal/mol. In addition, the use of DMC results in a highly concentrated spread of errors, with all 43 results within chemical accuracy at the 95% confidence level. These results indicate that DMC is an extremely reliable method for calculating radical stabilization energies and could be used as a benchmark method for larger systems in future.

Density functional orbitals in quantum Monte Carlo: The importance of accurate densities.

There has been significant recent attention surrounding the accuracy of electronic densities produced by modern parameterized density functional approximations (DFAs). Here, we investigate the impact of using orbitals from density functional calculations in fixed-node Diffusion Monte Carlo (DMC) methods, which is common practice in the calculation of large systems. We find that the accuracy of the density is a strong indicator of the quality of the many-body nodal surface produced by a determinant of the corresponding Kohn-Sham orbitals. Functionals which produce the most accurate electronic densities also produce the lowest variational DMC energies, while functionals that produce poor densities lead to significantly higher energies. This result simplifies the process of choosing orbitals for DMC calculations of large systems and suggests that prioritizing accurate densities in the future development of DFAs would also contribute to the continued improvement of DMC.

Identifying policies and strategies for general practitioner retention in direct patient care in the United Kingdom: a RAND/UCLA appropriateness method panel study.

BACKGROUND: The United Kingdom (UK) is experiencing a general practitioner (GP) workforce retention crisis. Research has focused on investigating why GPs intend to quit, but less is known about the acceptability and effectiveness of policies and strategies to improve GP retention. Using evidence from research and key stakeholder organisations, we generated a set of potential policies and strategies aimed at maximising GP retention and tested their appropriateness for implementation by systematically consulting with GPs. METHODS: 28 GP Partners and GPs working in national stakeholder organisations from South West England and London were purposively sampled, and asked to take part in a RAND/UCLA Appropriateness Method panel. Panellists were asked to read an evidence briefing summary, and then complete an online survey on two occasions. During each round, participants rated the appropriateness of policies and strategies aimed at improving GP retention using a nine point scale (1 'extremely inappropriate' to 9 'extremely appropriate'). Fifty-four potential policies and strategies (equating to 100 statements) were tested, focusing on factors influencing job satisfaction (e.g. well-being, workload, incentives and remuneration, flexible working, human resources systems). Ratings were analysed for panel consensus and categorised based on appropriateness ('appropriate', 'uncertain', 'inappropriate'). RESULTS: 12/28 GPs approached agreed to take part, 9/28 completed two rounds of the online survey between February and June 2018. Panellists identified 24/54 policy and strategy areas (41/100 statements) as 'appropriate'. Examples included providing GP practices 'at risk' of experiencing GP shortages with a toolkit for managing recruitment and retention, and interventions to facilitate peer support to enhance health and wellbeing, or support portfolio careers. Strategies to limit GP workload, and manage patient demand were also endorsed. CONCLUSIONS: The panel of experienced GPs identified a number of practical ways to improve GP retention through interventions that might enhance job satisfaction and work-life balance. Future research should evaluate the impact of implementing these recommendations.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

Cost and Outcome of Behavioural Activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial.

BACKGROUND: Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy-cognitive behavioural therapy (CBT)-is complex and costly. A simpler therapy-behavioural activation (BA)-might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. METHODS: In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity [Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19], antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat [mITT]) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol [PP]). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. FINDINGS: Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points [SD 7·5], BA 8·4 PHQ-9 points [7·0], mean difference 0·1 PHQ-9 points [95% CI -1·3 to 1·5], p=0·89; PP: CBT 7·9 PHQ-9 points [7·3]; BA 7·8 [6·5], mean difference 0·0 PHQ-9 points [-1·5 to 1·6], p=0·99). Two (1%) non-trial-related deaths (one [1%] multidrug toxicity in the BA group and one [1%] cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three [2%] participants in the BA group (two [1%] patients who overdosed and one [1%] who self-harmed) and eight (4%) participants in the CBT group (seven [4%] who overdosed and one [1%] who self-harmed). INTERPRETATION: We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. FUNDING: National Institute for Health Research.

7-Hexagon Multifocal Electroretinography for an Objective Functional Assessment of the Macula in 14 Seconds.

PURPOSE: We present the multifocal electroretinogram (mfERG) with a 7-hexagon array as an objective test of macular function that can be recorded in 14 s. We provide normal values and investigate its reproducibility and validity. METHODS: Healthy participants underwent mfERG testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards using the Espion Profile/D310 multifocal ERG system (Diagnosys, LLC, Lowell, MA, USA). One standard recording of a 61-hexagon array and 2 repeated recordings of a custom 7-hexagon array were obtained. RESULTS: A total of 13 subjects (mean age 46.9 years) were included. The median response densities were 12.5 nV/deg2 in the center and 5.2 nV/deg2 in the periphery. Intereye correlations were strong in both the center (ρCenter = 0.821; p < 0.0001) and the periphery (ρPeriphery = 0.862; p < 0.0001). Intraeye correlations were even stronger: ρCenter = 0.904 with p < 0.0001 and ρPeriphery = 0.955 with p < 0.0001. Bland-Altman plots demonstrated an acceptable retest mean difference in both the center and periphery, and narrow limits of agreement. We found strong correlations of the center (ρCenter = 0.826; p < 0.0001) and periphery (ρPeriphery = 0.848; p < 0.0001), with recordings obtained by the 61-hexagon method. CONCLUSIONS: The 7-hexagon mfERG provides reproducible results in agreement with results obtained according to the ISCEV standard.

Evidence of macular pigment in the central macula in albinism.

PURPOSE: Albinism represents a spectrum of disorders with diminished to absent amounts of melanin pigmentation including the posterior segment of the eye. Macular pigment (MP) consists of two main carotenoids, lutein and zeaxanthin, concentrated in the macula. MP serves as blue light absorbent, antioxidant, and may reduce chromatic aberration and glare. It remains unclear if albinos have detectable MP. The purpose was to investigate the distribution of MP in albino patients with psychophysical and imaging techniques. METHODS: MP was measured at the eccentricity of 0.5° by heterochromatic flicker perimetry (QuantifEye(®); Tinsley Precision Instruments Ltd.) or by scanning laser ophthalmoscopy (MPOD module, MultiColor Spectralis(®), Heidelberg Engineering, Heidelberg, Germany) in four albino patients, who were also investigated with multimodal ophthalmic imaging. RESULTS: Visual acuity ranged from 20/32 to 20/125, nystagmus was present in three patients, and all patients showed typical foveal hypoplasia on fundus exam and optical coherence tomography. Fundus autofluorescence (FAF) demonstrated various degrees of central FAF signal attenuation. Genetic testing was available in three patients and confirmed the diagnosis. Measurable amounts of MP were detected in all four patients and ranged from 0.05 to 0.24, which is below the normal range. CONCLUSIONS: We conclude that MP can be demonstrated and measured in albinos. Further studies are needed to investigate MP accumulation following carotenoid supplementation and its impact on visual performance.

Telephone triage for management of same-day consultation requests in general practice (the ESTEEM trial): a cluster-randomised controlled trial and cost-consequence analysis.

BACKGROUND: Telephone triage is increasingly used to manage workload in primary care; however, supporting evidence for this approach is scarce. We aimed to assess the effectiveness and cost consequences of general practitioner-(GP)-led and nurse-led telephone triage compared with usual care for patients seeking same-day consultations in primary care. METHODS: We did a pragmatic, cluster-randomised controlled trial and economic evaluation between March 1, 2011, and March 31, 2013, at 42 practices in four centres in the UK. Practices were randomly assigned (1:1:1), via a computer-generated randomisation sequence minimised for geographical location, practice deprivation, and practice list size, to either GP-led triage, nurse-led computer-supported triage, or usual care. We included patients who telephoned the practice seeking a same-day face-to-face consultation with a GP. Allocations were concealed from practices until after they had agreed to participate and a stochastic element was included within the minimisation algorithm to maintain concealment. Patients, clinicians, and researchers were not masked to allocation, but practice assignment was concealed from the trial statistician. The primary outcome was primary care workload (patient contacts, including those attending accident and emergency departments) in the 28 days after the first same-day request. Analyses were by intention to treat and per protocol. This trial was registered with the ISRCTN register, number ISRCTN20687662. FINDINGS: We randomly assigned 42 practices to GP triage (n=13), nurse triage (n=15), or usual care (n=14), and 20,990 patients (n=6695 vs 7012 vs 7283) were randomly assigned, of whom 16,211 (77%) patients provided primary outcome data (n=5171 vs 5468 vs 5572). GP triage was associated with a 33% increase in the mean number of contacts per person over 28 days compared with usual care (2·65 [SD 1·74] vs 1·91 [1·43]; rate ratio [RR] 1·33, 95% CI 1·30-1·36), and nurse triage with a 48% increase (2·81 [SD 1·68]; RR 1·48, 95% CI 1·44-1·52). Eight patients died within 7 days of the index request: five in the GP-triage group, two in the nurse-triage group, and one in the usual-care group; however, these deaths were not associated with the trial group or procedures. Although triage interventions were associated with increased contacts, estimated costs over 28 days were similar between all three groups (roughly £75 per patient). INTERPRETATION: Introduction of telephone triage delivered by a GP or nurse was associated with an increase in the number of primary care contacts in the 28 days after a patient's request for a same-day GP consultation, with similar costs to those of usual care. Telephone triage might be useful in aiding the delivery of primary care. The whole-system implications should be assessed when introduction of such a system is considered. FUNDING: Health Technology Assessment Programme UK National Institute for Health Research.

Implementing telephone triage in general practice: a process evaluation of a cluster randomised controlled trial.

BACKGROUND: Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. However, limited evidence exists of the challenges GP practices face in implementing telephone triage. We conducted a qualitative process evaluation alongside a UK-based cluster randomised trial (ESTEEM) which compared the impact of GP-led and nurse-led telephone triage with usual care on primary care workload, cost, patient experience, and safety for patients requesting a same-day GP consultation. The aim of the process study was to provide insights into the observed effects of the ESTEEM trial from the perspectives of staff and patients, and to specify the circumstances under which triage is likely to be successfully implemented. Here we report perspectives of staff. METHODS: The intervention comprised implementation of either GP-led or nurse-led telephone triage for a period of 2-3 months. A qualitative evaluation was conducted using staff interviews recruited from eight general practices (4 GP triage, 4 Nurse triage) in the UK, implementing triage as part of the ESTEEM trial. Qualitative interviews were undertaken with 44 staff members in GP triage and nurse triage practices (16 GPs, 8 nurses, 7 practice managers, 13 administrative staff). RESULTS: Staff reported diverse experiences and perceptions regarding the implementation of telephone triage, its effects on workload, and on the benefits of triage. Such diversity were explained by the different ways triage was organised, the staffing models used to support triage, how the introduction of triage was communicated across practice staff, and by how staff roles were reconfigured as a result of implementing triage. CONCLUSION: The findings from the process evaluation offer insight into the range of ways GP practices participating in ESTEEM implemented telephone triage, and the circumstances under which telephone triage can be successfully implemented beyond the context of a clinical trial. Staff experiences and perceptions of telephone triage are shaped by the way practices communicate with staff, prepare for and sustain the changes required to implement triage effectively, as well as by existing practice culture, and staff and patient behaviour arising in response to the changes made. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20687662. Registered 28 May 2009.

Impact of geographical cohorting, multidisciplinary rounding and incremental case management support on hospital length of stay and readmission rates: a propensity weighted analysis.

Hospital length of stay (LOS) in the USA has been increasing since the start of the COVID-19 pandemic, with numerous negative outcomes, including decreased quality of care, worsened patient satisfaction and negative financial impacts on hospitals. While many proposed factors contributing to prolonged LOS are challenging to modify, poor coordination of care and communication among clinical teams can be improved.Geographical cohorting of provider teams, patients and other clinical staff is proposed as a solution to prolonged LOS and readmissions. However, many studies on geographical cohorting alone have shown no significant impact on LOS or readmissions. Other potential benefits of geographical cohorting include improved quality of care, learning experience, communication, teamwork and efficiency.This paper presents a retrospective study at Duke University Hospital (DUH) on the General Medicine service, deploying a bundled intervention of geographical cohorting of patients and their care teams, twice daily multidisciplinary rounds and incremental case management support. The quality improvement study found that patients in the intervention arm had 16%-17% shorter LOS than those in the control arms, and there was a reduction in 30-day hospital readmissions compared with the concurrent control arm. Moreover, there was some evidence of improved accuracy of estimated discharge dates in the intervention arm.Based on these findings, the health system at DUH recognised the value of geographical cohorting and implemented additional geographically based medicine units with multidisciplinary rounds. Future studies will confirm the sustained impact of these care transformations on hospital throughput and patient outcomes, aiming to reduce LOS and enhance the quality of care provided to patients.

Syndromic retinitis pigmentosa caused by biallelic SCAPER frameshift variant.

PURPOSE: Mutations in the SCAPER gene have previously been reported to be a rare cause of syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). We report a case of syndromic RP caused by a frameshift heterozygous mutation in SCAPER. Our case has a relatively mild ocular phenotype with the presence of cone involvement noted on full field electroretinogram (ffERG) without impacting central or color vision. MATERIALS AND METHODS: A 17-year-old male presented with progressive nyctalopia in both eyes. He underwent ophthalmic examination and multimodal imaging. A complete retinal degeneration panel consisting of 322 genes was used to screen for molecular causes of retinal dystrophy in this patient along with family segregation analysis. RESULTS: Fundus examination of the proband revealed mild RP phenotype with waxy pallor of optic discs, attenuated retinal arterioles, and single bone spicule like pigmentary change in the mid-periphery bilaterally. Multimodal imaging and ffERG demonstrated a picture of RP with cone dysfunction without impacting central or color vision bilaterally. Examined family members were found to be normal. The proband was found to be heterozygous for two novel frameshift pathogenic variants in SCAPER c.3781del, p. (Val1261Serfs*26), c.868_869del, p. (Glu290Serfs*7) both leading to predicted premature termination. The family members tested were found to be heterozygous for SCAPER c.868_869del, p. (Glu290Serfs*7) pathogenic variant confirming their carrier status. CONCLUSION: We report a case of a syndromic RP of previously unreported ocular phenotype associated with SCAPER pathogenic variant, which will add to the phenotypic spectrum of retinopathy and systemic features associated with pathogenic variants in SCAPER.

Workload and workflow implications associated with the use of electronic clinical decision support tools used by health professionals in general practice: a scoping review.

BACKGROUND: Electronic clinical decision support tools (eCDS) are increasingly available to assist General Practitioners (GP) with the diagnosis and management of a range of health conditions. It is unclear whether the use of eCDS tools has an impact on GP workload. This scoping review aimed to identify the available evidence on the use of eCDS tools by health professionals in general practice in relation to their impact on workload and workflow. METHODS: A scoping review was carried out using the Arksey and O'Malley methodological framework. The search strategy was developed iteratively, with three main aspects: general practice/primary care contexts, risk assessment/decision support tools, and workload-related factors. Three databases were searched in 2019, and updated in 2021, covering articles published since 2009: Medline (Ovid), HMIC (Ovid) and Web of Science (TR). Double screening was completed by two reviewers, and data extracted from included articles were analysed. RESULTS: The search resulted in 5,594 references, leading to 95 full articles, referring to 87 studies, after screening. Of these, 36 studies were based in the USA, 21 in the UK and 11 in Australia. A further 18 originated from Canada or Europe, with the remaining studies conducted in New Zealand, South Africa and Malaysia. Studies examined the use of eCDS tools and reported some findings related to their impact on workload, including on consultation duration. Most studies were qualitative and exploratory in nature, reporting health professionals' subjective perceptions of consultation duration as opposed to objectively-measured time spent using tools or consultation durations. Other workload-related findings included impacts on cognitive workload, "workflow" and dialogue with patients, and clinicians' experience of "alert fatigue". CONCLUSIONS: The published literature on the impact of eCDS tools in general practice showed that limited efforts have focused on investigating the impact of such tools on workload and workflow. To gain an understanding of this area, further research, including quantitative measurement of consultation durations, would be useful to inform the future design and implementation of eCDS tools.

Protocol for a pragmatic cluster randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of Electronic RIsk-assessment for CAncer for patients in general practice (ERICA).

INTRODUCTION: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record. METHODS AND ANALYSIS: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years. ETHICS AND DISSEMINATION: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers. TRIAL REGISTRATION NUMBER: ISRCTN22560297.

Alternative splicing modulates inactivation of type 1 voltage-gated sodium channels by toggling an amino acid in the first S3-S4 linker.

Voltage-gated sodium channels underlie the upstroke of action potentials and are fundamental to neuronal excitability. Small changes in the behavior of these channels are sufficient to change neuronal firing and trigger seizures. These channels are subject to highly conserved alternative splicing, affecting the short linker between the third transmembrane segment (S3) and the voltage sensor (S4) in their first domain. The biophysical consequences of this alternative splicing are incompletely understood. Here we focus on type 1 sodium channels (Nav1.1) that are implicated in human epilepsy. We show that the functional consequences of alternative splicing are highly sensitive to recording conditions, including the identity of the major intracellular anion and the recording temperature. In particular, the inactivation kinetics of channels containing the alternate exon 5N are more sensitive to intracellular fluoride ions and to changing temperature than channels containing exon 5A. Moreover, Nav1.1 channels containing exon 5N recover from inactivation more rapidly at physiological temperatures. Three amino acids differ between exons 5A and 5N. However, the changes in sensitivity and stability of inactivation were reproduced by a single conserved change from aspartate to asparagine in channels containing exon 5A, which was sufficient to make them behave like channels containing the complete exon 5N sequence. These data suggest that splicing at this site can modify the inactivation of sodium channels and reveal a possible interaction between splicing and anti-epileptic drugs that stabilize sodium channel inactivation.

An exercise intervention to prevent falls in Parkinson's: an economic evaluation.

BACKGROUND: People with Parkinson's (PwP) experience frequent and recurrent falls. As these falls may have devastating consequences, there is an urgent need to identify cost-effective interventions with the potential to reduce falls in PwP. The purpose of this economic evaluation is to compare the costs and cost-effectiveness of a targeted exercise programme versus usual care for PwP who were at risk of falling. METHODS: One hundred and thirty participants were recruited through specialist clinics, primary care and Parkinson's support groups and randomised to either an exercise intervention or usual care. Health and social care utilisation and health-related quality of life (EQ-5D) were assessed over the 20 weeks of the study (ten-week intervention period and ten-week follow up period), and these data were complete for 93 participants. Incremental cost per quality adjusted life year (QALY) was estimated. The uncertainty around costs and QALYs was represented using cost-effectiveness acceptability curves. RESULTS: The mean cost of the intervention was £76 per participant. Although in direction of favour of exercise intervention, there was no statistically significant differences between groups in total healthcare (-£128, 95% CI: -734 to 478), combined health and social care costs (£-35, 95% CI: -817 to 746) or QALYs (0.03, 95% CI: -0.02 to 0.03) at 20 weeks. Nevertheless, exploration of the uncertainty surrounding these estimates suggests there is more than 80% probability that the exercise intervention is a cost-effective strategy relative to usual care. CONCLUSION: Whilst we found no difference between groups in total healthcare, total social care cost and QALYs, analyses indicate that there is high probability that the exercise intervention is cost-effective compared with usual care. These results require confirmation by larger trial-based economic evaluations and over the longer term.

Potassium Ion Channels in Malignant Central Nervous System Cancers.

Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.

Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?

Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.

How well do Cognitive Behavioural Therapy and Behavioural Activation for depression repair anhedonia? A secondary analysis of the COBRA randomized controlled trial.

A secondary analysis of the COBRA randomized controlled trial was conducted to examine how well Cognitive Behavioural Therapy (CBT) and Behavioural Activation (BA) repair anhedonia. Patients with current major depressive disorder (N = 440) were randomized to receive BA or CBT, and anhedonia and depression outcomes were measured after acute treatment (six months) and at two further follow up intervals (12 and 18 months). Anhedonia was assessed using the Snaith Hamilton Pleasure Scale (SHAPS; a measure of consummatory pleasure). Both CBT and BA led to significant improvements in anhedonia during acute treatment, with no significant difference between treatments. Participants remained above healthy population averages of anhedonia at six months, and there was no further significant improvement in anhedonia at 12-month or 18-month follow up. Greater baseline anhedonia severity predicted reduced repair of depression symptoms and fewer depression-free days across the follow-up period in both the BA and CBT arms. The extent of anhedonia repair was less marked than the extent of depression repair across both treatment arms. These findings demonstrate that CBT and BA are similarly and only partially effective in treating anhedonia. Therefore, both therapies should be further refined or novel treatments should be developed in order better to treat anhedonia.