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BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.ResultsThe GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.ConclusionWe set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Objective Older people and people with complex needs often require both health and social care services, but there is limited insight into individual journeys across these services. To help inform joint health and social care planning, we aimed to assess the relationship between hospital admissions and domiciliary care receipt.Design Retrospective cohort study, using linked data on primary care activity, hospital admissions and social care records.Setting London Borough of Barking and Dagenham, England.Participants Adults aged 19 and over who lived in the area on 1 April 2018 and who were registered at a general practice in East London between 1 April 2018 and 31 March 2020 (n=140 987).Outcome measures The outcome was initiation of domiciliary care. We estimated the rate of hospital-associated care package initiation, and of care packages unrelated to hospital admission. We also described the characteristics of hospital admissions that preceded domiciliary care, including primary diagnosis codes.Results 2041/140 987 (1.4%) participants had a domiciliary care package during a median follow-up of 1.87 years. 32.6% of packages were initiated during a hospital stay or within 7 days of discharge. The rate of new domiciliary care packages was 120 times greater (95% CI 110 to 130) during or after a hospital stay than at other times, and this association was present for all age groups. Primary admission reasons accounting for the largest number of domiciliary care packages were hip fracture, pneumonia, stroke, urinary tract infection, septicaemia and exacerbations of long-term conditions (chronic obstructive pulmonary disease and heart failure). Admission reasons with the greatest likelihood of a subsequent domiciliary care package were fractures and strokes.Conclusion Hospitals are a major referral route into domiciliary care. While patients admitted due to new and acute illnesses account for many domiciliary care packages, exacerbations of long-term conditions and age-related and frailty-related conditions are also important drivers.

Objectives Older people and people with complex needs often require both health and social care services, but there is limited insight into individual journeys across these services. To help inform joint health and social care planning, we aimed to assess the relationship between hospital admissions and domiciliary care receipt. Approach We used an individually linked dataset of primary care activity, hospital admissions and local authority-held social care records for adults living in Barking and Dagenham, a borough in London, England, on 1 April 2018, and followed them up until 31 March 2020. The outcome was initiation of a new domiciliary care package. We estimated the rate of hospital-associated care package initiation, and of care packages unrelated to hospital admissions. We also described the characteristics of hospital admissions that preceded domiciliary care and examined which primary diagnoses codes were associated with receiving domiciliary care after discharge. Results In our cohort, 1.4 of participants had a domiciliary care package during a median follow-up of 1.87 years. One in three domiciliary care packages were initiated during a hospital stay or within 7 days of discharge. The rate of new domiciliary care packages was 120 times greater (95% CI 110-130) during or after a hospital stay than at other times, and this association was present for all age groups. Primary admission reasons accounting for the largest number of domiciliary care packages were hip fracture, pneumonia, urinary tract infection, septicaemia, and exacerbations of long-term conditions (COPD and heart failure). Admission reasons with the greatest likelihood of a subsequent domiciliary care package were fractures and strokes. Conclusion Hospitals are a major referral route into domiciliary care. While new and acute illnesses account for many domiciliary care packages, exacerbations of long-term conditions and age- and frailty-related conditions are also an important driver. National-level linked datasets are needed for a better understanding of the relationship between health and social care receipt.

Abstract Awake veno‐venous ECMO without anticoagulation is a safe and successful way to remove a significantly obstructive malignancy in the trachea.

Abstract Objective Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real‐world clinical setting. Methods We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome‐wide association studies and exome studies, comprising 281 candidate genes. Results Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (

Abstract Objective To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12‐month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08‐1.13], P

The formation and breakup of an axisymmetric immiscible, viscous, laminar compound jet flowing vertically downward into and breaking up in another immiscible liquid is studied numerically. We use a front-tracking/finite difference method to track the unsteady motion and the breakup of the compound jet interfaces, which are governed by the incompressible Navier-Stokes equations for Newtonian fluids. We consider the formation and breakup of a three-fluid compound jet in which the inner fluid density is greater than the shell's fluid density, and compare with the case when the inner fluid density is less than the shell's fluid density. The effects of interfacial tensions in terms of Weber number and interfacial tension ratio are investigated. An increase in Weber number leads to an increase in the breakup length of the compound jet and a decrease in the size of compound drops.

Strategic intentions reflect the aspirations of an organization. They can also be translated into targets for the rest of the organization and structures, procedures, measures and associated rules introduced to meet them. Drawing upon insight from social systems theory, and case study evidence from the telecommunications industry, this conceptual paper suggests that the ensuing implementation processes can conflict with the principles and objectives of actors at operational levels and lead to behaviors that can hinder the pursuit of those high level goals. This misalignment, or pathological autopoiesis, is manifest through a restructuring in which the organization becomes the environment for operational actors who in turn focus upon the "translation" of imposed conditions into their own psychic and social needs. In effect the organization turns in on itself and away from the need to acquire information about, and respond to, its own environment, a condition that is fundamental to the resilience and survival of any system. URN: urn:nbn:de:0114-fqs1003272