Autogenic training for chronic health conditions: A service evaluation.

BACKGROUND: Autogenic training (AT) is a structured meditative-style practice, consisting of a sequence of simple mental exercises intended to induce a relaxed state in patients. There is some emerging evidence to suggest that AT can be effective in treating certain chronic conditions, however, further evidence is required. A service evaluation of AT services at the Royal London Hospital for Integrated Medicine was conducted to evaluate the impact of AT on patients with chronic conditions. METHODS: The service evaluation consisted of the completion of validated quantitative outcome measures pre and posttreatment to explore the impact of AT. AT patients were asked to complete the Measure Yourself Medical Outcomes Profile (MYMOP) and Perceived Stress Scale (PSS) at their first hospital appointment (baseline) and then again 8 weeks later following completion of their AT sessions. Pre- and posttreatment scores for each outcome measure were analysed in SPSS using the Wilcoxon signed-rank test. RESULTS: One hundred ninety-nine patients completed both initial and follow-up MYMOP forms and were included in the evaluation. The most common presenting complaints for MYMOP symptom 1 were prolonged anxiety/stress and depression (n = 70, 35.2%), chronic pain and migraine headache (n = 44, 22.1%), chronic insomnia and sleep problems (n = 42, 21.1%) and, long-term exhaustion and fatigue (n = 18, 9%). The change in median score pre- and posttreatment for all MYMOP categories (symptoms, activity and well-being) were statistically highly significant p < 0.001. Anxiety, stress, depression, pain and insomnia were the symptoms that had the largest statistically significant difference between the median score pre- and posttreatment. Fifty-five patients completed the PSS questionnaire at two time points (pre- and posttreatment). It showed a highly statistically significant change in PSS median score in patients experiencing stress (p < 0.001). DISCUSSION: The findings of the evaluation indicate that 8 weeks of AT appears to be effective in improving symptoms of concern to patients and enhancing patients' overall well-being. In particular, AT was found to be beneficial for patients with symptoms of anxiety, stress, depression, pain and insomnia.

Rising incidence, progression and changing patterns of liver disease in Wales 1999-2019.

BACKGROUND: Liver disease incidence and hence demand on hepatology services is increasing. AIM: To describe trends in incidence and natural history of liver diseases in Wales to inform effective provision of hepatology services. METHODS: The registry is populated by International Classification of Diseases-10 (ICD-10) code diagnoses for residents derived from mortality data and inpatient/day case activity between 1999-2019. Pseudo-anonymised linkage of: (1) Causative diagnoses; (2) Cirrhosis; (3) Portal hypertension; (4) Decompensation; and (5) Liver cancer diagnoses enabled tracking liver disease progression. RESULTS: The population of Wales in 2019 was 3.1 million. Between 1999 and 2019 73054 individuals were diagnosed with a hepatic disorder, including 18633 diagnosed with cirrhosis, 10965 with liver decompensation and 2316 with hepatocellular carcinoma (HCC). Over 21 years the incidence of liver diseases increased 3.6 fold, predominantly driven by a 10 fold increase in non-alcoholic fatty liver disease (NAFLD); the leading cause of liver disease from 2014. The incidence of cirrhosis, decompensation, HCC, and all-cause mortality tripled. Liver-related mortality doubled. Alcohol-related liver disease (ArLD), autoimmune liver disease and congestive hepatopathy were associated with the highest rates of decompensation and all-cause mortality. CONCLUSION: A 10 fold increase in NAFLD incidence is driving a 3.6 fold increase in liver disease in Wales over 21 years. Liver-related morbidity and mortality rose more slowly reflecting the lower progression rate in NAFLD. Incidence of ArLD remained stable but was associated with the highest rates of liver-related and all-cause mortality.

Real-world effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab on preventing hospital admission among higher-risk patients with COVID-19 in Wales: A retrospective cohort study.

OBJECTIVE: To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community. DESIGN: Retrospective cohort study of non-hospitalized adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank. SETTING: A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK. PARTICIPANTS: Adult patients with COVID-19 in the community, at higher risk of hospitalization and death, testing positive for SARS-CoV-2 between 16th December 2021 and 22nd April 2022. INTERVENTIONS: Molnupiravir, nirmatrelvir-ritonavir, and sotrovimab given in the community by local health boards and the National Antiviral Service in Wales. MAIN OUTCOME MEASURES: All-cause admission to hospital or death within 28 days of a positive test for SARS-CoV-2. STATISTICAL ANALYSIS: Cox proportional hazard model with treatment status (treated/untreated) as a time-dependent covariate and adjusted for age, sex, number of comorbidities, Welsh Index of Multiple Deprivation, and vaccination status. Secondary subgroup analyses were by treatment type, number of comorbidities, and before and on or after 20th February 2022, when omicron BA.1 and omicron BA.2 were the dominant subvariants in Wales. RESULTS: Between 16th December 2021 and 22nd April 2022, 7013 higher-risk patients were eligible for inclusion in the study. Of these, 2040 received treatment with molnupiravir (359, 17.6%), nirmatrelvir-ritonavir (602, 29.5%), or sotrovimab (1079, 52.9%). Patients in the treatment group were younger (mean age 53 vs 57 years), had fewer comorbidities, and a higher proportion had received four or more doses of the COVID-19 vaccine (36.3% vs 17.6%). Within 28 days of a positive test, 628 (9.0%) patients were admitted to hospital or died (84 treated and 544 untreated). The primary analysis indicated a lower risk of hospitalization or death at any point within 28 days in treated participants compared to those not receiving treatment. The adjusted hazard rate was 35% (95% CI: 18-49%) lower in treated than untreated participants. There was no indication of the superiority of one treatment over another and no evidence of a reduction in risk of hospitalization or death within 28 days for patients with no or only one comorbidity. In patients treated with sotrovimab, the event rates before and on or after 20th February 2022 were similar (5.0% vs 4.9%) with no significant difference in the hazard ratios for sotrovimab between the time periods. CONCLUSIONS: In higher-risk adult patients in the community with COVID-19, those who received treatment with molnupiravir, nirmatrelvir-ritonavir, or sotrovimab were at lower risk of hospitalization or death than those not receiving treatment.

Digital Approaches to Music-Making for People With Dementia in Response to the COVID-19 Pandemic: Current Practice and Recommendations.

Before COVID-19, dementia singing groups and choirs flourished, providing activity, cognitive stimulation, and social support for thousands of people with dementia in the UK. Interactive music provides one of the most effective psychosocial interventions for people with dementia; it can allay agitation and promote wellbeing. Since COVID-19 has halted the delivery of in-person musical activities, it is important for the welfare of people with dementia and their carers to investigate what alternatives to live music making exist, how these alternatives are delivered and how their accessibility can be expanded. This community case study examines recent practice in online music-making in response to COVID-19 restrictions for people with dementia and their supporters, focusing on a UK context. It documents current opportunities for digital music making, and assesses the barriers and facilitators to their delivery and accessibility. Online searches of video streaming sites and social media documented what music activities were available. Expert practitioners and providers collaborated on this study and supplied input about the sessions they had been delivering, the technological challenges and solutions they had found, and the responses of the participants. Recommendations for best practice were developed and refined in consultation with these collaborators. Over 50 examples of online music activities were identified. In addition to the challenges of digital inclusion and accessibility for some older people, delivering live music online has unique challenges due to audio latency and sound quality. It is necessary to adapt the session to the technology's limitations rather than expect to overcome these challenges. The recommendations highlight the importance of accessibility, digital safety and wellbeing of participants. They also suggest ways to optimize the quality of their musical experience. The pandemic has prompted innovative approaches to deliver activities and interventions in a digital format, and people with dementia and their carers have adapted rapidly. While online music is meeting a clear current need for social connection and cognitive stimulation, it also offers some advantages which remain relevant after COVID-19 restrictions are relaxed. The recommendations of this study are intended to be useful to musicians, dementia care practitioners, and researchers during the pandemic and beyond.

Developing a population data science approach to assess increased risk of COVID-19 associated with attending large events.

Introduction: In summer 2021, as rates of COVID-19 decreased and social restrictions were relaxed, live entertainment and sporting events were resumed. In order to inform policy on the safe re-introduction of spectator events, a number of test events were organised in Wales, ranging in setting, size and audience. Objectives: To design and test a method to assess whether test events were associated with an increase in risk of confirmed COVID-19, in order to inform policy. Methods: We designed a cohort study with fixed follow-up time and measured relative risk of confirmed COVID-19 in those attending two large sporting events. First, we linked ticketing information to individual records on the Welsh Demographic Service (WDS), a register of all people living in Wales and registered with a GP, and identified NHS numbers for attendees. Where NHS numbers were not found we used combinations of other identifiers such as email, name, postcode and/or mobile number. We then linked attendees to routine SARS-CoV-2 test data to calculate positivity rates in people attending each event for the period one to fourteen days following the event. We selected a comparison cohort from WDS for each event, individually matched by age band, gender and locality of residence. As many people attended events in family groups we explored the possibility of also matching on household clusters within the comparison group. Risk ratios were then computed for the two events. Results: We successfully assigned NHS numbers to 91% and 84% of people attending the two events respectively. Other identifiers were available for the remainder. Only a small number of attendees (<10) had a record of confirmed COVID-19 following attendance at each event (14 day cumulative incidence: 36 and 26 per 100,000, respectively). There was no evidence of significantly increased risk of COVID-19 at either event. However, the event that didn't include pre-event testing in their mitigations, had a higher risk ratio (3.0 compared to 0.3). Conclusions: We demonstrate the potential for using population data science methods to inform policy. We conclude that, at that point in the epidemic, and with the mitigations that were in place, attending large outdoor sporting events did not significantly increase risk of COVID-19. However, these analyses were carried out between epidemic waves when background incidence and testing rate was low, and need to be repeated during periods of greater transmission. Having a mechanism to identify attendees at events is necessary to calculate risk and feasibility and acceptability of data sharing should be considered.

Oxygen saturation instability in suspected covid-19 patients; contrasting effects of reduced VA/Q and shunt.

Patients in the UK at risk of Covid-19 pneumonia, but not needing immediate hospital attention, are to be given pulse oximeters to identify a fall in oxygen saturation (SaO2 or SpO2) at home. A recent finding in Covid-19 pneumonia is a dominant reduction in ventilation to perfused alveoli (VA/Q). A mathematical model of gas exchange was used to predict the effect of shunt or reduced VA/Q on SaO2 stability inferred from the slope of the PIO2 vs SaO2 curve as it intersected the line representing ambient PIO2. A {+/-}1 kPa variation in PIO2 predicted a 1.5% and 8% change in SpO2 with 15% shunt and 0.4 VA/Q respectively. As a consistency check, two patients with pre-existing lung disease and 12 hour continuous SpO2 monitoring breathing air had gas exchange impairment analysed in terms of shunt and reduced VA/Q. The patient with 16% shunt and normal VA/Q had a stable but reduced SpO2 (circa 93{+/-}1%) throughout the 12 hr period. The patient with a VA/Q reduced to 0.48 had SpO2 ranging from 75-95% during the same period. SpO2 monitoring in suspected covid-19 patients should focus on SpO2 varying >5% in 30 minutes. Such instability in at risk patients is not diagnostic of Covid-19 pneumonia but this may be suspected from a dominant reduction in VA/Q if episodic hypoxaemia has progressed from a stable SpO2.

Congenital myasthenic syndrome due to a TOR1AIP1 mutation: a new disease pathway for impaired synaptic transmission.

Congenital myasthenic syndromes are inherited disorders characterized by fatiguable muscle weakness resulting from impaired signal transmission at the neuromuscular junction. Causative mutations have been identified in genes that can affect the synaptic function or structure. We identified a homozygous frameshift deletion c.127delC, p. Pro43fs in TOR1AIP1 in two siblings with limb-girdle weakness and impaired transmission at the neuromuscular synapse. TOR1AIP1 encodes the inner nuclear membrane protein lamin-associated protein 1. On muscle biopsy from the index case, lamin-associated protein 1 was absent from myonuclei. A mouse model with lamin-associated protein 1 conditionally knocked out in striated muscle was used to analyse the role of lamin-associated protein 1 in synaptic dysfunction. Model mice develop fatiguable muscle weakness as demonstrated by using an inverted screen hang test. Electromyography on the mice revealed a decrement on repetitive nerve stimulation. Ex vivo analysis of hemi-diaphragm preparations showed both miniature and evoked end-plate potential half-widths were prolonged which was associated with upregulation of the foetal acetylcholine receptor γ subunit. Neuromuscular junctions on extensor digitorum longus muscles were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased. Following these findings, electromyography was performed on cases of other nuclear envelopathies caused by mutations in LaminA/C or emerin, but decrement on repetitive nerve stimulation or other indications of defective neuromuscular transmission were not seen. Thus, this report highlights the first nuclear membrane protein in which defective function can lead to impaired synaptic transmission.

Understanding and responding to COVID-19 in Wales: protocol for a privacy-protecting data platform for enhanced epidemiology and evaluation of interventions.

INTRODUCTION: The emergence of the novel respiratory SARS-CoV-2 and subsequent COVID-19 pandemic have required rapid assimilation of population-level data to understand and control the spread of infection in the general and vulnerable populations. Rapid analyses are needed to inform policy development and target interventions to at-risk groups to prevent serious health outcomes. We aim to provide an accessible research platform to determine demographic, socioeconomic and clinical risk factors for infection, morbidity and mortality of COVID-19, to measure the impact of COVID-19 on healthcare utilisation and long-term health, and to enable the evaluation of natural experiments of policy interventions. METHODS AND ANALYSIS: Two privacy-protecting population-level cohorts have been created and derived from multisourced demographic and healthcare data. The C20 cohort consists of 3.2 million people in Wales on the 1 January 2020 with follow-up until 31 May 2020. The complete cohort dataset will be updated monthly with some individual datasets available daily. The C16 cohort consists of 3 million people in Wales on the 1 January 2016 with follow-up to 31 December 2019. C16 is designed as a counterfactual cohort to provide contextual comparative population data on disease, health service utilisation and mortality. Study outcomes will: (a) characterise the epidemiology of COVID-19, (b) assess socioeconomic and demographic influences on infection and outcomes, (c) measure the impact of COVID-19 on short -term and longer-term population outcomes and (d) undertake studies on the transmission and spatial spread of infection. ETHICS AND DISSEMINATION: The Secure Anonymised Information Linkage-independent Information Governance Review Panel has approved this study. The study findings will be presented to policy groups, public meetings, national and international conferences, and published in peer-reviewed journals.

Exploring the association of the discharge medicines review with patient hospital readmissions through national routine data linkage in Wales: a retrospective cohort study.

OBJECTIVE: To evaluate the association of the discharge medicines review (DMR) community pharmacy service with hospital readmissions through linking National Health Service data sets. DESIGN: Retrospective cohort study. SETTING: All hospitals and 703 community pharmacies across Wales. PARTICIPANTS: Inpatients meeting the referral criteria for a community pharmacy DMR. INTERVENTIONS: Information related to the patient's medication and hospital stay is provided to the community pharmacists on discharge from hospital, who undertake a two-part service involving medicines reconciliation and a medicine use review. To investigate the association of this DMR service with hospital readmission, a data linking process was undertaken across six national databases. PRIMARY OUTCOME: Rate of hospital readmission within 90 days for patients with and without a DMR part 1 started. SECONDARY OUTCOME: Strength of association of age decile, sex, deprivation decile, diagnostic grouping and DMR type (started or not started) with reduction in readmission within 90 days. RESULTS: 1923 patients were referred for a DMR over a 13-month period (February 2017-April 2018). Provision of DMR was found to be the most significant attributing factor to reducing likelihood of 90-day readmission using χ2 testing and classification methods. Cox regression survival analysis demonstrated that those receiving the intervention had a lower hospital readmission rate at 40 days (p<0.000, HR: 0.59739, CI 0.5043 to 0.7076). CONCLUSIONS: DMR after a hospital discharge is associated with a reduction in risk of hospital readmission within 40 days. Linking data across disparate national data records is feasible but requires a complex processual architecture. There is a significant value for integrated informatics to improve continuity and coherency of care, and also to facilitate service optimisation, evaluation and evidenced-based practice.

Effects and costs of implementing predictive risk stratification in primary care: a randomised stepped wedge trial.

AIM: We evaluated the introduction of a predictive risk stratification model (PRISM) into primary care. Contemporaneously National Health Service (NHS) Wales introduced Quality and Outcomes Framework payments to general practices to focus care on those at highest risk of emergency admission to hospital. The aim of this study was to evaluate the costs and effects of introducing PRISM into primary care. METHODS: Randomised stepped wedge trial with 32 general practices in one Welsh health board. The intervention comprised: PRISM software; practice-based training; clinical support through two 'general practitioner (GP) champions' and technical support. The primary outcome was emergency hospital admissions. RESULTS: Across 230 099 participants, PRISM implementation increased use of health services: emergency hospital admission rates by 1 % when untransformed (while change in log-transformed rate ΔL=0.011, 95% CI 0.010 to 0.013); emergency department (ED) attendance rates by untransformed 3 % (while ΔL=0.030, 95% CI 0.028 to 0.032); outpatient visit rates by untransformed 5 % (while ΔL=0.055, 95% CI 0.051 to 0.058); the proportion of days with recorded GP activity by untransformed 1 % (while ΔL=0.011, 95% CI 0.007 to 0.014) and time in hospital by untransformed 3 % (while ΔL=0.029, 95% CI 0.026 to 0.031). Thus NHS costs per participant increased by £76 (95% CI £46 to £106). CONCLUSIONS: Introduction of PRISM resulted in a statistically significant increase in emergency hospital admissions and use of other NHS services without evidence of benefits to patients or the NHS.

Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap.

Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis.

Lesions and neurologic disability in inflammatory CNS diseases such as multiple sclerosis (MS) result from the translocation of leukocytes and humoral factors from the vasculature, first across the endothelial blood-brain barrier (BBB) and then across the astrocytic glia limitans (GL). Factors secreted by reactive astrocytes open the BBB by disrupting endothelial tight junctions (TJs), but the mechanisms that control access across the GL are unknown. Here, we report that in inflammatory lesions, a second barrier composed of reactive astrocyte TJs of claudin 1 (CLDN1), CLDN4, and junctional adhesion molecule A (JAM-A) subunits is induced at the GL. In a human coculture model, CLDN4-deficient astrocytes were unable to control lymphocyte segregation. In models of CNS inflammation and MS, mice with astrocyte-specific Cldn4 deletion displayed exacerbated leukocyte and humoral infiltration, neuropathology, motor disability, and mortality. These findings identify a second inducible barrier to CNS entry at the GL. This barrier may be therapeutically targetable in inflammatory CNS disease.

Karyopherin Alpha Proteins Regulate Oligodendrocyte Differentiation.

Proper regulation of the coordinated transcriptional program that drives oligodendrocyte (OL) differentiation is essential for central nervous system myelin formation and repair. Nuclear import, mediated in part by a group of karyopherin alpha (Kpna) proteins, regulates transcription factor access to the genome. Understanding how canonical nuclear import functions to control genomic access in OL differentiation may aid in the creation of novel therapeutics to stimulate myelination and remyelination. Here, we show that members of the Kpna family regulate OL differentiation, and may play distinct roles downstream of different pro-myelinating stimuli. Multiple family members are expressed in OLs, and their pharmacologic inactivation dose-dependently decreases the rate of differentiation. Additionally, upon differentiation, the three major Kpna subtypes (P/α2, Q/α3, S/α1) display differential responses to the pro-myelinating cues T3 and CNTF. Most notably, the Q/α3 karyopherin Kpna4 is strongly upregulated by CNTF treatment both compared with T3 treatment and other Kpna responses. Kpna4 inactivation results in inhibition of CNTF-induced OL differentiation, in the absence of changes in proliferation or viability. Collectively, these findings suggest that canonical nuclear import is an integral component of OL differentiation, and that specific Kpnas may serve vital and distinct functions downstream of different pro-myelinating cues.

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination.

Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage.

Oligodendrocytes derive from progenitors (OPCs) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis but was characterized by a profound defect of differentiation associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPCs is not sufficient to induce a lineage switch but acts as an important determinant of the coordination between RNA splicing and protein synthesis necessary for myelin formation.

Relapses in multiple sclerosis: Relationship to disability.

Multiple sclerosis (MS) is a recurrent inflammatory disease of the central nervous system, which ultimately causes substantial disability in many patients. A key clinical feature of this disease is the occurrence of relapses, consisting of episodes of neurological dysfunction followed by periods of remission. This review considers in detail the importance of the occurrence of relapses to the ultimate course of MS and the impact of relap setreatment (both acutely and prophylactically) on the long-term outcome for individuals. The ultimate goal of therapy in MS is the reduction of long-term disability. Clinical trials in MS, however, typically only extend for a very short time period compared to the time it takes for disability to evolve. Consequently, short-term outcome measures that are associated with, and predict, future disability need to be identified. In this regard, not only are relapses a characteristic feature of MS, they have also been proven to be associated with the occurrence of long-term disability. Moreover, treatments that reduce the number and severity of these attacks improve the long-term prognosis.

Prevalence of defined ultrasound findings of unknown significance at the second trimester fetal anomaly scan and their association with adverse pregnancy outcomes: the Welsh study of mothers and babies population-based cohort.

OBJECTIVE: The aim of this article was to estimate the population prevalence of seven defined ultrasound findings of uncertain significance ('markers') in the second trimester and the associated risk of adverse pregnancy outcomes. METHOD: A prospective record-linked cohort study of 30 078 pregnant women who had second trimester anomaly scans between July 2008 and March 2011 in Wales was conducted. RESULTS: The prevalence of markers ranged from 43.7 per 1000 singleton pregnancies for cardiac echogenic foci [95% confidence interval (CI): 38.8, 51.1] to 0.6 for mild-to-moderate ventriculomegaly (95% CI: 0.3, 1.0). Isolated echogenic bowel was associated with an increased risk of congenital anomalies [risk ratio (RR) 4.54, 95% CI: 2.12, 9.73] and preterm birth (RR 2.30, 95% CI: 1.08, 4.90). Isolated pelvicalyceal dilatation was associated with an increased risk of congenital anomalies (RR 3.82, 95% CI: 2.16, 6.77). Multiple markers were associated with an increased risk of congenital anomalies (RR 5.00, 95% CI: 1.35, 18.40) and preterm birth (RR 3.38, 95% CI 1.20, 9.53). CONCLUSIONS: These data are useful for counselling families and developing clinical guidance and care pathways following the detection of markers in clinical practice, particularly the need for follow-up scans to monitor placental function and growth in pregnancies with isolated echogenic bowel, and further investigation for multiple markers. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain.

Alterations in the structure and organization of the aging central nervous system (CNS), and associated functional deficits, result in cognitive decline and increase susceptibility to neurodegeneration. Age-related changes to the neurovascular unit (NVU), and their consequences for cerebrovascular function, are implicated as driving cognitive impairment during aging as well as in neurodegenerative disease. The molecular events underlying these effects are incompletely characterized. Similarly, the mechanisms underlying effects of factors that reduce the impact of aging on the brain, such as physical exercise, are also opaque. A study in this issue of PLOS Biology links the NVU to cognitive decline in the aging brain and suggests a potential underlying molecular mechanism. Notably, the study further links the protective effects of chronic exercise on cognition to neurovascular integrity during aging.

Update on biomarkers in neuromyelitis optica.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.