Illness representations of people with later-onset functional seizures.

PURPOSE: Although functional seizures can start at any age, little is known about the individuals for whom onset occurs after the age of 40. It has been proposed that health-related traumatic events are more relevant causal factors for people with 'later-onset functional seizures' than for those whose functional seizures begin earlier in life, however, the illness representations of people with later-onset functional seizures have not yet been investigated. This study aimed to understand the experiences and illness representations of people with later-onset functional seizures. METHODS: This was a mixed-methods study. People with later-onset functional seizures were recruited via a neurologist's caseload and online membership-led organisations. Semi-structured interview transcripts were analysed using Template Analysis according to the Common-Sense Model (CSM). Self-report measures of demographic and clinical details were collected to characterise the sample and verify themes. RESULTS: Eight people with later-onset functional seizures participated in the study. Illness representations relating to all domains of the CSM as well as an additional theme of 'Triggers' were identified. Functional seizures were characterised as a mysterious brain disorder analogous to a computer malfunction and involving involuntary movements associated with alterations in consciousness. Perceptions of duration were indefinite, and triggers were unknown or at the extremes of autonomic arousal. Half of the sample identified health-related events/trauma as causal. Opinions were divided on 'cumulative life stress' as a causal factor. Most perceived themselves to have limited or no control but having 'control' over seizures was conceptualised as different to reducing their likelihood, frequency, or impact. Later-onset functional seizures were viewed as being more detrimental for caring and financial responsibilities but to have advantages for acceptance. CONCLUSIONS: This is the first study to assess the illness representations of people with later-onset functional seizures. Many themes were similar to those identified in samples including people with earlier-onset functional seizures. Health-related trauma or events were the most strongly endorsed perceived causal factor, but with the exception of 'consequences', all representations were characterised by uncertainty. Clinicians should hold in mind the interaction between life stage and the consequences of later-onset functional seizures.

Directional hydrophone clusters reveal evasive responses of small cetaceans to disturbance during construction at offshore windfarms.

Mitigation measures to disperse marine mammals prior to pile-driving include acoustic deterrent devices and piling soft starts, but their efficacy remains uncertain. We developed a self-contained portable hydrophone cluster to detect small cetacean movements from the distributions of bearings to detections. Using an array of clusters within 10 km of foundation pile installations, we tested the hypothesis that harbour porpoises (Phocoena phocoena) respond to mitigation measures at offshore windfarm sites by moving away. During baseline periods, porpoise movements were evenly distributed in all directions. By contrast, animals showed significant directional movement away from sound sources during acoustic deterrent device use and piling soft starts. We demonstrate that porpoises respond to measures aimed to mitigate the most severe impacts of construction at offshore windfarms by swimming directly away from these sound sources. Portable directional hydrophone clusters now provide opportunities to characterize responses to disturbance sources across a broad suite of habitats and contexts.

Comparison of the marine soundscape before and during the COVID-19 pandemic in dolphin habitat in Sarasota Bay, FL.

During the COVID-19 pandemic, changes in vessel activity and associated noise have been reported globally. Sarasota Bay is home to a large and increasing number of recreational vessels as well as a long-term resident community of bottlenose dolphins, Tursiops truncatus. Data were analyzed from two hydrophones to compare the soundscape during the COVID-19 pandemic to previous years (March-May 2020 and 2018/2019). Hourly metrics were calculated: vessel passes, 95th percentile sound levels [125 Hz and 16 kHz third octave bands (TOBs), and two broader bands: 88-1122 Hz and 1781-17 959 Hz], and dolphin whistle detection to understand changes in vessel activity and the effect on wildlife. Vessel activity increased during COVID-19 restrictions by almost 80% at one site and remained the same at the other site. Of the four sound level measures, only the 125 Hz TOB and 88-1122 Hz band increased with vessel activity at both sites, suggesting that these may be appropriate measures of noise from rapid pass-bys of small vessels in very shallow (<10 m) habitats. Dolphin whistle detection decreased during COVID-19 restrictions at one site but remained the same at the site that experienced increased vessel activity. The results suggest that pandemic effects on wildlife should not be viewed as homogeneous globally.

Incidence and sociodemographic, living environment and maternal health associations with stillbirth in a tertiary healthcare setting in Kano, Northern Nigeria.

BACKGROUND: Almost two million stillbirths occur annually, most occurring in low- and middle-income countries. Nigeria is reported to have one of the highest stillbirth rates on the African continent. The aim was to identify sociodemographic, living environment, and health status factors associated with stillbirth and determine the associations between pregnancy and birth factors and stillbirth in the Murtala Mohammed Specialist Hospital, Kano, Nigeria. METHODS: A three-month single-site prospective observational feasibility study. Demographic and clinical data were collected. We fitted bivariable and multivariable models for stillbirth (yes/no) and three-category livebirth/macerated stillbirth/non-macerated stillbirth outcomes to explore their association with demographic and clinical factors. FINDINGS: 1,998 neonates and 1,926 mothers were enrolled. Higher odds of stillbirth were associated with low-levels of maternal education, a further distance to travel to the hospital, living in a shack, maternal hypertension, previous stillbirth, birthing complications, increased duration of labour, antepartum haemorrhage, prolonged or obstructed labour, vaginal breech delivery, emergency caesarean-section, and signs of trauma to the neonate following birth. INTERPRETATION: This work has obtained data on some factors influencing stillbirth. This in turn will facilitate the development of improved public health interventions to reduce preventable deaths and to progress maternal health within this site.

Antibiotic resistance genes in the gut microbiota of mothers and linked neonates with or without sepsis from low- and middle-income countries.

Early development of the microbiome has been shown to affect general health and physical development of the infant and, although some studies have been undertaken in high-income countries, there are few studies from low- and middle-income countries. As part of the BARNARDS study, we examined the rectal microbiota of 2,931 neonates (term used up to 60 d) with clinical signs of sepsis and of 15,217 mothers screening for blaCTX-M-15, blaNDM, blaKPC and blaOXA-48-like genes, which were detected in 56.1%, 18.5%, 0% and 4.1% of neonates' rectal swabs and 47.1%, 4.6%, 0% and 1.6% of mothers' rectal swabs, respectively. Carbapenemase-positive bacteria were identified by MALDI-TOF MS and showed a high diversity of bacterial species (57 distinct species/genera) which exhibited resistance to most of the antibiotics tested. Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae/E. cloacae complex, the most commonly found isolates, were subjected to whole-genome sequencing analysis and revealed close relationships between isolates from different samples, suggesting transmission of bacteria between neonates, and between neonates and mothers. Associations between the carriage of antimicrobial resistance genes (ARGs) and healthcare/environmental factors were identified, and the presence of ARGs was a predictor of neonatal sepsis and adverse birth outcomes.

The COVANOS trial - insight into post-COVID olfactory dysfunction and the role of smell training.

BACKGROUND: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted. METHODOLOGY: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants. RESULTS: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia. CONCLUSIONS: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

A follow-up on quantitative and qualitative olfactory dysfunction and other symptoms in patients recovering from COVID-19 smell loss.

BACKGROUND: Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection. METHODS: This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness. RESULTS: At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2. CONCLUSIONS: While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.

PrEP Use, Sexual Behaviour, and PrEP Adherence Among Men who have Sex with Men Living in Wales Prior to and During the COVID-19 Pandemic.

We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20-0.95), CAS (OR 0.35, 95%CI 0.17-0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34-0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade.

Who's challenging who training for staff empathy towards adults with challenging behaviour: cluster randomised controlled trial.

BACKGROUND: One in five adults with intellectual disabilities (ID) known to services display challenging behaviours (CBs), and these individuals are at risk for restrictive practices and poor care. Staff attitudes may contribute to the development and/or maintenance of CBs. We investigated the effectiveness of co-produced Who's Challenging Who? training delivered by people with ID to staff. METHOD: This study involved a cluster randomised controlled trial (RCT) of Who's Challenging Who? training with follow-up at six and 20 weeks post-randomisation. PARTICIPANTS: two staff from each of 118 residential care settings for adults with ID at least one of whom displayed aggressive CB. PRIMARY OUTCOME: Self-reported Staff Empathy for people with Challenging Behaviour Questionnaire. ANALYSIS: intention to treat of all randomised settings. ISCRTN registration: ISRCTN53763600. RESULTS: 118 residential settings (including 236 staff) were randomised to either receive training (59 settings) or to receive training after a delay (59 settings). The primary analysis included data from 121 staff in 76 settings (51% of staff, 64% of settings). The adjusted mean difference on the transformed (cubed) Staff Empathy for people with Challenging Behaviour Questionnaire score at the primary end point was 1073.2 (95% CI: -938.1 to 3084.5, P = 0.296) in favour of the intervention group (effect size Cohen's d = .19). CONCLUSIONS: This is the first large-scale RCT of a co-produced training course delivered by people with ID. Findings indicated a small positive (but statistically non-significant) effect on increased staff empathy at 20 weeks, and small to moderate effects for staff reported secondary outcomes in favour of the intervention group.

AKT overactivation can suppress DNA repair via p70S6 kinase-dependent downregulation of MRE11.

Deregulated AKT kinase activity due to PTEN deficiency in cancer cells contributes to oncogenesis by incompletely understood mechanisms. Here, we show that PTEN deletion in HCT116 and DLD1 colon carcinoma cells leads to suppression of CHK1 and CHK2 activation in response to irradiation, impaired G2 checkpoint proficiency and radiosensitization. These defects are associated with reduced expression of MRE11, RAD50 and NBS1, components of the apical MRE11/RAD50/NBS1 (MRN) DNA damage response complex. Consistent with reduced MRN complex function, PTEN-deficient cells fail to resect DNA double-strand breaks efficiently after irradiation and show greatly diminished proficiency for DNA repair via the error-free homologous recombination (HR) repair pathway. MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro. In primary human fibroblasts, activated AKT suppresses MRN complex expression to escalate RAS-induced DNA damage and thereby reinforce oncogene-induced senescence. Taken together, our data demonstrate that deregulation of the PI3K-AKT/ mTORC1/ p70S6K pathways, an event frequently observed in cancer, exert profound effects on genome stability via MRE11 with potential implications for tumour initiation and therapy.

PERK inhibits DNA replication during the Unfolded Protein Response via Claspin and Chk1.

Stresses such as hypoxia, nutrient deprivation and acidification disturb protein folding in the endoplasmic reticulum (ER) and activate the Unfolded Protein Response (UPR) to trigger adaptive responses through the effectors, PERK, IRE1 and ATF6. Most of these responses relate to ER homoeostasis; however, here we show that the PERK branch of the UPR also controls DNA replication. Treatment of cells with the non-genotoxic UPR agonist thapsigargin led to a rapid inhibition of DNA synthesis that was attributable to a combination of DNA replication fork slowing and reduced replication origin firing. DNA synthesis inhibition was dependent on the UPR effector PERK and was associated with phosphorylation of the checkpoint adaptor protein Claspin and activation of the Chk1 effector kinase, both of which occurred in the absence of detectable DNA damage. Remarkably, thapsigargin did not inhibit bulk DNA synthesis or activate Chk1 in cells depleted of Claspin, or when Chk1 was depleted or subject to chemical inhibition. In each case thapsigargin-resistant DNA synthesis was due to an increase in replication origin firing that compensated for reduced fork progression. Taken together, our results unveil a new aspect of PERK function and previously unknown roles for Claspin and Chk1 as negative regulators of DNA replication in the absence of genotoxic stress. Because tumour cells proliferate in suboptimal environments, and frequently show evidence of UPR activation, this pathway could modulate the response to DNA replication-targeted chemotherapies.

Cognitive behavioural anger management intervention for people with intellectual disabilities: costs of intervention and impact on health and social care resource use.

BACKGROUND: Anger and aggression among adults with intellectual disability (ID) are associated with a range of adverse consequences for their well-being and that of their family or staff carers. The aims were to evaluate the effectiveness of an anger management intervention for adults with mild to moderate ID and to evaluate the costs of the intervention and its impact on health and social care resource use. This paper is concerned with the latter aim. METHODS: A cluster-randomised controlled trial was conducted involving day services for adults with ID in Scotland, England and Wales. Incremental costs of delivering the intervention and its impact on subsequent total health and social care package costs were calculated. Full data comparing costs between baseline and follow-up 10 months later were collected for 67 participants in the intervention arm and 62 participants in the control arm. Cost differences between the groups at follow-up, adjusted for baseline levels, were calculated using non-parametric bootstrapping controlling for clustering. RESULTS: The mean hourly excess cost of intervention over treatment as usual was £12.34. A mean adjusted cost difference of £22.46 per person per week in favour of the intervention group was found but this was not statistically significant. CONCLUSIONS: The baseline-adjusted cost difference at follow-up would result in a fairly immediate compensation for the excess costs of intervention, provided the difference is not a statistical artefact. Further research is needed to clarify the extent to which it might represent a real saving in service support costs.

Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells.

While murine CD4(+) CD39(+) regulatory T cells (T(reg)) co-express CD73 and hydrolyze exogenous (e) adenosine triphosphate (ATP) to immunosuppressive adenosine (ADO), surface co-expression of CD73 on human circulating CD4(+) CD39(+) T(reg) is rare. Therefore, the ability of human T(reg) to produce and utilize ADO for suppression remains unclear. Using mass spectrometry, we measured nucleoside production by subsets of human CD4(+) CD39(+) and CD4(+) CD39(-)CD73(+) T cells or CD19(+) B cells isolated from blood of 30 volunteers and 14 cancer patients. CD39 and CD73 expression was evaluated by flow cytometry, Western blots, confocal microscopy or reverse transcription-polymerase chain reaction (RT-PCR). Circulating CD4(+) CD39(+) T(reg) which hydrolyzed eATP to 5'-AMP contained few intracytoplasmic granules and had low CD73 mRNA levels. Only ∼1% of these T(reg) were CD39(+) CD73(+) . In contrast, CD4(+) CD39(neg) CD73(+) T cells contained numerous CD73(+) granules in the cytoplasm and strongly expressed surface CD73. In vitro-generated T(reg) (Tr1) and most B cells were CD39(+) CD73(+) . All these CD73(+) T cell subsets and B cells hydrolyzed 5'-AMP to ADO. Exosomes isolated from plasma of normal control (NC) or cancer patients carried enzymatically active CD39 and CD73(+) and, when supplied with eATP, hydrolyzed it to ADO. Only CD4(+) CD39(+) T(reg) co-incubated with CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes produced ADO. Thus, contact with membrane-tethered CD73 was sufficient for ADO production by CD4(+) CD39(+) T(reg). In microenvironments containing CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes, CD73 is readily available to CD4(+) CD39(+) CD73(neg) T(reg) for the production of immunosuppressive ADO.

A cluster randomised controlled trial of a manualised cognitive behavioural anger management intervention delivered by supervised lay therapists to people with intellectual disabilities.

BACKGROUND: Anger is a frequent problem for many people with intellectual disabilities, and is often expressed as verbal and/or physical aggression. Cognitive-behaviour therapy (CBT) is the treatment of choice for common mental health problems, but CBT has only recently been adapted for people with intellectual disabilities. Anger is the main psychological presentation in which controlled trials have been used to evaluate CBT interventions for people with intellectual disabilities but these do not include rigorous randomised studies. OBJECTIVES: To evaluate (1) the impact of a staff-delivered manualised CBT anger management intervention on (a) reported anger among people with mild to moderate intellectual disabilities, and (b) anger coping skills, aggression, mental health, quality of life and costs of health and social care; (2) factors that influence outcome; and (3) the experience of service users, lay therapists and service managers. DESIGN: A cluster randomised controlled trial based on 30 day centres (15 intervention and 15 control). Intention-to-treat comparisons of outcomes used a two-level linear regression model to allow for clustering within centres with baseline outcome levels as a covariate. Comparison of cost data used non-parametric bootstrapping. Qualitative analysis used interpretative phenomenological analysis and thematic analysis. SETTING: Recruited day centres had four-plus service users with problem anger who were prepared to participate, two-plus staff willing to be lay therapists, a supportive manager and facilities for group work, and no current anger interventions. PARTICIPANTS: A total of 212 service users with problem anger were recruited. Thirty-three were deemed ineligible (30 could not complete assessments and three withdrew before randomisation). Retention at follow-up was 81%, with 17 withdrawals in each arm. Two to four staff per centre were recruited as lay therapists. Eleven service users, nine lay therapists and eight managers were interviewed. INTERVENTIONS: The manualised intervention comprised 12 weekly 2-hour group sessions supplemented by 'homework'. Lay therapists received training and ongoing supervision from a clinical psychologist. Treatment fidelity, group attendance and resources used in intervention delivery were monitored. MAIN OUTCOME MEASURES: The primary outcome was the service user-rated Provocation Index (PI), a measure of response to hypothetical situations that may provoke anger. Secondary trial outcomes were the key worker-rated PI; the service user- and key worker-rated Profile of Anger Coping Skills (PACS); the service user-rated PACS imaginal provocation test (PACS-IPT), a measure of response to actual situations known to provoke anger; aggression; mental health; self-esteem; quality of life; and health and social care resource use. Assessments were administered before randomisation and at 16 weeks and 10 months after randomisation. RESULTS: Fourteen treatment groups were delivered, each with 12 sessions lasting an average of 114 minutes, with a mean of 4.9 service users and 2.0 lay therapists. The mean hourly cost per service user was £ 25.26. The mean hourly excess cost over treatment as usual was £ 12.34. There was no effect of intervention on the primary outcome - self-rated PI. There was a significant impact on the following secondary outcomes at the 10-month follow-up: key worker-rated PI, self-rated PACS-IPT and self- and key worker-rated PACS. Key workers and home carers reported significantly lower aggression at 16 weeks, but not at 10 months. There was no impact on mental health, self-esteem, quality of life or total cost of health and social care. Service users, key workers and service managers were uniformly positive. CONCLUSIONS: The intervention was effective at changing anger coping skills and staff-rated anger. Impact on self-rated anger was equivocal. With hindsight there are reasons, from an analysis of factors influencing outcomes, to think that self-rated PI was not a well-chosen primary outcome. Widespread implementation of manualised lay therapist-led but psychologist-supervised anger management CBT for people with mild to moderate intellectual disabilities is recommended.