Human Antibodies Protect against Aerosolized Eastern Equine Encephalitis Virus Infection.

Eastern equine encephalitis virus (EEEV) is one of the most virulent viruses endemic to North America. No licensed vaccines or antiviral therapeutics are available to combat this infection, which has recently shown an increase in human cases. Here, we characterize human monoclonal antibodies (mAbs) isolated from a survivor of natural EEEV infection with potent (<20 pM) inhibitory activity of EEEV. Cryo-electron microscopy reconstructions of two highly neutralizing mAbs, EEEV-33 and EEEV-143, were solved in complex with chimeric Sindbis/EEEV virions to 7.2 Å and 8.3 Å, respectively. The mAbs recognize two distinct antigenic sites that are critical for inhibiting viral entry into cells. EEEV-33 and EEEV-143 protect against disease following stringent lethal aerosol challenge of mice with highly pathogenic EEEV. These studies provide insight into the molecular basis for the neutralizing human antibody response against EEEV and can facilitate development of vaccines and candidate antibody therapeutics.

Target-selective vertebrate motor axon regeneration depends on interaction with glial cells at a peripheral nerve plexus.

A critical step for functional recovery from peripheral nerve injury is for regenerating axons to connect with their pre-injury targets. Reestablishing pre-injury target specificity is particularly challenging for limb-innervating axons as they encounter a plexus, a network where peripheral nerves converge, axons from different nerves intermingle, and then re-sort into target-specific bundles. Here, we examine this process at a plexus located at the base of the zebrafish pectoral fin, equivalent to tetrapod forelimbs. Using live cell imaging and sparse axon labeling, we find that regenerating motor axons from 3 nerves coalesce into the plexus. There, they intermingle and sort into distinct branches, and then navigate to their original muscle domains with high fidelity that restores functionality. We demonstrate that this regeneration process includes selective retraction of mistargeted axons, suggesting active correction mechanisms. Moreover, we find that Schwann cells are enriched and associate with axons at the plexus, and that Schwann cell ablation during regeneration causes profound axonal mistargeting. Our data provide the first real-time account of regenerating vertebrate motor axons navigating a nerve plexus and reveal a previously unappreciated role for Schwann cells to promote axon sorting at a plexus during regeneration.

Agrin/Lrp4 signal constrains MuSK-dependent neuromuscular synapse development in appendicular muscle.

The receptor tyrosine kinase MuSK, its co-receptor Lrp4 and the Agrin ligand constitute a signaling pathway that is crucial in axial muscle for neuromuscular synapse development, yet whether this pathway functions similarly in appendicular muscle is unclear. Here, using the larval zebrafish pectoral fin, equivalent to tetrapod forelimbs, we show that, similar to axial muscle, developing appendicular muscles form aneural acetylcholine receptor (AChR) clusters prior to innervation. As motor axons arrive, neural AChR clusters form, eventually leading to functional synapses in a MuSK-dependent manner. We find that loss of Agrin or Lrp4 function, which abolishes synaptic AChR clusters in axial muscle, results in enlarged presynaptic nerve regions and progressively expanding appendicular AChR clusters, mimicking the consequences of motoneuron ablation. Moreover, musk depletion in lrp4 mutants partially restores synaptic AChR patterning. Combined, our results provide compelling evidence that, in addition to the canonical pathway in which Agrin/Lrp4 stimulates MuSK activity, Agrin/Lrp4 signaling in appendicular muscle constrains MuSK-dependent neuromuscular synapse organization. Thus, we reveal a previously unappreciated role for Agrin/Lrp4 signaling, thereby highlighting distinct differences between axial and appendicular synapse development.

Regional AT-8 reactive tau species correlate with intracellular Aß levels in cases of low AD neuropathologic change.

The amyloid cascade hypothesis states that Aß aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the spatio-temporal divide between plaques and NFTs. This has been addressed by the inclusion of soluble Aß and tau species in the revised amyloid cascade hypothesis. Nevertheless, despite the potential for non-plaque Aß to contribute to tau pathology, few studies have examined relative correlative strengths between total Aß, plaque Aß and intracellular Aß with tau pathology within a single tissue cohort. Employing frozen and fixed frontal cortex grey and white matter tissue from non-AD controls (Con; n = 39) and Alzheimer's disease (AD) cases (n = 21), biochemical and immunohistochemical (IHC) measures of Aß and AT-8 phosphorylated tau were assessed. Biochemical native-state dot blots from crude tissue lysates demonstrated robust correlations between total Aß and AT-8 tau, when considered as a combined cohort (Con and AD) and when as Con and AD cases, separately. In contrast, no associations between Aß plaques and AT-8 were reported when using IHC measurements in either Con or AD cases. However, when intracellular Aß was measured via the Aß specific antibody MOAB-2, a correlative relationship with AT-8 tau was reported in non-AD controls but not in AD cases. Collectively the data suggests that accumulating intracellular Aß may influence AT-8 pathology, early in AD-related neuropathological change. Despite the lower levels of phospho-tau and Aß in controls, the robust correlative relationships observed suggest a physiological association of Aß production and tau phosphorylation, which may be modified during disease. This study is supportive of a revised amyloid cascade hypothesis and demonstrates regional associative relationships between tau pathology and intracellular Aß, but not extracellular Aß plaques.

A randomized comparison of online mindfulness-based group sex therapy vs supportive group sex education to address sexual dysfunction in breast cancer survivors.

BACKGROUND: Sexual difficulties and vaginal pain are common following treatment for breast cancer. AIM: The goal of this study was to evaluate an online mindfulness-based group sex therapy vs an online supportive sex education group therapy to address these sexual difficulties. METHODS: Breast cancer survivors (n = 118) were randomized to 1 of the 2 arms; 116 provided informed consent and completed the time 1 assessment. Treatment included 8 weekly 2-hour online group sessions. Those randomized to the mindfulness group completed daily mindfulness exercises, and those in the comparison arm read and completed exercises pertaining to sex education. OUTCOMES: Assessments were repeated at posttreatment and 6 months after the completion of the group. RESULTS: There was a main effect of treatment on primary endpoints of sexual desire, sexual distress, and vaginal pain, with all outcomes showing significant improvements, with no differential impact by treatment arm. Secondary endpoints of interoceptive awareness, mindfulness, and rumination about sex also significantly improved with both treatments, with no group-by-time interaction. CONCLUSION: Both mindfulness-based sex therapy and supportive sex education delivered in group format online are effective for improving many facets of sexual function, vaginal pain, rumination, mindfulness, and interoceptive awareness in breast cancer survivors. STRENGTHS AND LIMITATIONS: We used a randomized methodology. Future studies should seek to diversify participants. CLINICAL IMPLICATIONS: These findings highlight the need to offer similar treatments to more breast cancer survivors immediately after and in the years following cancer treatment as a means of improving survivorship quality of life.

Incorporating transgender and nonbinary participants in phase 1 clinical drug trials: Current knowledge gaps and considerations.

Phase 1 clinical drug trials critically depend on the participation of healthy volunteers to evaluate the safety and pharmacokinetics of new medicinal products. Current selection criteria and health definitions often overlook the unique health profiles of transgender and nonbinary individuals, potentially excluding them from participating in these essential early-stage studies. This review aims to identify and discuss current knowledge gaps and considerations regarding the inclusion of transgender and nonbinary participants in phase 1 clinical drug trials. We highlight the need for research on how gender-affirming hormone therapy may affect drug pharmacokinetics and call for the development of inclusive biological reference ranges that account for the physiological effects of hormone therapies.

Oligomer Formation Effects on the Separation of Trivalent Lanthanide Fission Products.

The assessment of trivalent lanthanide yields from the fission of uranium-235 is currently achieved using LN (LaNthanide) resin, di(2-ethylhexyl)orthophosphoric acid immobilized on a solid support. However, coelution of lighter lanthanides into terbium (Tb3+) fractions remains a significant problem in recovery of analytically pure fractions. In order to understand how the separation of trivalent lanthanides and yttrium (Ln3+) with LN resin proceeds and how to improve it, their speciation with the organic extractant HDEHP must be fully understood under aqueous conditions. A comprehensive luminescence analysis of aqueous solutions of Ln3+ in contact with HDEHP, along with infrared spectroscopy, elemental combustion analysis, inductively coupled plasma atomic emission spectroscopy (ICP-AES), and mass spectrometry, was used to indicate that an intermediate species is responsible for the coelution; where similar Ln3+ centers (e.g., Eu3+ and Tb3+) are bridged by the O-P-O moiety of deprotonated HDEHP to form large heteronuclear oligomeric structures with the general formula [Ln2(DEHP)6]n. Energy transfer from Tb3+ to Eu3+ in this structure confirms that lanthanide centers are within 10 Å and was used to propose that the oligomeric [Ln2(DEHP)6]n structure is formed rather than a dimeric Ln2(DEHP)6 structure. The effect of this speciation on LN resin column elution is investigated using luminescence spectroscopy, confirming that the oligomeric [Ln2(DEHP)6]n species could disrupt regular elution behavior and cause the problematic bleeding of lighter lanthanides (Sm3+ and Eu3+) into Tb3+ fractions. Resin luminescence measurements were used to propose that the bleeding of the organic extractant HDEHP from its solid support causes the formation of the disruptive oligometallic species.

Patient Reported Sexual Adaptation Following Prostate Cancer Treatment: An Analysis of Related Variables and Sexual Outcomes Associated with Sexual Adaptation Styles.

Sexual concerns after prostate cancer (PCa) treatment are high. Flexible coping is a crucial element to maintaining sexual activity after PCa and improves adaptation outcomes. We aimed to identify potential sexual adaptation styles reported by men following PCa treatment, and to assess relationships among associated variables and outcomes. Individuals (n = 223) with PCa treatment history (e.g., radical prostatectomy [n = 165, 74.0%], external beam radiation [n = 83, 37.2%], hormone/androgen deprivation therapy [n = 83, 37.2%]), completed an online survey assessing sexual variables and processes of sexual adaptation. Using a combination of inductive and deductive coding, open-ended responses were thematically analyzed and grouped into sexual adaptation styles. Factors potentially associated with sexual adaptation styles (e.g., age, perceived partner involvement, co-morbidities, relationship duration, time since PCa treatment, desire for physical affection, depression, relationship adjustment) were tested using multinomial logistic regression. Outcomes of sexual well-being (sexual distress, sexual bother, sexual satisfaction) and relationship adjustment were compared against each sexual adaptation style using a multivariate analysis of variance. Sexual activity status and satisfaction with the adaptation process was assessed across the sexual adaptation styles using a chi-square analysis and post-hoc tests. Two distinct categories were identified: those who had Adapted (n = 185) and those who had Not Adapted (n = 38). Four sexual adaptation styles emerged in the adapted category: Relationship Renegotiation (n = 53) and Sexual Renegotiation (n = 47), which were couples-focused styles, and Acceptance/Resignation (n = 34) and Masturbation/Erection (n = 48), which were individual-focused styles. Participants who could not be categorized as one style, but rather met several, were identified as Mixed (n = 3). Higher rates of depression, lower relationship adjustment, lack of sexual activity, and greater dissatisfaction with the adaptation process were observed for Not Adapted participants. Participants engaged in any type of adaptation style fared better than those who had Not Adapted. Couples-focused styles tended to emphasize renegotiation, including a changed perspective on the expression of the relationship. Perceived direct engagement of the partner facilitated adaptation and emphasized engagement with flexible coping, either through redefining priorities or ways of being sexual. Individual-focused styles emphasized pre-cancer erectile function, and either aimed to return to capacity for penetrative sexual activity or accepted its inaccessibility and largely an abandonment of partnered sexual activity.

Neonatal Extracorporeal Membrane Oxygenation: Associations between Continuous Renal Replacement Therapy, Thrombocytopenia, and Outcomes.

INTRODUCTION: The incidence of thrombocytopenia in neonates receiving extracorporeal membrane oxygenation (ECMO) with and without concurrent continuous renal replacement therapy (CRRT) and associated complications have not been well described. The primary aims of the current study were to (1) characterize thrombocytopenia in neonates receiving ECMO (including treated concurrently with CRRT) and (2) evaluate risk factors (including CRRT utilization) associated with severe thrombocytopenia. In a planned exploratory secondary aim, we explored the association of severe thrombocytopenia with outcomes in neonates receiving ECMO. METHODS: We conducted a retrospective single-center chart review of neonates who received ECMO 07/01/14 - 03/01/20 and evaluated associations between CRRT, severe thrombocytopenia (platelet count <50,000/mm3), and outcomes (ECMO duration, length of stay, and survival). RESULTS: Fifty-two neonates received ECMO; 35 (67%) received concurrent CRRT. Severe thrombocytopenia occurred in 27 (52%) neonates overall and in 21 (60%) neonates who received concurrent CRRT. Underlying diagnosis, ECMO mode, care unit, and moderate/severe hemolysis differed between those who did and did not receive CRRT. CRRT-receivers experienced shorter hospital stays than CRRT non-receivers, but ECMO duration, length of intensive care unit (ICU) stay, and survival did not differ between groups. CRRT receipt was associated with severe thrombocytopenia. Exploratory classification and regression tree (CART) analysis suggests CRRT use, birthweight, and ICU location are all predictors of interest for severe thrombocytopenia. CONCLUSIONS: In our cohort, CRRT use during ECMO was associated with severe thrombocytopenia, and patients who received ECMO with CRRT experienced shorter hospital stays than those who did not receive CRRT. Exploratory CART analysis suggests CRRT use, birthweight, and ICU location are all predictors for severe thrombocytopenia and warrant further investigations in larger studies.

Shaping research for people living with co-existing mental and physical health conditions: A research priority setting initiative from the United Kingdom.

INTRODUCTION: Those with severe and enduring mental ill health are at greater risk of long-term physical health conditions and have a reduced life expectancy as a result. Multiple factors compound this health inequality, and the need for setting research priorities in this area is highlighted with physical and mental healthcare services being separate, and limited multimorbidity research. METHODS: The aim of this exercise was to work in partnership with healthcare professionals and carers, family, friends and individuals with lived experience of both mental and physical health conditions, to set research priorities to help people with mental health conditions to look after their physical health. The exercise was guided by the James Lind Alliance approach. For this, a steering group was set up, two surveys were completed and a final priority workshop was conducted. RESULTS: This priority setting exercise guided by people's needs and lived experience has produced a set of well-defined research topics. Initially, 555 research questions were suggested in the first survey, which were refined to 54 questions for the second survey. A priority setting workshop was then conducted to get the final 10 priorities. CONCLUSIONS: Taking these topics forward to improve services and treatment for both mental and physical ill health may in turn improve physical health and lessen the reduced life expectancy of those living with mental ill health. PATIENT OR PUBLIC CONTRIBUTION: This work was completed in collaboration with people who have lived experience of mental ill health and physical health conditions, as well as carers, family and friends. Their contribution has been significant for this work from piloting surveys, amending language used and educating the researchers and contributing to this paper. The initial work was completed with a steering group and continued with surveys and workshops.

Understanding perceptions of the public and key stakeholders toward a localised cancer screening promotion campaign.

The aim of this study was to explore perceptions of members of the public and key stakeholders of a localised campaign to increase engagement with cervical cancer screening. Whilst numerous interventions have been trialled to increase engagement with cancer screening, the evidence for their effectiveness is somewhat mixed. In addition, few studies have explored the perceptions of members of the public targeted by such campaigns nor the perceptions of healthcare professionals who may be involved in delivering such campaigns in the United Kingdom. Members of the public who had potentially been exposed to the campaign in the North-East of England were approached to take part in individual interviews whilst stakeholders were invited to take part in a focus group. A total of 25 participants (13 members of the public, 12 stakeholders) took part. All interviews were audio recorded, transcribed verbatim and analysed using applied thematic analysis. Four themes were identified, two of which were cross-cutting (barriers to screening and factors promoting screening), with one theme identified as specific to the public interviews (knowledge of and attitudes toward awareness campaigns) and one theme specific to the focus group (keeping campaigns relevant. Awareness of the localised campaign was limited; however, when made aware, participants were mostly positive towards the approach, although mixed responses were noted in relation to financial incentives. Members of the public and stakeholders identified some common barriers to screening although differed in their perceptions of promotional factors. This study highlights the importance of multiple strategies to promote cervical screening as one size fits all approach may limit engagement.

Health-risk behaviours among people with severe mental ill health: understanding modifiable risk in the Closing the Gap Health Study.

BACKGROUND: People with severe mental ill health (SMI) experience some of the largest health inequalities of any sector within society. For these inequalities to be reduced, an understanding of the behavioural determinants of health in this population is needed. AIMS: Utilising data from the Closing the Gap Health Study, we aimed to assess the extent to which people with SMI report health-risk factors and behaviours, their interest in modifying them, and the factors associated with being motivated to modify these behaviours. METHOD: Adult (≥18 years old) participants were recruited via primary and secondary care in the English National Health Service. To be eligible, participants needed to have a documented diagnosis of schizophrenia, psychotic disorders or bipolar disorder. Data were collected by survey on demographics, general physical health, diet, physical activity, alcohol, smoking and body mass index. RESULTS: Between April 2016 and March 2020, n = 9914 participants were recruited. Among people with SMI, high rates of obesity (37.5%), infrequent physical activity (62.0%), not meeting current guidelines (≥5) for the consumption of fruit and vegetables (85.0%) and smoking (42.2%) were observed. However, most participants were motivated to reduce health-risk behaviours. Perceiving the importance of health-promoting behaviours, being of poorer general health and being female were significantly associated with being motivated to modify health-risk behaviours. CONCLUSIONS: Despite experiencing poor physical and mental health outcomes compared with the general population, and contrary to popular misconceptions, people with SMI perceive health as important and are motivated to make behavioural changes to improve health.

Prion-like α-synuclein pathology in the brain of infants with Krabbe disease.

Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.

Feasibility and Acceptability of a Group-Based Mindfulness Intervention for Sexual Interest/Arousal Disorder Following Breast Cancer Treatment.

This study aimed to assess feasibility and preliminary efficacy of an 8-week Mindfulness-Based Cognitive Therapy (MBCT) group program to treat Sexual Interest/Arousal Disorder (SIAD) in women following breast cancer (BrCa) treatment. Thirty women participated, of whom 67% (n = 20) attended at least 6 of 8 group sessions. Feedback indicated the program was relevant and valuable; minor modifications were suggested to further address survivorship concerns. Results of pre-post questionnaires demonstrated significant improvements in sexual distress and sexual interest/desire, with large effect sizes. Results support the feasibility and preliminary efficacy of an 8-week MBCT program among women following breast cancer treatment.

Interventions for reducing anticholinergic medication burden in older adults-a systematic review and meta-analysis.

INTRODUCTION: Anticholinergic medications block the neurotransmitter acetylcholine in the brain and peripheral nervous system. Many medications have anticholinergic properties, and the cumulative effect of these medications is termed anticholinergic burden. Increased anticholinergic burden can have short-term side effects such as dry mouth, blurred vision and urinary retention as well as long-term effects including dementia, worsening physical function and falls. METHODS: We carried out a systematic review (SR) with meta-analysis (MA) looking at randomised controlled trials addressing interventions to reduce anticholinergic burden in older adults. RESULTS: We identified seven papers suitable for inclusion in our SR and MA. Interventions included multi-disciplinary involvement in medication reviews and deprescribing of AC medications. Pooled data revealed no significant difference in outcomes between control and intervention group for falls (OR = 0.76, 95% CI: 0.52-1.11, n = 647), cognition (mean difference = 1.54, 95% CI: -0.04 to 3.13, n = 405), anticholinergic burden (mean difference = 0.04, 95% CI: -0.11 to 0.18, n = 710) or quality of life (mean difference = 0.04, 95% CI: -0.04 to 0.12, n = 461). DISCUSSION: Overall, there was no significant difference with interventions to reduce anticholinergic burden. As we did not see a significant change in anticholinergic burden scores following interventions, it is likely other outcomes would not change. Short follow-up time and lack of training and support surrounding successful deprescribing may have contributed.

Immunomodulatory interventions for focal epilepsy.

BACKGROUND: This is an updated version of an original Cochrane Review published in 2013 (Walker 2013). Epilepsy is a common neurological disorder affecting 0.5% to 1% of the population. Pharmacological treatment remains the first choice to control epilepsy. However, up to 30% of people do not respond to drug treatment, and therefore do not achieve seizure remission. Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy. OBJECTIVES: To assess the efficacy and tolerability of immunomodulatory interventions on seizures, adverse effect profile, cognition, and quality of life, compared to placebo controls, when used as additional therapy for focal epilepsy in children and adults. SEARCH METHODS: For the latest update, we searched the following databases on 11 November 2021: Cochrane Register of Studies (CRS Web) and Medline (Ovid) 1946 to 10 November 2021. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. We placed no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies. SELECTION CRITERIA: Randomised placebo-controlled trials of add-on immunomodulatory drug interventions, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. Eligible participants were children (aged over 2 years) and adults with focal epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. We assessed the following outcomes. 1. 50% or greater reduction in seizure frequency. 2. Seizure freedom. 3. Treatment withdrawal for any reason. 4. Quality of life. 5. ADVERSE EFFECTS: We used an intention-to-treat (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (95% Cl). MAIN RESULTS: We included three randomised, double-blind, placebo-controlled trials on a total of 172 participants. All trials included children and adults over two years of age with focal epilepsy. Treatment phases lasted six weeks and follow-up from six weeks to six months. One of the three included trials described an adequate method of concealment of randomisation, whilst the other two trials were rated as having an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in all three trials. All analyses were by ITT. One trial was sponsored by the manufacturer of an immunomodulatory agent and therefore was at high risk of funding bias. Immunomodulatory interventions were significantly more effective than placebo in reducing seizure frequency (risk ratio (RR) 2.30, 95% confidence interval (CI) 1.15 to 4.60; 3 studies, 172 participants; moderate-certainty evidence). For treatment withdrawal, there was insufficient evidence to conclude that people were more likely to discontinue immunomodulatory intervention than placebo (RR 1.04, 95% CI 0.28 to 3.80; 3 studies, 172 participants; low-certainty evidence). The RR for adverse effects was 1.16 (95% CI 0.84 to 1.59; 1 study, 66 participants; low-certainty evidence). Certain adverse effects such as dizziness, headache, fatigue, and gastrointestinal disorders were more often associated with immunomodulatory interventions. There were little to no data on cognitive effects and quality of life. No important heterogeneity between studies was found for any of the outcomes. We judged the overall certainty of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals. AUTHORS' CONCLUSIONS: Immunomodulatory interventions as add-on treatment for children and adults with focal epilepsy appear to be effective in reducing seizure frequency. It is not possible to draw any conclusions about the tolerability of these agents in children and adults with epilepsy. Further randomised controlled trials are needed.

Peer supporters' mental health and emotional wellbeing needs: Key factors and opportunities for co-produced training.

INTRODUCTION: Peer supporters are a valuable asset to mental health and support services, but their own mental health needs are often overlooked in research and practice. This study explored peer supporters' perceived challenges of maintaining their mental health and emotional wellbeing and co-produced training needs. METHODS: A qualitative approach was used to explore factors affecting peer supporters' mental health and emotional wellbeing. Semi-structured interviews and focus groups were conducted online with 11 peer supporters across North East England. RESULTS: A thematic analysis identified: 'Lack of training and support', 'Role ambiguity' and 'Emotional labour' as challenges experienced by peer supporters in relation to maintaining their mental health and emotional wellbeing. Peer supporters' own lived experiences had the potential to act as a barrier towards providing support to others. Conflict with peer 'supportees' sometimes negatively impacted on the peer supporter experience. Participant responses emphasised a need for person-centred, co-produced training. CONCLUSION: This work highlights the need for targeted training for peer supporters, including both role-specific education and strategies to support their mental health and emotional wellbeing. PATIENT OR PUBLIC CONTRIBUTION: Participants were contacted and asked to provide feedback on finalised themes to ensure the analysis was congruent with their experiences, further enabling the future development of an emotional wellbeing training programme for peer supporters.

Examining Healthcare Professionals' Communication Around Decision-Making with Internet-Informed Patients.

In the last ten years the use of the internet as a health resource has transformed, and while patients increasingly consult online resources for health decision-making, less is known about how healthcare professionals (HCPs) currently discuss decision-making with internet informed patients (IIPs). In this paper we examine how HCPs perceive IIPs and specifically how bringing online information into appointments can prompt different communicative strategies around decision-making. Ten HCPs with experience working across different healthcare roles, took part in semi-structured interviews and discussed their interactions with IIPs around decision-making. Vignettes based on descriptions of real patients bringing online health information to their HCPs were used to prompt further discussion. The analysis identified two themes in relation to communication: (i) being honest about information sources and (ii) from compliance to co-construction: improving communication around decision-making. HCPs were overwhelmingly positive toward IIPs and encouraged patients to be transparent about their online searching to understand their motivations, priorities, and concerns. Although compliance remains part of the narrative, HCPs recognized practical ways in which discussing online health information could improve HCP-patient communication around shared decision-making. We discuss the findings in relation to early work on communicative strategies between HCP's and patients bringing resources to their consultations. We argue that for HCPs the concept of the internet as a provider of health information is no longer seen as inherently damaging or risky. There is growing acceptance of pre-consultation internet searching with the caveat that any information sourced online should inform rather than dictate decision-making with HCPs.

Pharmacokinetics of ß-d-N4-Hydroxycytidine, the Parent Nucleoside of Prodrug Molnupiravir, in Nonplasma Compartments of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

ß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at SARS-CoV-2 transmission sites in 12 patients enrolled in AGILE Candidate-Specific Trial-2. Saliva, nasal, and tear NHC concentrations were 3%, 21%, and 22% that of plasma. Saliva and nasal NHC were significantly correlated with plasma (P < .0001). Clinical Trials Registration. NCT04746183.

Dysfunction of the blood-brain barrier in Alzheimer's disease: Evidence from human studies.

The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer's disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid-ß (Aß) aggregation, vascular damage and altered immune response interact at the blood-brain barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta-analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid-ß or ß-amyloid or abeta and BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise BBB damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD-specific brain regions. The toxic effects of Aß and apolipoprotein E (ApoE) are likely to induce a non-cerebral-amyloid-angiopathy-related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, proinflammatory signalling and cerebral amyloid angiopathy enhance BBB damage. Novel therapeutic approaches for AD, including magnetic resonance-guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aß along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE-modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of proinflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aß deposition as a primary versus a secondary event in the complex pathogenesis of AD.