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Abstract Background Paramedics are responsible for critical resuscitation decisions when attending Out of Hospital Cardiac Arrests (OHCA). Existing research indicates that a range of clinical and non-clinical factors moderate their decision-making. Within the United Kingdom (UK), there is little evidence on how and why paramedics make their decisions at actual OHCA events. Methods We explored the experiences of UK paramedics using individually recalled OHCA events as catalysts for discussion. Pen portraits developed from semi-structured interviews with 31 paramedics across two UK ambulance services were thematically analysed, enabling cross-participant comparisons whilst retaining depth and context. Results We identified four themes: uncertainties encountered in resuscitation guidelines, influences on decision-making, holistic perspectives, and indirect moderators. We found that paramedics experienced uncertainty at all stages of the resuscitation process. Uncertainties arose from indeterminate, ambiguous or complex information and were described as having both clinical and ethical dimensions. Whilst guidelines drove paramedics’ decisions, non-clinical personal, practical and relational factors moderated their assessments of survivability and decision-making, with attitudes to interactions between patient age, frailty and quality of life playing a substantial role. Coping strategies such as uncertainty reduction, assumption-based reasoning and weighing pros and cons were evident from interviews. Conclusions The complexity of interactions between clinical and non-clinical factors points to an element of variability in paramedics’ responses to uncertainty. Exploring UK paramedics’ uncertainties and decision-making during specific OHCA events can help acknowledge and address uncertainties in resuscitation guidelines and paramedic training, providing paramedics with the tools to manage uncertainty in a consistent and transparent way.

Abstract This paper employs insights from earth science on the financial risk of project developments to present an economic theory of critical minerals. Our theory posits that back-ended critical mineral projects that have unaddressed technical and non-technical barriers, such as those involving lithium and cobalt, exhibit an additional risk for investors which we term the “back-ended risk premium”. We show that the back-ended risk premium increases the cost of capital and, therefore, has the potential to reduce investment in the sector. We posit that the back-ended risk premium may also reduce the gains in productivity expected from artificial intelligence (AI) technologies in the mining sector. Progress in AI may, however, lessen the back-ended risk premium itself by shortening the duration of mining projects and the required rate of investment by reducing the associated risk. We conclude that the best way to reduce the costs associated with energy transition is for governments to invest heavily in AI mining technologies and research.

Abstract Background Preterm infants often require non-invasive breathing support while their lungs and control of respiration are still developing. Non-invasive neurally adjusted ventilatory assist (NIV-NAVA) is an emerging technology that allows infants to breathe spontaneously while receiving support breaths proportional to their effort. This study describes the first Australian Neonatal Intensive Care Unit (NICU) experience of NIV-NAVA. Methods Retrospective cohort study of infants admitted to a major tertiary NICU between October 2017 and April 2021 supported with NIV-NAVA. Infants were divided into three groups based on the indication to initiate NIV-NAVA (post-extubation; apnoea; escalation). Successful application of NIV-NAVA was based on the need for re-intubation within 48 h of application. Results There were 169 NIV-NAVA episodes in 122 infants (82 post-extubation; 21 apnoea; 66 escalation). The median (range) gestational age at birth was 25 + 5 weeks (23 + 1 to 43 + 3 weeks) and median (range) birthweight was 963 g (365–4320 g). At NIV-NAVA application, mean (SD) age was 17 days (18.2), and median (range) weight was 850 g (501–4310 g). Infants did not require intubation within 48 h in 145/169 (85.2%) episodes [72/82 (87.8%) extubation; 21/21 (100%) apnoea; 52/66 (78.8%) escalation). Conclusion NIV-NAVA was successfully integrated for the three main indications (escalation; post-extubation; apnoea). Prospective clinical trials are still required to establish its effectiveness versus other modes of non-invasive support.

Abstract Background Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. Methods We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. Results Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440–21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. Conclusions We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.

The field of special education is thought to be a stressful profession due to the complex needs of the students. The current study aimed to assess the effectiveness of a mindfulness-based smartphone application intervention for reducing burnout in special educators. We used the Copenhagen Burnout Inventory scale (with three subscales; personal, work-related and student-related) to measure burnout and the Five Facets of Mindfulness (shortened version) to assess mindfulness. Special educators (n = 29) were assigned to either the experimental group (n = 14) which used the 'Smiling Mind' app for guided meditations or the active control group (n = 15) which used 'Day One', a note-taking app, for a list-making activity. Both groups used their assigned apps for 10 days. The experimental group showed significant reductions from baseline to post-intervention on the personal burnout subscale while the control group did not, indicating that the intervention affected this domain of burnout. This was maintained at a 2-week follow-up. Mindfulness scores did not significantly increase in the experimental condition, meaning that the mechanism of this decrease in personal burnout is unknown. Further research is needed in order to add to the knowledge on preventing and treating burnout in special educators.

Educator attitudes towards inclusive education impact its success. Attitudes differ depending on the SEN cohort, and so the current systematic review is the first to focus solely on students with autism spectrum disorders (ASD). Seven databases searched yielded 13 relevant articles. The majority reported positive educator attitudes towards ASD inclusion but with considerable variety in the measures used. There were mixed findings regarding the impact of training and experience on attitudes but, where measured, higher self-efficacy was related to positive attitudes. In summary, educator ASD inclusion attitudes are generally positive but we highlight the need to move towards more homogeneous attitudinal measures. Further research is needed to aggregate data on attitudes towards SEN cohorts other than those with ASD.

Young children with visual impairment and their families often require specialized assistance through early intervention to develop adaptive routines, cues, and environmental settings during mealtimes and other daily tasks. There is little empirical data in the area of mealtime routines available to support families of young children with visual impairment, and the need for research-based interventions is great. The purpose of this initial needs assessment survey was to gather information as little is already known about what teachers of students with visual impairment trained in early intervention (TSVI-EIs) and other early interventionists who work with infants and toddlers with visual impairment already know about the development of independent mealtime skills. The results of this survey indicate that early intervention professionals would like additional opportunities to learn about mealtime routine strategies for young children with visual impairment, confirm their current experiences and knowledge, and identify additional training and resources.

BACKGROUND: Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. METHODS: DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing. FINDINGS: Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis. INTERPRETATION: These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: Daiichi Sankyo and AstraZeneca.

Abstract Shear instability is a dominant mechanism for mixing in the stratified oceans and coastal seas. For the first time, we present fine‐scale, direct measurements of shear instabilities in the bottom front generated by the Kuroshio intrusion into the Changjiang (Yangtze) river plume. Shear instabilities were identified using a shipboard echo‐sounder and the resulting turbulent mixing was quantified using a turbulence microstructure profiler. The shear instabilities generate vigorous turbulent mixing with dissipation rate and vertical diffusivity up to O (10−4 m2 s−3) and O (10−1 m2 s−1), respectively, comparable to values associated with shear instabilities observed in river plumes and western boundary currents but several orders of magnitude larger than typical values in the open ocean. The enhanced turbulence may contribute significantly to mixing between the Kuroshio water and coastal water and thereby alter the coastal biogeochemistry cycles.

ABSTRACT Introduction Organised by the ‘Qualitative Long Covid Network’, a workshop for qualitative Long COVID (LC) researchers, LC charity representatives and people with LC took place in June 2023, where research on the intersectional inequalities affecting LC prevalence, recognition and care was shared and discussed. Methods Five key themes were drawn up from presentations, discussions and reflections during the workshop, which are presented in this study. Results The following five themes are discussed: the unfairness of LC, difficulties in accessing care, mistrust of the healthcare system, a lack of understanding of LC and experiences of stigma and discrimination. Factors that widen or narrow inequalities related to LC were identified. Conclusion A call to action is proposed to investigate and address inequalities through a robust LC research agenda that speaks with conviction to policy and decision‐makers. We argue that there needs to be a strong investment in research and evidence‐based policy and practice to mitigate the worst effects of the condition and address the inequalities in experience, treatment and support, which are experienced more often and more acutely by some of society's most vulnerable and disadvantaged individuals. Patient and Public (PPI) Contribution Projects included in this article had PPI ongoing activity to inform their research. A member of the CONVALESCENCE PPI group presented at the QLC Network ‘Long Covid and Health Inequalities’ workshop, as did members of Long COVID Kids, Long COVID Support and Long COVID SOS charities. They were all invited to be co‐authors of this article.

BackgroundEmerging evidence suggests a positive association between relevant aspects of one’s psychological identity and physical activity engagement, but the current understanding of this relationship is primarily based on scales designed to assess identity as a person who exercises, leaving out essential aspects of physical activities (eg, incidental and occupational physical activity) and sedentary behavior. ObjectiveThe goal of this study is to evaluate the validity of a new physical activity and sedentary behavior (PA/SB) identity scale using 2 independent samples of US adults. MethodsIn study 1, participants answered 21 candidate items for the PA/SB identity scale and completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Study 2 participants completed the same PA/SB identity items twice over a 1-week interval and completed the IPAQ-SF at the end. We performed factor analyses to evaluate the structure of the PA/SB identity scale, evaluated convergent validity and test-retest reliability (in study 2) of the final scale scores, and examined their discriminant validity using tests for differences in dependent correlations. ResultsThe final PA/SB identity measure was comprised of 3 scales: physical activity role identity (F1), physical activity belief (F2), and sedentary behavior role identity (F3). The scales had high test-retest reliability (Pearson correlation coefficient: F1, r=0.87; F2, r=0.75; F3, r=0.84; intraclass correlation coefficient [ICC]: F1: ICC=0.85; F2: ICC=0.75; F3: ICC=0.84). F1 and F2 were positively correlated with each other (study 1, r=0.76; study 2, r=0.69), while both were negatively correlated with F3 (Pearson correlation coefficient between F1 and F3: r=–0.58 for study 1 and r=–0.73 for study 2; F2 and F3: r=–0.46 for studies 1 and 2). Data from both studies also demonstrated adequate discriminant validity of the scale developed. Significantly larger correlations with time in vigorous and moderate activities and time walking and sitting assessed by IPAQ-SF with F1, compared with F2, were observed. Significantly larger correlations with time in vigorous and moderate activities with F1, compared with F3, were also observed. Similarly, a larger correlation with time in vigorous activities and a smaller correlation with time walking were observed with F2, compared with F3. ConclusionsThis study provided initial empirical evidence from 2 independent studies on the reliability and validity of the PA/SB identity scales for adults.

The evaluation of the Road Home (RH) program has revealed many learnings of interest to practitioners, researchers and evaluators. The focus of this analysis is twofold - on an innovative approach to building an evidence base using a developmental evaluation and action learning design and how research knowledge and skills can be applied in practitioner contexts and be robust, rigorous and above all useful. It particularly features the role of reflective practice, an affordable, underutilised and easy to access evaluation and program improvement method for practitioners working with evaluators and researchers. Appreciating what is involved in approaching evaluation and other forms of organisational research in this way is important if industry collaborations and innovations that bring theory to practice and practice to theory are to be successful.

Se presenta un estudio del estado del arte sobre las prácticas pedagógicas en la Educación Física escolar, el cual se realizó mediante la búsqueda y análisis de documentos académicos con enclave geográfico en Latinoamérica. El objetivo principal es interpretar la circulación de las tipologías de prácticas, los temas recurrentes y las metodologías empleadas en cada caso. Para ello, se llevó a cabo un análisis de contenido de 31 documentos, incluyendo artículos de revistas y trabajos presentados en eventos científicos. Los resultados obtenidos permiten identificar una temática de interés para el campo de la Educación Física en los últimos años, en la que se pueden observar cuatro tipologías de prácticas pedagógicas organizadas a partir de dimensiones teóricas que las distinguen y metodologías específicas desarrolladas por la comunidad de investigadores/as.

Background: Precision oncology is gaining momentum in managing patients with gastrointestinal cancers. This study examines the implementation of personalized medicine technologies in upper gastrointestinal (UGI) oncology across European academic centers. Material and methods: Forty-five oncology specialists from 41 European institutions completed a survey designed by the Personalized Medicine Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Working Group, providing insights into molecular testing, timing, availability of targeted therapies, funding sources, and utilization of molecular tumor boards (MTBs) for patients with UGI cancers. Frequencies and percentages were calculated. Results: Routine testing for human epidermal growth factor receptor 2 (HER2, 100%), programmed death-ligand 1 (PD-L1, 89%), and DNA mismatch repair (MMR, 91%) is implemented in most centers. Comprehensive gene panels on tumor tissue are frequently utilized, especially in biliary tract cancer, with almost all centers incorporating them into routine practice. Blood-based sequencing is increasingly employed, and half of centers carry out comprehensive gene panels for circulating tumor DNA analyses. MTBs are regularly held in 76% of centers, predominantly utilizing ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)-based recommendations for tissue molecular alterations. The translation of genomic information into prescribed treatments remains limited, however, with the majority of centers reporting ∼25% of molecularly stratified treatment decisions following comprehensive genetic testing. Conclusion: This survey provides important insights into current personalized medicine practice in European academic clinical centers for UGI oncology. Despite widespread adoption of molecular testing and implementation of MTBs, further efforts are needed to optimize the integration of personalized medicine into clinical practice.

The evaluation of programmed death-ligand 1 (PD-L1) expression and the methodology employed are central to identify suitable candidates for immunotherapy among patients with gastro-oesophageal cancer (GC). Yet, there are no comprehensive global studies comparing the various methods and antibodies utilized for assessing PD-L1 positivity in GC. The ASPIRE study, led by the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Group (EORTC GITCG) and the National University Health System, Singapore, seeks to standardize the assessment of PD-L1 expression in GC. By comparing various PD-L1 scoring systems and assays, the study aims to simplify and harmonize the quantification and qualification of PD-L1 expression. Ultimately, this effort aims to facilitate the translation of endpoints in companion diagnostic settings. Here, we report the protocol of the study.

Background: Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. Objectives: The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. Design: A prospective cohort study. Methods: CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants ( n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Results: Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Conclusion: Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo’s data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Purpose Epigenetic modifications including DNA methylation (DNAm) are proposed mechanisms by which social or environmental exposures may influence health and behaviours as we age. The Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) DNAm cohort, established in 2013, is one of several worldwide, nationally representative prospective studies of ageing with biological samples from participants who consented to multiomic analysis.Participants NICOLA recruited 8478 participants (8283 aged 50 years or older and 195 spouses or partners at the same address aged under 50 years). Computer-Assisted Personal Interviews, Self-Completion Questionnaires and detailed Health Assessments (HA) were completed. Of the 3471 (44.1%) participants who attended the HA in wave 1, which included venous blood sampling, 2000 were identified for the DNAm cohort. Following technical and data quality control checks, DNAm data are currently available for n=1870.Findings to date There was no significant difference based on age, self-reported gender, education, employment, smoking or alcohol status and subjective health reports between the DNAm cohort and other HA attendees. Participants were more likely to be in the DNAm group if they lived with one other person (OR 1.26, 95% CI 1.07 to 1.49). The DNAm group had a lower proportion of depressed participants and those meeting criteria for post-traumatic stress disorder (11.7% and 4.4% vs 13.5% and 4.5%, respectively) categorised by objective assessment tools but this was not significant (OR 0.84, 95% CI 0.69 to 1.02 and OR 0.87, 95% CI 0.64 to 1.19).Future plans The deeply phenotyped DNAm cohort in NICOLA with planned prospective follow-up and additional multiomic data releases will increase the cohort’s utility for research into ageing. The genomic and epigenetic data for the DNAm cohort has been deposited on the European Genome-Phenome Archive, increasing the profile of this cohort and data availability to researchers.

Substance use, including cigarettes and cannabis, is associated with poorer sustained attention in late adolescence and early adulthood. Previous studies were predominantly cross-sectional or under-powered and could not indicate if impairment in sustained attention was a predictor of substance use or a marker of the inclination to engage in such behavior. This study explored the relationship between sustained attention and substance use across a longitudinal span from ages 14 to 23 in over 1000 participants. Behaviors and brain connectivity associated with diminished sustained attention at age 14 predicted subsequent increases in cannabis and cigarette smoking, establishing sustained attention as a robust biomarker for vulnerability to substance use. Individual differences in network strength relevant to sustained attention were preserved across developmental stages and sustained attention networks generalized to participants in an external dataset. In summary, brain networks of sustained attention are robust, consistent, and able to predict aspects of later substance use.

Interventions for attention-deficit/hyperactivity disorder (ADHD) include positive behavior supports (e.g., parent training, school-based contingency management, behavioral peer interventions), training interventions (e.g., organizational skills training, social skills training, etc.), and other interventions (e.g., academic accommodations/modifications, self-monitoring). There is a need to conduct a comprehensive meta-analysis of psychosocial treatments for ADHD given discrepancies between meta-analyses. The present meta-analysis reports the results of between-group studies that compared a psychosocial treatment to a control condition from 1968 to 2016. In total, 226 studies were identified that met inclusion criteria. Results of the meta-analysis were organized by treatment type, rater, and domain of outcome assessed. Results indicated considerable variability across these parameters, with the strongest effects for proximal outcomes of behavioral parent training (improvements in parenting behaviors yielded a standardized mean difference of 0.70) and improvements in child behavior following implementation of behavioral school intervention (standardized mean difference of 0.66 and 0.72 for teacher ratings of ADHD symptoms and impairment, respectively). Other interventions were not extensively studied as stand-alone approaches. Results are discussed in light of current support for the use of psychosocial interventions for individuals with ADHD.

PurposeEvaluate the initial ocular safety and tolerability and efficacy of VVN001 Ophthalmic Solution (VVN001), a small-molecule antagonist of lymphocyte function-associated antigen-1 (LFA-1), in subjects with dry eye disease (DED).MethodsThis was a multi-center, double-masked, randomized, dose-response, vehicle-controlled, parallel-group study conducted in 170 subjects with DED. Subjects were randomized to receive VVN001 (1% or 5%) or its vehicle, twice-daily in both eyes for 84 days. The primary outcome measure was inferior region corneal fluorescein staining (iCFS, 0-4 scale) at Day 84. Visual Analogue Scale eye dryness (VAS, 0-100 scale) was a secondary outcome.ResultsThe primary and first secondary outcomes were not met. At Day 84 treatment effects in favor of VVN001 5% relative to its vehicle for iCFS were 0.29 units (p = 0.054), and for VAS were 3.18 units (p = 0.533). In other secondary outcomes, treatment effects in favor of VVN001 5% relative to its vehicle were seen in total CFS (1.61 units, 0-20 scale, p = 0.004) and Schirmer score (1.77 and 2.32 mm, p = 0.049 and p = 0.17 at Days 14 and 28 respectively). Adverse events of incidence 5% or greater in either active treatment group were instillation site pain (3/57, 5.3%), dysgeusia (3/56, 5.4%) and urinary tract infection (3/57, 5.3%).ConclusionsThere were no major safety issues of note. Appropriately powered studies will be required with a priori selection of the efficacy endpoints to evaluate VVN001's therapeutic potential.

INTRODUCTION: Individuals with greater affect variability (i.e., moment-to-moment fluctuations possibly reflecting emotional dysregulation) are at risk for greater systemic inflammation, which is associated with cardiovascular disease. Some evidence suggests that affect variability is linked with poorer health indicators only among those with higher average levels of affect, particularly for positive affect (PA), and that associations may be non-linear. The present study sought to examine whether links between both PA and negative affect (NA) variability and inflammation are moderated by average level of affect. METHODS: Participants (N = 300, 50 % female, ages 21-70, 60 % non-Hispanic White, 19 % Hispanic, 15 % non-Hispanic Black) completed a lab assessment and provided a blood sample to measure systemic inflammation (i.e., TNF-α, IL-6, CRP). Affect was collected via a two-day ecological momentary assessment protocol where reports were collected about every 45-min during waking hours. Momentary affect ratings were averaged across both days (i.e., iM), separately for PA and NA, for each participant. Affect variability was calculated as the person-specific SD (i.e., iSD) of affect reports, separately for PA and NA. Linear and quadratic interactions were tested. Models included covariates for sex, race, and body mass index. RESULTS: There were significant interactions between NA iM and NA iSD predicting TNF-α (b = 6.54; p

ObjectiveThe authors of this study evaluated the safety and efficacy of stereotactic laser ablation (SLA) for the treatment of drug-resistant epilepsy (DRE) in children.MethodsSeventeen North American centers were enrolled in the study. Data for pediatric patients with DRE who had been treated with SLA between 2008 and 2018 were retrospectively reviewed.ResultsA total of 225 patients, mean age 12.8 ± 5.8 years, were identified. Target-of-interest (TOI) locations included extratemporal (44.4%), temporal neocortical (8.4%), mesiotemporal (23.1%), hypothalamic (14.2%), and callosal (9.8%). Visualase and NeuroBlate SLA systems were used in 199 and 26 cases, respectively. Procedure goals included ablation (149 cases), disconnection (63), or both (13). The mean follow-up was 27 ± 20.4 months. Improvement in targeted seizure type (TST) was seen in 179 (84.0%) patients. Engel classification was reported for 167 (74.2%) patients; excluding the palliative cases, 74 (49.7%), 35 (23.5%), 10 (6.7%), and 30 (20.1%) patients had Engel class I, II, III, and IV outcomes, respectively. For patients with a follow-up ≥ 12 months, 25 (51.0%), 18 (36.7%), 3 (6.1%), and 3 (6.1%) had Engel class I, II, III, and IV outcomes, respectively. Patients with a history of pre-SLA surgery related to the TOI, a pathology of malformation of cortical development, and 2+ trajectories per TOI were more likely to experience no improvement in seizure frequency and/or to have an unfavorable outcome. A greater number of smaller thermal lesions was associated with greater improvement in TST. Thirty (13.3%) patients experienced 51 short-term complications including malpositioned catheter (3 cases), intracranial hemorrhage (2), transient neurological deficit (19), permanent neurological deficit (3), symptomatic perilesional edema (6), hydrocephalus (1), CSF leakage (1), wound infection (2), unplanned ICU stay (5), and unplanned 30-day readmission (9). The relative incidence of complications was higher in the hypothalamic target location. Target volume, number of laser trajectories, number or size of thermal lesions, or use of perioperative steroids did not have a significant effect on short-term complications.ConclusionsSLA appears to be an effective and well-tolerated treatment option for children with DRE. Large-volume prospective studies are needed to better understand the indications for treatment and demonstrate the long-term efficacy of SLA in this population.