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Abstract This is a randomized, double-blind, placebo-controlled phase 3 clinical trial (ClinicalTrials.gov, NCT04878016) conducted in 54 hospitals in China. Adults who were histologically diagnosed and never treated for extensive-stage small cell lung cancer (ES-SCLC) were enrolled. Eligible Patients were randomly assigned (1:1) to receive four cycles (21 days as one cycle) of intravenous carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m² of body-surface area, on days 1–3 of each cycle) with either socazolimab (5 mg/kg, day 1 of each cycle) or matching placebo, following maintenance therapy with socazolimab or placebo. From July 15, 2021, to May 12, 2022, 498 eligible patients were randomly assigned to receive socazolimab (250 patients) or placebo (248 patients) combined with chemotherapy. As of October 13, 2023, patients treated with socazolimab presented significant overall survival (OS) benefit (13.90 months) compared with the placebo plus EC group (11.58 months) (hazard ratio for death, 0.799; 95% CI, 0.652–0.979; p = 0.0158). The median progression free survival (PFS) was 5.55 months in the socazolimab plus EC group, prolonging disease progression or death by nearly 1.2 months (5.55 months vs 4.37 months, hazard ratio for progression or death, 0.569; 95% CI, 0.457–0.708; p

Abstract COVID-19 can increase the long-term risk of multiorgan dysfunction. Few studies investigated the long-term risk in Asian populations or investigated the association between viral load and long-term risk. We aimed to investigate the post-discharge rates of hospitalization and association with baseline viral load in all patients with COVID-19 in Hong Kong. This was a population-based cohort study included all patients with a positive RT-PCR test for SARS-CoV-2 in Hong Kong between January 1st 2020 and August 30th 2020, routinely admitted to public health care facilities for isolation and treatment. Viral Ct values were available in 3433 (85%) of patients. Outcomes of interest included death, cause-specific hospitalizations, and initiation of medication from the Hospital Authority's territory-wide electronic health records from the Clinical Data Analysis and Reporting System. In total, 4054 people in Hong Kong tested positive for COVID-19 and were admitted to a public health care facility, of whom 167 (4.1%) were admitted to ICU. During a median follow-up time of 251 (interquartile range 240–279) days, 408 (11.9%) were hospitalized for any reason and 16 (0.5%) patients died. After discharge, patients were most often readmitted for respiratory reasons, followed by gastro-intestinal reasons. A higher viral load (lower RT-PCR Ct values) was associated with a higher likelihood of death (Hazard ratio [HR] 5.86, 95% Confidence interval [CI] 2.57–13.33), hospitalization (HR 1.22, 95%CI 1.08–1.39) or hospitalization for cardiovascular disease (HR 12.78, 95%CI 3.67–44.48). Patients with higher viral loads more likely started ACE-inhibitors (HR 1.37, 95%CI 1.12–1.68) and non-opioid analgesics (HR 1.01, 95%CI 1.01–1.23). In a relatively mild COVID-19 population from Hong Kong, the post-acute risk of complications was substantial. Our results highlight that higher viral load predict post-acute complications in patients with relatively mild disease.

Understanding the prey preference of Malayan tiger (Panthera tigris jacksoni) in Malaysia is important to guide conservation planning initiatives. The utilisation of DNA metabarcoding provides valuable insights, particularly in the field of carnivora diet research. This technique has been proven to be effective for identifying various species within complex mixtures such as scat materials, where visual identification is challenging. The Cytochrome c oxidase subunit I (COI) locus has been selected as it is a widely used as an effective non-invasive approach for diet studies. Hence, given this advance approach, Malayan tiger scats were collected on the basis of existing records of their presence in two types of habitats, namely, protected areas (PA) and human–tiger conflict (HTC) areas. This study aimed to identify prey species in Peninsular Malaysia, based on Malayan tiger scat samples using DNA metabarcoding. Based on the partial mitochondrial COI region, DNA metabarcoding led to the taxonomic resolution of prey DNA remnants in scats and the identification of prey species consumed by Malayan tiger, which were predominately small-to-medium-sized prey, including livestock. The dominant DNA prey detected belongs to the family Canidae, followed by Bovidae, Vespertilionidae, Homonidae, Felidae, Phasianidae and Muridae. A significant difference (p < 0.05) was observed in alpha and beta diversity using the Shannon index and PERMANOVA with regard to prey richness and evenness in two different habitat groups, namely, PA and HTC. Our finding provides insights into Malayan tiger dietary requirements, which can be used to develop conservation plans and strategies for Malayan tiger, particularly for habitat priorities.

Abstract Background Head and neck malignancy, and in particular squamous cell carcinoma (SCC), is responsible for a significant disease burden globally. The lack of an optimal in vitro model system to accurately recapitulate in vivo response to therapy in HNSCC remains a challenge. The development of patient‐derived three‐dimensional tumour cultures, or tumoroids, has enabled improved modelling of the tumour microenvironment through simulation of important characteristics such as tumour hypoxia, cell–cell interactions and nutrient diffusion characteristics. Methods We performed a comprehensive English‐language literature review of current methods of tumoroid development utilising Matrigel and Cultrex Basement Membrane Extract 2 (key terms: tumour organoids, tumoroids, hydrogels, Matrigel, Cultrex, squamous cell carcinoma, head and neck)—two common proprietary murine‐derived hydrogels containing extracellular matrix proteins. Nascent literature on the establishment of a novel hydrogel‐free platform for tumoroid development as distinct from these existing methods was also explored. Results Whilst useful for facilitating cell‐matrix interactions and providing a scaffold for three‐dimensional cell growth and organisation, murine‐derived cell matrix methods were noted to have notable limitations including temperature sensitivity and the medium forming a barrier to analysis of the supernatant. A novel hydrogel‐free method of establishing in vitro tumoroid cultures has been subject to experimentation in colorectal but not head and neck malignancy. The absence of a hydrogel provides for the de novo synthesis of extracellular matrix native to the tumour and self‐organisation of cells within this scaffold through the use of ultralow attachment plates. This model demonstrates similar structural and physiological properties to native tissue, whilst enabling more accurate biomimicry of the tumour microenvironment for drug testing. Conclusions In the absence of prior experimentation on a hydrogel‐free method for establishing HNSCC tumoroids, and comparisons between hydrogel and hydrogel‐free models, the future development of a comparative protocol encompassing recruitment, collection, processing and analysis represents a valuable opportunity.

This pilot study explored undergraduate students’ experiences with goal setting and time management. We embedded a series of mandatory planning and reflection assignments into two undergraduate courses. Assignments were unique to each course, but emphasized goal setting, planning and time management, and reflection. Qualitative analyses revealed that students valued the importance of academic success and well-being. They used various strategies to plan and manage their time but struggled with balancing schoolwork and well-being. Our findings highlight the need to support students in developing goal setting and time management skills, setting realistic goals, and following through on their plans.

Abstract Objective Neurostimulation is an emerging treatment for patients with drug‐resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. Methods We performed high‐throughput testing of high‐frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. Results We found that the spike‐suppressive effects of high‐frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. Significance These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti‐seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. Plain Language Summary In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode's placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure‐like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy.

Background and Aims: No studies have evaluated the relationship between maternal arterial partial pressure of carbon dioxide (mPaCO2) and umbilical cord venous partial pressure of carbon dioxide (PCO2) in critically ill pregnant women at delivery. Based on the studies in healthy pregnant women, an mPaCO2 target of ≤50 mmHg is a suggested threshold during mechanical ventilation in critically ill parturients. We evaluated the relationship between mPaCO2 and neonatal cord gases in critically ill parturients at delivery as the primary objective. The relationship between mPaCO2 and APGAR scores at delivery was also analysed as a secondary objective. Methods: Maternal and neonatal cord gas data at delivery and APGAR scores were obtained by a retrospective chart review of 25 consecutive parturients with severe respiratory compromise who were delivered during mechanical ventilation. Linear regression was used to assess the relationship between mPaCO2 and umbilical artery and vein PCO2 and between mPaCO2 and APGAR scores at 1 and 5 min. Results: There was a positive correlation between mPaCO2 and neonatal cord venous PCO2 (P = 0.013). Foetal venous PCO2 exceeded predelivery mPaCO2 by 17.5 (7.5) mmHg. There was an inverse relationship between mPaCO2 and neonatal APGAR scores at 1 and 5 min (P = 0.006 and P = 0.007, respectively). Conclusion: Foetal cord venous PCO2 can be predicted if mPaCO2 values are known. Unlike in healthy pregnant women, there was an inverse relationship between rising mPaCO2 levels and neonatal APGAR scores in critically ill pregnant women who had several associated compounding factors.

Abstract Objective Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF. However, no studies have examined the relationship between antidepressant use and AF burden (time in AF). This retrospective cohort study examined cardiac implantable device‐detected AF episodes and their relationship with antidepressant use, among other treatment factors. Methods Consecutive patients from the Western Health Cardiology Department attending pacemaker checks between 2015 and 2021 were included. Patients with permanent AF were excluded, yielding 285 patients with no or paroxysmal AF, with a total of 772 patient encounters. Generalized estimating equations were used to model two processes: binary AF (present/absent) and the number of days in AF for patients with AF. Results Each yearly increase with age was associated with an increase in the odds of developing AF (OR 1.03 [1.00–1.05], p = .027). Male gender conferred a reduction in AF incidence (OR 0.30 [0.13–0.68], p = .004). Digoxin use was associated with incident AF (OR 4.43 [1.07–18.4], p = .04). Sotalol and heart‐failure beta blocker use were associated with a decrease in AF burden (IRR 0.30 [0.12–0.78], p = .013 and 0.33 [0.14–0.81], p = .015). Selective serotonin reuptake inhibitor antidepressant use was associated with reduced AF burden (IRR 0.27 [0.09–0.81], p = .019), as was selective serotonin/noradrenaline reuptake inhibitor use (IRR 0.07 [0.03–0.15], p

Abstract Achieving high solar-to-hydrogen (STH) efficiency concomitant with long-term durability using low-cost, scalable photo-absorbers is a long-standing challenge. Here we report the design and fabrication of a conductive adhesive-barrier (CAB) that translates >99% of photoelectric power to chemical reactions. The CAB enables halide perovskite-based photoelectrochemical cells with two different architectures that exhibit record STH efficiencies. The first, a co-planar photocathode-photoanode architecture, achieved an STH efficiency of 13.4% and 16.3 h to t60, solely limited by the hygroscopic hole transport layer in the n-i-p device. The second was formed using a monolithic stacked silicon-perovskite tandem, with a peak STH efficiency of 20.8% and 102 h of continuous operation before t60 under AM 1.5G illumination. These advances will lead to efficient, durable, and low-cost solar-driven water-splitting technology with multifunctional barriers.

Scientific inquiry skills (e.g., observation, critical analysis, hypothesis generation) are the cornerstone of scientific training, yet these skills are seldom taught. Consequently, an inquiry-based course was created at McMaster University, Science of Fictional Characters, that facilitates students to develop scientific inquiry skills. By analysing the feasibility of fictional characters in the real world, students apply and understand concepts in various scientific disciplines (e.g., biology, psychology, physics). This course embeds a variety of active learning strategies to foster the development of skills relevant to the scientific process, including group projects, written reflections, and Socratic discussions and debates. To gather student opinions about the effectiveness of the course, we administered an end-of-term survey, a modified version of the Course Interest Survey (CIS). This self-reported CIS included five subscales: student attention, relevance, confidence, satisfaction, and scientific inquiry skill development. Of the 17 surveys completed, on average the subscales scored above four on a five-point scale. Additionally, we performed a thematic analysis on 15 reflective assignments. Qualitatively, 10 codes were extracted from the student testimonies, which were grouped into four themes: student satisfaction, perceived applicability, course flexibility, and barriers to learning. Both data types revealed that students were engaged with the course and felt they improved their scientific inquiry skills. Our data further suggest the course would benefit from additional foundational scientific content. Nevertheless, the study provides an example of how fiction and an active learning model can create an engaging, skills-based learning environment in a science course.

Due to the COVID-19 pandemic, many in-person classes shifted to emergency remote learning, with Zoom being the adopted software choice of communication for many schools. Despite its accessibility, students have expressed fatigue and challenges with conversations using Zoom. Additionally, emergency remote learning has led to decreased interpersonal interactions. Thus, we wondered whether Gather.town, a teleconferencing software with proximity-chat features, might lead to a more positive learning environment than Zoom. We utilized both software in an inquiry and problem-based course, Science of Fictional Characters, at McMaster University during the Fall 2021 semester. We surveyed students’ preference between Gather.town and Zoom across five different domains: engagement, enjoyment, social connectedness, ease of use, and willingness to communicate using each software. Twelve out of 30 enrolled students responded to the survey. Participants reported more engagement (58%), higher enjoyment (58%), and greater social connectedness (92%) to their peers using Gather.town compared to Zoom, despite participants also reporting Zoom being easier to use (92%). The results further revealed no preference towards either software in terms of willingness to communicate. Although our sample size is small, our results nonetheless suggest a software with proximity chat features such as Gather.town could be a potential alternative to Zoom for fostering positive learning environments.

Abstract Background Small-cell carcinoma (SMCC) of hypopharynx is an extreme rare entity in the head and neck region. It is commonly arising from pulmonary in origin. We report a rare case of small-cell carcinoma of hypopharynx that caused upper airway obstruction in an elderly gentleman. Case presentation A 67-year-old man is presented to otorhinolaryngology clinic with a 4-month history of worsening shortness of breath and stridor. He was heavy tobacco smoker for 60 pack-years. Flexible nasopharyngolaryngoscopy revealed a large mass at the right pyriform fossa extending superiorly and obstructing the laryngeal inlet. He underwent tracheostomy, examination under general anesthesia with tissue biopsy. Histology from tissue biopsy revealed small-cell carcinoma. The positron emission tomography-CT showed exophytic mass from right pyriform sinus with regional and lung pleural metastasis as well. There was the absence of formal staging system for SMCC due to its limited and rare incidence. He was treated with combination of carboplatin and etoposide, similar to the regime for cell carcinoma of lung. The tumor regressed loco-regionally, and his pleural metastasis had shrunk to sub-centimeter in size. Conclusions To date, there is very limited data available on head and neck small cell carcinomas to guide treatment recommendations as well as staging system. Paucity of clinical data and outcome about this rare malignancy makes this report a valuable piece of experience to be shared together with existing literature.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Abstract Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1 −/−) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 −/− mice compared to normal animals. Cln1 −/− mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency.

In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.

Key Clinical Message Coronary artery fistulae are an uncommon abnormality of the coronary arteries, but when hemodynamically significant can present as angina, dyspnea, and arrhythmia as a rare cause of functional myocardial ischemia via ‘coronary steal phenomenon’.

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features.

Objective Multiple sclerosis (MS) is an inflammatory degenerative condition of central nervous system. The disease course and presentation of MS is highly heterogeneous. Advanced retinal imaging techniques such as optic coherence tomography (OCT) can capture abnormalities of anterior visual pathway with high resolution, which may contribute greater insights into the pathophysiology of MS.Methods People with newly diagnosed relapsing-remitting MS were recruited for FutureMS retinal imaging study from two study centres in Scotland. The baseline visit was completed within 6 months of diagnosis with initial follow-up 12 months after the baseline visit. The assessments included in FutureMS retinal imaging study were visual acuity test, self-reported eye questionnaire and OCT scan.Results A total of 196 FutureMS participants completed the retinal imaging study of FutureMS with 185 participants at M0 and 155 at M12. A total of 144 participants completed both M0 and M12 visits. At the whole cohort level, the distribution of retinal measures is generally consistent between baseline and follow-up.Conclusion The FutureMS retinal imaging study aims to demonstrate that patient with MS present with different extent of retinal abnormalities that can be captured by retinal imaging modalities such as OCT soon after diagnosis. These changes may sensitively mirror the brain atrophy or serve as predictors for disease activity. By developing sensitive, quantifiable and objective retinal biomarkers, FutureMS retinal imaging study will provide an opportunity to stratify patient with MS at an early stage and support future therapeutic strategies for a better outcome.

In undergraduate science education, emphasis is often placed on teaching subject matter rather than science process skills (e.g., critical thinking, problem solving). Although important to scientific training, these skills are often not taught because science educators do not feel equipped to teach them. We therefore present a case-scenario activity that aims to facilitate the development of science process skills. This activity, which takes the form of a visual novel, asks students to generate hypotheses for the seemingly odd events that are described in the story. We implemented this activity in a science-process-focused course. Upon completion of the activity, we asked students to submit a written response to the prompt: “What are you taking away from the activity?” In this exploratory study, we conducted a qualitative analysis of these written responses to ascertain whether meaningful codes and themes related to science process would arise from this open-ended prompt. Based on student responses, four main themes emerged: scientific inquiry, student satisfaction, flexibility, and collaboration. These results demonstrated the activity was both enjoyable, and it successfully enabled students to apply science process skills. We offer this activity in anticipation it will provide educators with a tool to include these skills in their classes.

During obesity and high fat-diet (HFD) feeding in mice, sustained low-grade inflammation includes not only increased pro-inflammatory macrophages in the expanding adipose tissue, but also bone marrow (BM) production of invasive Ly6Chigh monocytes. As BM adiposity also accrues with HFD, we explored the relationship between the gains in BM white adipocytes and invasive Ly6Chigh monocytes by in vivo and ex vivo paradigms. We find a temporal and causal link between BM adipocyte whitening and the Ly6Chigh monocyte surge, preceding the adipose tissue macrophage rise during HFD in mice. Phenocopying this, ex vivo treatment of BM cells with conditioned media from BM adipocytes or bona fide white adipocytes favoured Ly6Chigh monocyte preponderance. Notably, Ly6Chigh skewing was preceded by monocyte metabolic reprogramming towards glycolysis, reduced oxidative potential and increased mitochondrial fission. In sum, short-term HFD changes BM cellularity, resulting in local adipocyte whitening driving a gradual increase and activation of invasive Ly6Chigh monocytes.

Objective: To investigate the association of normal BMI with central obesity (CO), high BMI with CO, high BMI without CO, and normal BMI without CO, with function and cognition in older adults. Methods: Cross-sectional study involving 754 participants ≥ 65 years. Data collected include demographics, cognition, and physical measurements. Results: Females had a higher prevalence of high BMI with CO and a lower prevalence of high BMI without CO than males (61.0% vs 44.6% and 4.6% vs 15.0%, respectively). Within gender, CO groups, regardless of BMI, had lower mini-mental state examination (MMSE), handgrip strength (HGS), and longer timed-up-and-go (TUG) scores. Overall, the high BMI without CO group had the highest MMSE scores, HGS, and shortest TUG. Amongst males, HGS was significantly lower in the normal BMI with CO group (B −3.28, 95% CI −6.32 to −0.23, P = 0.04). CO, regardless of normal/high BMI, had significantly lon ger TUG time (B 2.65, 95% CI 0.45 to 4.84, P = 0.02; B 1.07, 95% CI 0.25 to 1.88, P = 0.01, respectively) than normal BMI without CO group. CO was associated with lower MMSE scores in both genders but significant only in males with normal BMI and CO (B −1.60, 95% CI −3.15 to −0.06, P = 0.04). Conclusion: CO may be a better predictor of obesity and adverse outcomes in older adults. High BMI without CO was associated with better outcomes especially in males but require further validation. Prospective longitudinal studies are needed to ascertain the impact of BMI and/or CO on function, cognition, mortality, and gender diff erences.

Abstract Background This process evaluation explored the implementation and mechanisms of impact of a Park Prescription Intervention trial (PPI), including the effects of hypothesised mediators (motivation, social support, recreational physical activity [PA], park use and park PA) on trial outcomes. Methods Participants from the community were randomly allocated to intervention (n = 80) or control (n = 80) group. The intervention included baseline counselling, a prescription of exercise in parks, materials, three-month follow-up counselling and 26 weekly group exercise sessions in parks. Process evaluation indicators were assessed at three- and six-months. Implementation indicators included participation rates in intervention components and survey questions plus focus group discussions (FGDs) to understand which components participants valued. FGDs further assessed barriers and facilitators to intervention participation. To explore mechanisms of impact, linear regression was used to compare objectively measured PA between quantiles of group exercise participation. Structural equation modelling (SEM) explored hypothesised mediation of the significant intervention effects. Framework analysis was conducted for FGDs. Results Participants were middle-aged (mean 51, SD ± 6.3 years), predominantly female (79%) and of Chinese ethnicity (81%). All intervention participants received baseline counselling, the park prescription and materials, whilst 94% received the follow-up counselling. Mean minutes of moderate-to-vigorous PA/week (95% CI) differed by group exercise participation (p = 0.018): 0% participation (n = 18) 128.3 (69.3, 187.2) minutes, > 0–35.9% participation (n = 18) 100.3 (36.9, 163.6) minutes, > 35.9–67.9% participation (n = 17) 50.5 (− 4.9, 105.9) minutes and > 67.9% participation (n = 18) 177.4 (122.0, 232.8) minutes. Park PA at three-months had significant mediating effects (95% CI) on recreational PA 26.50 (6.65, 49.37) minutes/week, park use 185.38 (45.40, 353.74) minutes/month, park PA/month 165.48 (33.14, 334.16) minutes and psychological quality of life score 1.25 (0.19, 2.69) at six-months. Prioritising time with family and preferences for unstructured activities were barriers to intervention participation. Human interaction via follow-up or group exercise were facilitators. Conclusion This process evaluation showed park PA consistently mediated effects of the PPI, suggesting activity in parks was a mechanism of its effects. To optimise effectiveness, participants’ preference for prioritising time with family through family involvement and tailoring the intervention to participants’ preferences for structured or unstructured PA could be considered in future studies. Trial registration ClinicalTrials.gov NCT02615392 , 26 November 2015.

Mutations of α2-Na/K ATPase can cause familial hemiplegic migraine via unclear mechanisms. Here, the authors show that deletion of α2-Na/K ATPase in astrocytes results in gene expression and metabolic changes leading to cortical spreading depression and episodic transient motor paralysis in mice.

Abstract Background Programs promoting population health through physical activity (PA) and exposure to nature are popular, but few have been evaluated in randomized-controlled trials (RCTs). Objective To investigate the effectiveness of a park prescription intervention (PPI) for improving total moderate-to-vigorous PA (MVPA), other PA related behaviors, quality of life (QoL) and cardio-metabolic health among adults. Methods Healthy individuals aged 40 to 65 years were recruited through community health screenings and randomly assigned to 1) PPI: face-to-face Park Prescription + invitation to weekly exercise sessions in parks, or 2) control: standard PA materials. After the six-month intervention, participants completed accelerometer assessments, questionnaires on health behaviors and QoL, and health screenings. Independent sample t-tests were used to compare outcomes between groups, with secondary analysis adjusted for co-variates via multiple linear regression. A p-value

Literature suggests post-secondary students feel disengaged and socially isolated while learning virtually, especially during the COVID-19 pandemic. Here we explored whether a sense of belonging is differentially achieved in an inquiry-based course between two different delivery formats: virtual and blended (combination of virtual and in-person). Our primary measurement instrument was a modified version of the 26-item Sense of Belonging-Revised Scale, which we distributed to all first-year Bachelor of Health Sciences (BHSc) (Honours) Program students enrolled in an Inquiry course at McMaster University during the 2021-2022 school year. Data analyses revealed no statistically significant difference between the two groups across the four subscales of the Sense of Belonging-Revised Scale: perceived peer support, perceived classroom comfort, perceived isolation, and perceived faculty support. As promoting community is a core skill in our Inquiry course, this may have reduced the perceived difference between the two groups. Future directions include exploring facilitators' perceptions and experiences across course delivery formats.

Abstract Background Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, different types of glial cells have been increasingly recognized to play important roles in the phenotypes of TSC. Main body This review summarizes the literature supporting glial dysfunction from both mouse models and clinical studies of TSC. In particular, evidence for the role of astrocytes, microglia, and oligodendrocytes in the pathophysiology of epilepsy and TAND in TSC is analyzed. Therapeutic implications of targeting glia cells in developing novel treatments for the neurological manifestations of TSC are also considered. Conclusions Different types of glial cells have both cell autonomous effects and interactions with neurons and other cells that are involved in the pathophysiology of the neurological phenotype of TSC. Targeting glial-mediated mechanisms may represent a novel therapeutic approach for epilepsy and TAND in TSC patients.

Astrocytes serve many functions in the human brain, many of which focus on maintenance of homeostasis. Astrocyte dysfunction in Tuberous Sclerosis Complex (TSC) has long been appreciated with activation of the mTORC1 signaling pathway resulting in gliosis and possibly contributing to the very frequent phenotype of epilepsy. We hypothesized that aberrant expression of the astrocyte protein aquaporin-4 (AQP4) may be present in TSC and contribute to disease pathology. Characterization of AQP4 expression in epileptic cortex from TSC patients demonstrated a diffuse increase in AQP4. To determine if this was due to exposure to seizures, we examined Aqp4 expression in mouse models of TSC in which Tsc1 or Tsc2 inactivation was targeted to astrocytes or glial progenitors, respectively. Loss of either Tsc1 or Tsc2 from astrocytes resulted in a marked increase in Aqp4 expression which was sensitive to mTORC1 inhibition with rapamycin. Our findings in both TSC epileptogenic cortex and in a variety of astrocyte culture models demonstrate for the first time that AQP4 expression is dysregulated in TSC. The extent to which AQP4 contributes to epilepsy in TSC is not known, though the similarities in AQP4 expression between TSC and temporal lobe epilepsy supports further studies targeting AQP4 in TSC.

Background: We surveyed patients in an adult reconstruction practice as to their use of the Web-based portal provided by our electronic health record, seeking to reveal patterns of use and helpfulness. Methods: A total of 150 completed surveys were received. The survey queried demographics, the number of clinic visits, Internet access, portal activation, portal use frequency, and portal information questions and how patients answered them. Helpfulness was rated from 1 (not helpful) to 5 (very helpful). Statistical analysis included bivariate analysis and logistic regression, with odds ratio (OR) and 95% confidence interval (CI) reported. Results: The mean age was 67.6 years. Most were females (n = 97, 65.1%). Most (68.7%) patients used the portal. Younger age (OR, 0.94; CI, 0.90-0.99) and access to Internet (OR, 31.8; CI, 8.5-119.4) predicted portal use (P < .005), whereas gender and number of clinic visits did not (P > .373). Of all, 47.5% of patients were unclear about online chart information. Older age indicated being unclear of portal information (68.5 vs 66, P = .0002). Of those who clarified doubts regarding information (n = 67), 23 used the Internet (34.3%), 32 (47.7%) called the physician, and 12 (17.9%) asked a friend and/or family member. Most (90.3%) patients felt the portal was helpful in gathering health information. Conclusions: Age and Internet access affected portal usage; ability to understand chart information decreased with age. Most patients used the Internet or a family member to clarify doubts regarding portal information. The use of portal data resulted in 32 extra communications to the physician. Keywords: Electronic, Patient portal, Online, Access, Personal

Background: The objective of this study was to assess the educational quality of YouTube videos pertaining to total knee arthroplasty and knee osteoarthritis. Methods: A systematic search for the terms “knee replacement” and “knee arthritis” was performed using YouTube's search function. Data from the 60 most relevant videos were collected for each search term. Quality assessment checklists with a scale of 0 to 10 points were developed to evaluate the video content. Videos were grouped into poor quality (grade 0-3), acceptable quality (grade 4-7), and excellent quality (grade 8-10), respectively. Results: Overall, 106 videos were categorized. For videos regarding total knee arthroplasty (n = 50), 64% of videos were of poor educational quality (32/50), 28% were of acceptable quality (14/50), and 8% were of good educational quality (4/50). Common missing information included discussion of surgical complications and implant duration. For videos regarding knee arthritis (n = 56), 66% of videos were of poor educational quality (37/56), 32% were of acceptable quality (18/56), and 2% were of good educational quality. Common missing information were causes and risk factors for knee arthritis and long-term prognosis. Conclusions: The present study suggests that YouTube is a poor educational source for patients regarding knee arthroplasty and knee arthritis. Recognizing the limitations of YouTube as well as which topics are not commonly presented may better guide physicians to educate their patients. Keywords: Internet, YouTube, Knee, Arthritis, Replacement

BackgroundManual axon histomorphometry (AH) is time- and resource-intensive, which has inspired many attempts at automation. However, there has been little investigation on implementation of automated programs for widespread use. Ideally such a program should be able to perform AH across imaging modalities and nerve states. AxonDeepSeg (ADS) is an open source deep learning program that has previously been validated in electron microscopy. We evaluated the robustness of ADS for peripheral nerve axonal histomorphometry in light micrographs prepared using two different methods.MethodsAxon histomorphometry using ADS and manual analysis (gold-standard) was performed on light micrographs of naïve or regenerating rat median nerve cross-sections prepared with either toluidine-resin or osmium-paraffin embedding protocols. The parameters of interest included axon count, axon diameter, myelin thickness, and g-ratio.ResultsManual and automatic ADS axon counts demonstrated good agreement in naïve nerves and moderate agreement on regenerating nerves. There were small but consistent differences in measured axon diameter, myelin thickness and g-ratio; however, absolute differences were small. Both methods appropriately identified differences between naïve and regenerating nerves. ADS was faster than manual axon analysis.ConclusionsWithout any algorithm retraining, ADS was able to appropriately identify critical differences between naïve and regenerating nerves and work with different sample preparation methods of peripheral nerve light micrographs. While there were differences between absolute values between manual and ADS, ADS performed consistently and required much less time. ADS is an accessible and robust tool for AH that can provide consistent analysis across protocols and nerve states.

Isolated patellofemoral arthritis is a common debilitating condition in adults older than 40 years of age. Surgical options such as patellofemoral arthroplasty exist for those who failed to respond to nonoperative treatment. However, early patellofemoral arthroplasty techniques often resulted in poor outcomes due to mal-tracking and malalignment of components. Robotic-assisted surgery recently has been introduced as an alternative to classic patellofemoral arthroplasty, with the potential to improve the anatomical fit and reproducibility of implant positioning. We present the technique for minimally invasive robotic-assisted patellofemoral arthroplasty system.

The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti–PD-L1 immunotherapy to achieve better treatment outcome.

Abstract We utilise spray-coating under ambient conditions to sequentially deposit compact-TiO2, mesoporous-TiO2, CH3NH3PbI(3−x)Clx perovskite and doped spiro-OMeTAD layers, creating a mesoporous standard architecture perovskite solar cell (PSC). The devices created had an average power conversion efficiency (PCE) of 9.2% and a peak PCE of 10.2%; values that compare favourably with control-devices fabricated by spin-casting that had an average efficiency of 11.4%. We show that our process can be used to create devices having an active-area of 1.5 cm2 having an independently verified efficiency of 6.6%. This work demonstrates the versatility of spray-coating as well as its potential as a method of manufacturing low-cost, large-area, efficient perovskite devices.

Abstract Astrocytes have been implicated in epileptogenesis and seizure-induced brain injury. Pathological studies reveal a variety of structural abnormalities in astrocytes, such as vacuolization and astrogliosis. While in vivo imaging methods have demonstrated rapid changes in astrocytes under a variety of physiological and pathological conditions, the acute effects of seizures on astrocyte morphology in vivo and corresponding mechanisms of seizure-induced astrocytic injury have not been documented. In this study, we utilized in vivo two-photon imaging to directly monitor the acute structural effects of kainate-induced seizures on cortical astrocytes. Kainate seizures cause an immediate, but transient, vacuolization of astrocytes, followed over several days by astrogliosis. These effects are prevented by pre- or post-treatment with rapamycin, indicating the mTOR pathway is involved in mediating seizure-induced astrocyte injury. These finding have clinical implications for mechanisms of seizure-induced astrocyte injury and potential therapeutic applications with mTOR inhibitors.

Abstract In space, multiple unique environmental factors, particularly microgravity and space radiation, pose constant threat to the DNA integrity of living organisms. Specifically, space radiation can cause damage to DNA directly, through the interaction of charged particles with the DNA molecules themselves, or indirectly through the production of free radicals. Although organisms have evolved strategies on Earth to confront such damage, space environmental conditions, especially microgravity, can impact DNA repair resulting in accumulation of severe DNA lesions. Ultimately these lesions, namely double strand breaks, chromosome aberrations, micronucleus formation, or mutations, can increase the risk for adverse health effects, such as cancer. How spaceflight factors affect DNA damage and the DNA damage response has been investigated since the early days of the human space program. Over the years, these experiments have been conducted either in space or using ground-based analogs. This review summarizes the evidence for DNA damage induction by space radiation and/or microgravity as well as spaceflight-related impacts on the DNA damage response. The review also discusses the conflicting results from studies aimed at addressing the question of potential synergies between microgravity and radiation with regard to DNA damage and cellular repair processes. We conclude that further experiments need to be performed in the true space environment in order to address this critical question.

Tuberous sclerosis complex (TSC) is a genetic disease related to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and manifested by neurological symptoms, such as epilepsy and sleep disorders. The pathophysiology of sleep dysfunction is poorly understood and is likely multifactorial, but may involve intrinsic biological regulators in the brain. Here, we characterized a mouse model of sleep disorders in TSC and investigated mechanisms of sleep dysfunction in this conditional knockout model involving inactivation of the Tsc1 gene in neurons and astrocytes (Tsc1GFAPCKO mice). Sleep studies utilizing EEG, EMG, and behavioral analysis found that Tsc1GFAPCKO mice have decreased REM sleep and impaired sleep-wake differentiation between light and dark phases. mTOR activity and orexin expression were increased in hypothalamic sections and cultured hypothalamic neurons from Tsc1GFAPCKO mice. Both the sleep abnormalities and increased orexin expression in Tsc1GFAPCKO mice were reversed by rapamycin treatment, indicating their dependence on mTOR activation. An orexin antagonist, suvorexant, also restored normal REM levels in Tsc1GFAPCKO mice. These results identify a novel mechanistic link between mTOR and orexin in the hypothalamus related to sleep dysfunction and suggest a targeted therapeutic approach to sleep disorders in TSC.

Calreticulin (CRT) is a high-capacity Ca2+ protein whose expression is up-regulated during cellular transformation and is associated with disease progression in multiple types of malignancies. At the same time, CRT has been characterized as an important stress-response protein capable of inducing immunogenic cell death (ICD) when translocated to the cell surface. It remains unclear why CRT expression is preserved by malignant cells during the course of transformation despite its immunogenic properties. In this study, we identify a novel, critical function of CRT as a cell survival factor in multiple types of human solid-tissue malignancies. CRT knockdown activates p53, which mediates cell-death response independent of executioner caspase activity and accompanied full-length poly ADP ribose polymerase (PARP) cleavage. Mechanistically, we show that down-regulation of CRT results in mitochondrial Ca2+ overload and induction of mitochondria permeability transition pore (mPTP)-dependent cell death, which can be significantly rescued by the mPTP inhibitor, Cyclosporin A (CsA). The clinical importance of CRT expression was revealed in the analysis of the large cohort of cancer patients (N = 2,058) to demonstrate that high levels of CRT inversely correlates with patient survival. Our study identifies intracellular CRT as an important therapeutic target for tumors whose survival relies on its expression.

Objective Recent anticoagulation trials in all-comer cryptogenic stroke patients have yielded equivocal results, reinvigorating the focus on identifying reproducible markers of an atrial myopathy. We investigated the role of excessive premature atrial complexes (PACs) in ischaemic stroke, including cryptogenic stroke and its association with vascular risk factors.Methods and results A case–control study was conducted utilising a multicentre institutional stroke database to compare 461 patients with an ischaemic stroke or transient ischaemic attack (TIA) with a control group consisting of age matched patients without prior history of ischaemic stroke/TIA. All patients underwent 24-hour Holter monitoring during the study period and atrial fibrillation was excluded. An excessive PAC burden, defined as ≥200 PACs/24 hours, was present in 25.6% and 14.7% (p

Articular cartilage is critical for painless and low-friction range of motion; however, disruption of articular cartilage, particularly in the knee joint, is common. Treatment options are based on the size and depth of the chondral defect, as well as involvement of subchondral bone. The gold standard for evaluation of articular cartilage is with arthroscopy, but it is limited by its ability to objectively judge the depth and severity of chondral damage. Optical reflection spectroscopy has been introduced to objectively assess the thickness of cartilage. We present a technique to systematically evaluate the articular cartilage of the knee using BioOptico optical reflection spectroscopy (Arthrex) to better evaluate those with visible chondral and subchondral defects.

The management of incidental or unusual site venous thrombosis (VT) is challenging and is often extrapolated from studies on symptomatic deep venous thrombosis (DVT). There is a tendency to treat with anticoagulation, due to the theoretical risk of propagation and embolism; however, this is not without risk. Furthermore, there is little guidance on how to monitor incidental VT. The aim of this study was to describe the natural history of incidental uterine venous plexus thrombosis (UVPT) and provide a structured approach to its overall management. A prospective study was conducted in a university teaching hospital over a 16-month period. Women diagnosed with UVPT on transvaginal ultrasound (TVS) were followed up over a six-month period and managed based on an individualised risk assessments, in conjunction with haematologists. Fifty women were diagnosed with UVPT during the study period, of which 38 were managed expectantly. The resolution was documented in 70% of women. There were no cases of symptomatic DVT or pulmonary embolisms in either the expectant or treatment groups. Our study has shown that in a high proportion of women, incidental UVPT could be managed successfully without the need for anticoagulation. The overall management of UVPT should be based on individualised clinical risk assessments.

Background and aims: Postmenopausal endometrial polyps are commonly managed by surgical resection; however, expectant management may be considered for some women due to the presence of medical co-morbidities, failed hysteroscopies or patient’s preference. This study aimed to identify patient characteristics and ultrasound morphological features of polyps that could aid in the prediction of underlying pre-malignancy or malignancy in postmenopausal polyps. Methods: Women with consecutive postmenopausal polyps diagnosed on ultrasound and removed surgically were recruited between October 2015 to October 2018 prospectively. Polyps were defined on ultrasound as focal lesions with a regular outline, surrounded by normal endometrium. On Doppler examination, there was either a single feeder vessel or no detectable vascularity. Polyps were classified histologically as benign (including hyperplasia without atypia), pre-malignant (atypical hyperplasia), or malignant. A Chi-squared automatic interaction detection (CHAID) decision tree analysis was performed with a range of demographic, clinical, and ultrasound variables as independent, and the presence of pre-malignancy or malignancy in polyps as dependent variables. A 10-fold cross-validation method was used to estimate the model’s misclassification risk. Results: There were 240 women included, 181 of whom presented with postmenopausal bleeding. Their median age was 60 (range of 45–94); 18/240 (7.5%) women were diagnosed with pre-malignant or malignant polyps. In our decision tree model, the polyp mean diameter (≤13 mm or >13 mm) on ultrasound was the most important predictor of pre-malignancy or malignancy. If the tree was allowed to grow, the patient’s body mass index (BMI) and cystic/solid appearance of the polyp classified women further into low-risk (≤5%), intermediate-risk (>5%–≤20%), or high-risk (>20%) groups. Conclusions: Our decision tree model may serve as a guide to counsel women on the benefits and risks of surgery for postmenopausal endometrial polyps. It may also assist clinicians in prioritizing women for surgery according to their risk of malignancy.

This mixed-methods study aims to inform the development of a 'Park Prescription' intervention, including face-to-face counseling on physical activity and park use and providing weekly structured exercise sessions in the park to promote physical activity. Participants aged 40-65 years were recruited from regional health screening events in Singapore where they completed a questionnaire (N = 97) and consented to focus group (FG) participation (N = 16). The questionnaire assessed current park use, and the type, duration, and intensity of park-based activities that would be of interest. FGs explored the barriers and facilitators of physical activity (in parks). Short interviews (N = 16) with 'doers', i.e., people already engaging in park-based physical activity, identified motivational factors and ways to overcome common barriers. Participants acknowledged the health benefits of parks and valued them because of their pleasant landscapes, greenery and facilities. However, few participants engaged in physical activity at the parks, because they were too busy or too tired. Participants mostly indicated doing informal activities, such as walking, cycling or playing traditional Asian games when using the parks for exercise. A variety of low-to-moderate intensity park-based activities such as walking, cycling or aerobics were of interest to participants who expressed the willingness to engage in structured exercise sessions on weekday evenings or weekend mornings. Strategies to increase physical activity in parks included: encourage planning, create social support, identify alternatives for bad weather, improve proximity/accessibility to parks and park safety. The effectiveness of the Park Prescription intervention in promoting physical activity, park use, as well as physical and mental well-being will be tested in a one-year Randomized Controlled Trial.

Summary: Mutations of the transcriptional regulator PHF6 cause the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS), but the pathogenesis of BFLS remains poorly understood. Here, we report a mouse model of BFLS, generated using a CRISPR-Cas9 approach, in which cysteine 99 within the PHD domain of PHF6 is replaced with phenylalanine (C99F). Mice harboring the patient-specific C99F mutation display deficits in cognitive functions, emotionality, and social behavior, as well as reduced threshold to seizures. Electrophysiological studies reveal that the intrinsic excitability of entorhinal cortical stellate neurons is increased in PHF6 C99F mice. Transcriptomic analysis of the cerebral cortex in C99F knockin mice and PHF6 knockout mice show that PHF6 promotes the expression of neurogenic genes and represses synaptic genes. PHF6-regulated genes are also overrepresented in gene signatures and modules that are deregulated in neurodevelopmental disorders of cognition. Our findings advance our understanding of the mechanisms underlying BFLS pathogenesis. : Cheng et al. generated a mouse model of Börjeson-Forssman-Lehmann syndrome containing a patient-specific mutation of PHF6. PHF6 knockin mice display cognitive impairments, neuronal hyperexcitability, and seizure susceptibility. PHF6 promotes neurogenic and repressed synaptic genes in the cortex. This study advances understanding of the cellular and molecular underpinnings of BFLS. Keywords: PHF6, X-linked intellectual disability, mouse models, neuronal excitability, gene expression