Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans.

BACKGROUND: Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD's analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD's effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). METHODS: We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). DISCUSSION: Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD's analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. TRIAL REGISTRATION: This protocol is registered at clinicaltrials.gov under study number NCT06213233.

More Than Sport: A social-identity intervention to support transitions out of elite sport.

Elite athletes often make large personal sacrifices to pursue excellence, but there is insufficient support for them when they leave elite sport. Identity loss is central to athletes' transition trajectories and hence the management of identity change is a crucial area for support. The More Than Sport (MTS) program is a novel digital intervention that aims to provide this support-helping athletes manage identity change in the process of leaving elite sport. The present research aims to study elite athletes' experiences with the MTS program and their perceptions of its usefulness in managing the transition away from elite sport. We undertook a qualitative study with athletes (N=25) from three countries (the United Kingdom, Australia and Belgium) using reflexive thematic analysis to explore their experiences of the program and their feedback on program content. We identified three key themes and eight subthemes. The first key theme was Value of the Program, and this was underpinned by four sub-themes that centred on Program importance and novelty, how Positive and confronting experiences afford insight, the Value of developing shared understanding, and Realising the value of social groups. The second key theme was Engagement with Program Elements and here participants commented on Program content and Delivery format. The final key theme was Time and Place for Identity Management Programs which included the sub-themes of Optimal timing and Additional program beneficiaries. Overall, the results highlight the value of MTS specifically, and identity management efforts more broadly, to help elite athletes adjust successfully to life beyond sport.

More than meets the eye: Lid and conjunctival injuries in cases of non-sexual assault are frequently accompanied by non-fatal strangulation.

OBJECTIVE: To determine the associations between lid and conjunctival injuries (LACI), non-fatal strangulation (NFS) and domestic family violence (DFV) in non-sexual assault. METHODS: The present study involves an analysis of LACI in a clinical audit of 85 sequential non-sexual assault presentations. RESULTS: LACI was present in 26.9% of non-sexual assault cases, and 47.4% of LACI patients also experienced NFS. LACI was sustained in the context of DFV in 62.9% of cases. Females made up 69.2% of LACI patients, with those between 14 and 29 years most at risk. Children were present in 12.8% of cases, 78.2% of perpetrators were male and 44.9% of patients had previously been assaulted by the same perpetrator. CONCLUSIONS: LACI is frequently associated with NFS and/or DFV. Since NFS increases future homicide attempts and events more than sixfold, LACI is an important signal about a patient's homicide risk, expanding the dimensions of the care needed. Those experiencing LACI during an assault also need to be referred for comprehensive eye examination as soon as possible. With consent, systematic forensic photography of LACI enables its assessment and documentation, which assists the legal process. These conclusions should drive legislative consideration and reform, plus expanded education for clinicians and police.

Relations of optimism and purpose in life to immune markers in aging.

OBJECTIVE: Optimism and purpose in life are associated with improved health outcomes. More information is needed on biological mechanisms, including immunosenescence. We investigated if psychological well-being is associated with healthier immunosenescence-related measures including naïve and terminally differentiated CD4+ and CD8+ T cell percentages, CD4+:CD8+, and cytomegalovirus (CMV) IgG response. METHODS: Participants were adults over age 50 from the Health and Retirement Study. Optimism was measured using the Life Orientation Test Revised. Purpose in life was assessed using the subscale from the Ryff psychological well-being measure. We examined the cross-sectional associations of optimism and purpose in life with measures of T cell subsets using linear regression and with CMV IgG using ordered logit regression, controlling for potential confounding factors. RESULTS: The final analytic sample ranged from 7250 to 7870. After adjusting for sociodemographic factors, a 1-SD increment in optimism was associated with the percentage of naïve CD4+ T cells increasing by 0.6 (95%CI 0.2%, 1.0%). A 1-SD increment in purpose in life was associated with the percentage of naïve CD4+ T cells increasing by 0.9 (95%CI 0.5%, 1.3%) after adjusting for sociodemographic factors and the association was maintained after further adjustments for health conditions, depression, and health behaviors. For naïve CD8+ T cell percentages, CD4:CD8 ratios, and CMV IgG antibodies, associations were seen only in models that adjusted for age. No significant associations were seen in any models for the terminally differentiated CD4+ and CD8+ T cells. CONCLUSIONS: We found associations of optimism and purpose in life with naïve CD4+ T cell percentages.

Outbreak of Ralstonia pickettii associated with contamination of saline products distributed internationally, the United Kingdom, 2024.

We describe an outbreak of Ralstonia pickettii in the United Kingdom, with isolates genetically indistinguishable from a 2023 Australian outbreak linked to internationally distributed saline solutions. Confirmed cases (n = 3) had bacteraemia, clinically relevant infection, indwelling venous lines and frequent healthcare contact. Multi-stakeholder intervention was required including product recall and risk communications. We recommend a low threshold for investigating clusters of Ralstonia species and similar opportunistic pathogens, considering contaminated product sources. Effective mitigation requires multi-agency partnership and international collaboration.

Discrimination in Medical Settings across Populations: Evidence From the All of Us Research Program.

INTRODUCTION: Discrimination in medical settings (DMS) contributes to healthcare disparities in the United States, but few studies have determined the extent of DMS in a large national sample and across different populations. This study estimated the national prevalence of DMS and described demographic and health-related characteristics associated with experiencing DMS in seven different situations. METHODS: Survey data from 41,875 adults participating in the All of Us Research Program collected in 2021-2022 and logistic regression were used to examine the association between sociodemographic and health-related characteristics and self-reported DMS among adults engaged with a healthcare provider within the past 12 months. Statistical analysis was performed in 2023-2024. RESULTS: About 36.89% of adults reported having experienced at least one DMS situation. Adults with relative social and medical disadvantages had higher prevalence of experiencing DMS. Compared to their counterparts, respondents with higher odds of experiencing DMS in at least one situation identified as female, non-Hispanic Black, having at least some college, living in the South, renter, having other living arrangement, being publicly insured, not having a usual source of care, having multiple chronic conditions, having any disability, and reporting fair or poor health, p<0.05. CONCLUSIONS: The findings indicate a high prevalence of DMS, particularly among some population groups. Characterizing DMS may be a valuable tool for identifying populations at risk within the healthcare system and optimizing the overall patient care experience. Implementing relevant policies remains an essential strategy for mitigating the prevalence of DMS and reducing healthcare disparities.

An anti-mitotic compound, (+)-6-tuliposide A, isolated from the Canadian glacier lily, Erythronium grandiflorum.

The Canadian prairie ecosystem is subjected to abiotic and biotic conditions that induce plants to produce secondary metabolites that affect mammalian physiology. Extracts prepared from certain plant species native to Canadian prairie and montane cordillera ecosystems have previously been shown to have anti-mitotic activity on human cancer cell lines. In this study, we investigated the glacier lily, Erythronium grandiflorum (Liliaceae), in which the species was the most phylogenetically distant from Asteraceae and had anti-mitotic activity. When added to cell lines, E. grandiflorum extracts induced rounded cell morphology and arrested cells in the G2/M phase of the cell cycle. Of the cells that displayed a rounded phenotype, all were positive for phospho-histone H3 and contained a distorted mitotic spindle. This anti-mitotic activity was distinct from that of the compound colchicine, which has been previously isolated from the Liliaceae family. By biology-guided fractionation, we isolated the natural product (+)-6-tuliposide A and are the first to report its anti-mitotic activity. These results reveal a chemical motif in secondary metabolites and expand the range of Canadian prairie plants with anti-mitotic activity that can become new scientific tools or used in the development of anti-proliferative medicines.

The time of equipoise on the use of biological DMARDs in for inflammatory arthritis during pregnancy is finally over: a reappraisal of evidence to optimise pregnancy management.

Active inflammatory arthritis in pregnancy is associated with an increased risk of adverse pregnancy outcomes. Treatment of active inflammation and maintenance of low disease activity with medication reduces these risks. Therapeutic decisions on disease-modifying antirheumatic drugs (DMARDs) in pregnancy are complicated by safety concerns, which have led to inappropriate withdrawal of treatment and consequential harm to mother and fetus. Studies of inflammatory arthritis in pregnancy have consistently shown minimal safety concerns with the use of biological DMARDs and an increased risk of disease flare with discontinuation of biological DMARDs. It is our opinion that during pregnancy, the benefits of disease control with biological DMARDs, when required in addition to conventional synthetic DMARDs, outweigh the risks. In this Series paper, we review the reasons for reconsideration of equipoise and propose an agenda for future research to optimise the use of biological DMARDs in inflammatory arthritis during pregnancy.

P2X7 receptor antagonism by AZ10606120 significantly depletes glioblastoma cancer stem cells in vitro.

Glioblastoma is the most aggressive and lethal primary brain malignancy with limited treatment options and poor prognosis. Self-renewing glioblastoma cancer stem cells (GSCs) facilitate tumour progression, resistance to conventional treatment and tumour recurrence. GSCs are resistant to standard treatments. There is a need for novel treatment alternatives that effectively target GSCs. The purinergic P2X receptor 7 (P2X7R) is expressed in glioblastomas and has been implicated in disease pathogenesis. However, the roles of P2X7R have not been comprehensively elucidated in conventional treatment-resistant GSCs. This study characterised P2X7R channel and pore function and investigated the effect of pharmacological P2X7R inhibition in GSCs. Immunofluorescence and live cell fluorescent dye uptake experiments revealed P2X7R expression, and channel and pore function in GSCs. Treatment of GSCs with the P2X7R antagonist, AZ10606120 (AZ), for 72 hours significantly reduced GSC numbers, compared to untreated cells. When compared with the effect of the first-line conventional chemotherapy, temozolomide (TMZ), GSCs treated with AZ had significantly lower cell numbers than TMZ-treated cultures, while TMZ treatment alone did not significantly deplete GSC numbers compared to the control. AZ treatment also induced significant lactate dehydrogenase release by GSCs, indicative of treatment-induced cytotoxic cell death. There were no significant differences in the expression of apoptotic markers, Annexin V and cleaved caspase-3, between AZ-treated cells and the control. Collectively, this study reveals for the first time functional P2X7R channel and pore in GSCs and significant GSC depletion following P2X7R inhibition by AZ. These results indicate that P2X7R inhibition may be a novel therapeutic alternative for glioblastoma, with effectiveness against GSCs resistant to conventional chemotherapy.

Heightened vigilance and its associations with suicidal ideation and suicide attempt among 285 Korean transgender and nonbinary adults: Effect modification by connectedness to the LGBTQ+ community.

INTRODUCTION: Anti-transgender stigma presents threats of discrimination to transgender and nonbinary (TGNB) individuals, prompting them to stay vigilant. Using a longitudinal data of 285 South Korean TGNB adults, we examined vigilance and its associations with suicidal ideation and suicide attempt and explored the protective role of connectedness to the lesbian, gay, bisexual, transgender, and queer (LGBTQ+) community. METHODS: Data were collected in October 2021 (baseline) and October 2022 (follow-up). Vigilance was measured using the 4-item Heightened Vigilance Scale at baseline. At follow-up, 12-month suicidal ideation and suicide attempt, and connectedness to the LGBTQ+ community were measured. RESULTS: Having heightened levels of vigilance was associated with increased prevalence of suicidal ideation (Prevalence Ratio [PR]: 1.33, 95% Confidence Interval [CI]: 1.09-1.62) and suicide attempt (PR: 2.18, 95% CI: 1.23-3.86), after adjusting for covariates including anti-transgender discrimination experiences and lifetime suicidality at baseline. When stratified by connectedness to the LGBTQ+ community, the associations between vigilance and suicidality remained statistically significant among those with low connectedness whereas no statistically significant association was observed among those with high connectedness. CONCLUSION: The study provides empirical evidence for policies and interventions that ensure safety of TGNB individuals from discrimination and promote connectedness to the LGBTQ+ community to reduce the suicide risk among TGNB individuals.

Recognizing Complications in Youth With Diabetes Admitted With Diabetic Ketoacidosis Versus Hyperglycemic Hyperosmolar State.

INTRODUCTION: We compare in-hospital complications in youth with isolated diabetic ketoacidosis (DKA) to youth with hyperosmolarity. METHOD: We reviewed medical records of youth (1-20 years) admitted over two years with DKA, hyperglycemic hyperosmolar state (HHS), and hyperosmolar DKA. We evaluated outcomes, including hospital length of stay, altered mental status (AMS), and acute kidney injury (AKI). RESULTS: Of 369 admissions, 334 had isolated DKA, 32 had hyperosmolar DKA, and three had isolated HHS. Hyperosmolar youth had longer length of stay, larger initial fluid boluses, more frequent pediatric intensive care unit admissions, and increased risk of AKI and AMS. The odds of AKI were positively associated with serum osmolality and negatively associated with new-onset diabetes mellitus (DM) compared with established DM. CONCLUSIONS: In youth with DM, hyperosmolarity increases acute complications compared with isolated DKA. Larger-scale studies are needed to identify ways to prevent acute complications in youth experiencing hyperglycemic emergencies.

Nonoperative Versus Operative Treatment of Z-Type Comminuted Clavicle Fractures in Adolescents: A Prospective Substratified Cohort Analysis.

OBJECTIVES: To compare the clinical, radiographic, and patient-reported outcomes of nonoperative and operative treatment of adolescents with comminuted "Z-type" midshaft clavicle fractures. DESIGN: Prospective observational cohort. SETTING: Eight tertiary care pediatric centers. PATIENT SELECTION CRITERIA: Patients aged 10-18 years who were treated either operatively or nonoperatively for a diaphyseal clavicle fracture between 2013 and 2017 were screened/enrolled at the time of injury. The current subcohort analysis was derived from a larger adolescent clavicle study population of 907 patients. OUTCOME MEASUREMENTS AND COMPARISONS: Complications and validated patient-reported outcome measures (PROs):(ASES, QuickDASH, Marx Shoulder Activity Score, EQ-5D, EQ-VAS, and patient satisfaction score) were compared between operative and nonoperative cohorts. RESULTS: Eighty-one patients (69 male [85.2%], 12 female; average age 15 years [11.1-18.7]; 78 with sports participation [96.2%]) were followed through bony healing and return to sports, while 59 patients (73%) completed 2-year follow-up with PROs, 26 of whom were treated nonoperatively and 33 treated operatively. All demographic and fracture characteristics were similar (P > 0.05) between the 2-year follow-up cohorts except for fracture shortening, which was greater in the operative cohort (23 vs. 29 mm, P = 0.01). After controlling for this potential confounder through both regression and propensity matched subgroup analysis, nonoperative versus operative cohorts showed no difference in rates of nonunion (0%), delayed union (0% vs. 2.3%, P = 1.0), symptomatic malunion (2.7% vs. 0%, P = 0.4), refracture (2.7% vs. 2.2%, P = 1.0), unexpected subsequent surgery (5.4% vs. 11.4%, P = 0.45), or clinically significant complications (5.4% vs. 16%, P = 0.17). There were no differences in any PROs between cohorts, both before and after controlling for the difference in fracture shortening (all P-values >0.05). CONCLUSIONS: In this prospective comparison of complications and 2-year PROs in adolescents with comminuted Z-type clavicle fractures, nonoperative and operative treatment yielded similar outcomes. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Pediatric Gastrointestinal Outcomes During the Post-Acute Phase of COVID-19.

Background: The impact of COVID-19 on gastrointestinal (GI) outcomes in children during the post-acute and chronic phases of the disease is not well understood. Methods: We conducted a retrospective cohort study across twenty-nine healthcare institutions from March 2020 to September 2023, including 413,455 pediatric patients with confirmed SARS-CoV-2 infection and 1,163,478 controls without infection. Infection was confirmed via polymerase chain reaction (PCR), serology, antigen tests, or clinical diagnosis of COVID-19 and related conditions. We examined the incidence of predefined GI symptoms and disorders during the post-acute (28 to 179 days post-infection) and chronic (180 to 729 days post-infection) phases. The adjusted risk ratios (aRRs) were calculated using stratified Poisson regression, with stratification based on propensity scores. Results: Our cohort comprised 1,576,933 patients, with females representing 48.0% of the sample. The analysis revealed that children with SARS-CoV-2 infection had an increased risk of developing at least one GI symptom or disorder in both the post-acute (8.64% vs. 6.85%; aRR 1.25, 95% CI 1.24-1.27) and chronic phases (12.60% vs. 9.47%; aRR 1.28, 95% CI 1.26-1.30) compared to uninfected peers. Specifically, the risk of abdominal pain was higher in COVID-19 positive patients during the post-acute phase (2.54% vs. 2.06%; aRR 1.14, 95% CI 1.11-1.17) and chronic phase (4.57% vs. 3.40%; aRR 1.24, 95% CI 1.22-1.27). Interpretation: Children with a history of SARS-CoV-2 infection are at an increased risk of GI symptoms and disorders during the post-acute and chronic phases of COVID-19. This highlights the need for ongoing monitoring and management of GI outcomes in this population.

Six-Month Outcomes of a Theory- and Technology-Enhanced Physical Activity Intervention for Latina Women (Pasos Hacia La Salud II): Randomized Controlled Trial.

BACKGROUND: More than half (55%) of Latina women do not meet aerobic physical activity (PA) guidelines, and frequently cite time, childcare, and transportation as barriers to PA. In addition to linguistic adaptations for this population, successful PA interventions for Latina women addressed these barriers through remote intervention delivery approaches (eg, mail, phone, or web delivery). OBJECTIVE: We aimed to evaluate 6-month outcomes of a randomized trial comparing a Spanish-language, individually tailored, web-delivered PA intervention (original) to an enhanced version with text messages and additional features (enhanced). Further, we evaluated if increases in PA at 6 months were moderated by baseline activity status. METHODS: In total, 195 Latina women aged 18-65 years participated in a trial comparing the efficacy of the enhanced versus original interventions at initiating PA behavior change. We examined minutes per week of accelerometer-measured PA in the enhanced versus original arms, and the proportion of each arm meeting aerobic PA guidelines (150 min/wk at 6 mo). For moderator analyses, participants were classified as inactive (0 min/wk) or low active (1-90 min/wk) at baseline, measured via the 7 Day Physical Activity Recall interview. RESULTS: PA increased from 19.7 (SD 47.9) minutes per week at baseline to 46.9 (SD 66.2) minutes per week at 6 months in the enhanced arm versus 20.6 (SD 42.7) minutes per week to 42.9 (SD 78.2) minutes per week in the original arm (P=.78). Overall, 30% (31/103) of the enhanced group met aerobic PA guidelines at 6 months, compared to 21% (19/92) of the original group (odds ratio [OR] 1.75, 95% CI 0.87-3.55). Baseline PA (inactive vs low active) moderated treatment effects on PA. For inactive participants, there were no group differences at 6 months (b=7.1; SE 22.8; P=.75), while low-active participants increased more in enhanced than original (b=72.5; SE 27.9; P=.01). For low-active participants, 45% (46/103) of the enhanced group met PA guidelines at 6 months, versus 20% (18/92) of the original arm (OR 3.29, 95% CI 1.05-11.31). For inactive participants, there were no group differences (25/103, 24% vs n=19/92, 21% for enhanced vs original, respectively; OR 1.28, 95% CI 0.54-3.06). CONCLUSIONS: Intervention effects were conditional on baseline PA. For low-active Latina women, the enhanced intervention was more effective at increasing PA. Additional tailored intervention enhancements may be necessary to increase PA for inactive Latina women. TRIAL REGISTRATION: ClinicalTrials.gov NCT03491592; https://www.clinicaltrials.gov/study/NCT03491592. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-022-06575-4.

Ribosomal DNA copy number is associated with body mass in humans and other mammals.

Body mass results from a complex interplay between genetics and environment. Previous studies of the genetic contribution to body mass have excluded repetitive regions due to the technical limitations of platforms used for population scale studies. Here we apply genome-wide approaches, identifying an association between adult body mass and the copy number (CN) of 47S-ribosomal DNA (rDNA). rDNA codes for the 18 S, 5.8 S and 28 S ribosomal RNA (rRNA) components of the ribosome. In mammals, there are hundreds of copies of these genes. Inter-individual variation in the rDNA CN has not previously been associated with a mammalian phenotype. Here, we show that rDNA CN variation associates with post-pubertal growth rate in rats and body mass index in adult humans. rDNA CN is not associated with rRNA transcription rates in adult tissues, suggesting the mechanistic link occurs earlier in development. This aligns with the observation that the association emerges by early adulthood.

Why so slow? Models of parkinsonian bradykinesia.

Bradykinesia, or slowness of movement, is a defining feature of Parkinson disease (PD) and a major contributor to the negative effects on quality of life associated with this disorder and related conditions. A dominant pathophysiological model of bradykinesia in PD has existed for approximately 30 years and has been the basis for the development of several therapeutic interventions, but accumulating evidence has made this model increasingly untenable. Although more recent models have been proposed, they also appear to be flawed. In this Perspective, I consider the leading prior models of bradykinesia in PD and argue that a more functionally related model is required, one that considers changes that disrupt the fundamental process of accurate information transmission. In doing so, I review emerging evidence of network level functional connectivity changes, information transfer dysfunction and potential motor code transmission error and present a novel model of bradykinesia in PD that incorporates this evidence. I hope that this model may reconcile inconsistencies in its predecessors and encourage further development of therapeutic interventions.

Synthesis Studies and the Evaluation of C6 Raloxifene Derivatives.

Methodology is described for the synthesis of C6 derivatives of raloxifene, a prescribed drug for the treatment and prevention of osteoporosis. Studies have explored the incorporation of electron-withdrawing substituents at C6 of the benzothiophene core. Efficient processes are also examined to introduce hydrogen bond donor and acceptor functionality. Raloxifene derivatives are evaluated with in vitro testing to determine estrogen receptor (ER) binding affinity and gene expression in MC3T3 cells.

Real-World Clinical Experience of Oral Semaglutide in a Secondary Diabetes Clinic in the UK: A Retrospective Observational Study.

INTRODUCTION: Oral semaglutide improves cardiovascular risk factors in people with type 2 diabetes (T2D) in clinical trials, though real-world evidence is limited. We aimed to determine the real-world impact of oral semaglutide on routinely collected clinical data in our practice. METHODS: People with T2D initiated on oral semaglutide in secondary care diabetes clinics at two hospital sites in Wales (United Kingdom) were included. Data were collected on reasons for oral semaglutide initiation and changes in bodyweight, blood pressure, glycemic control, and lipid profiles over follow-up at 3-6 months, and at 6-12 months. Data were collected to determine the safety of oral semaglutide. RESULTS: Seventy-six patients were included, with a median age 59.3 [51.4-67.6] years, and 38 (50.0%) patients were female. The most common reasons for oral semaglutide were need for weight loss and improved glycemia (69.8%), and improved glycemia alone (25.0%). Oral semaglutide associated with significantly reduced bodyweight (- 3.3 kg), body mass index (BMI) (- 0.9 kg/m2), glycated hemoglobin (HbA1c) (- 11 mmol/mol), and total cholesterol (- 0.4 mmol/l) by 3-6 months follow-up. At 6-12 months, there was a significant reduction in systolic blood pressure (- 7.0 mmHg), in addition to sustained reductions in other metabolic parameters. By 12 months, 18 (23.6%) patients had discontinued the drug, largely resulting from gastrointestinal disturbance, but there were no serious events in this cohort. CONCLUSIONS: Oral semaglutide was effective in improving cardiovascular risk factors in this real-world population living with T2D, and no serious events were identified related to oral semaglutide in this patient group.

A fear conditioned cue orchestrates a suite of behaviors in rats.

Pavlovian fear conditioning has been extensively used to study the behavioral and neural basis of defensive systems. In a typical procedure, a cue is paired with foot shock, and subsequent cue presentation elicits freezing, a behavior theoretically linked to predator detection. Studies have since shown a fear conditioned cue can elicit locomotion, a behavior that - in addition to jumping, and rearing - is theoretically linked to imminent or occurring predation. A criticism of studies observing fear conditioned cue-elicited locomotion is that responding is non-associative. We gave rats Pavlovian fear discrimination over a baseline of reward seeking. TTL-triggered cameras captured 5 behavior frames/s around cue presentation. Experiment 1 examined the emergence of danger-specific behaviors over fear acquisition. Experiment 2 examined the expression of danger-specific behaviors in fear extinction. In total, we scored 112,000 frames for nine discrete behavior categories. Temporal ethograms show that during acquisition, a fear conditioned cue suppresses reward seeking and elicits freezing, but also elicits locomotion, jumping, and rearing - all of which are maximal when foot shock is imminent. During extinction, a fear conditioned cue most prominently suppresses reward seeking, and elicits locomotion that is timed to shock delivery. The independent expression of these behaviors in both experiments reveals a fear conditioned cue to orchestrate a temporally organized suite of behaviors.

Knowing that an animal is fearful is crucial for many psychology and neuroscience studies. For instance, this knowledge allows researchers to examine the brain pathways involved in processing and responding to fear. Typically, researchers consider that a rodent is experiencing fear if it 'freezes' ­ a response which, in the wild, helps to evade detection by predators. In Pavlovian fear conditioning experiments, for example, rats and mice freeze when exposed to a stimulus (often a specific sound) previously associated with unpleasant sensations. However, rodents can also respond more actively to threats, for instance by running or jumping away. It remains unclear whether the 'fearful stimuli' used in Pavlovian approaches specifically elicits only freezing, or other fear-related behaviors as well. To investigate this, Chu et al. used high-speed cameras to record rats' responses to a sound cue they had 'learned' to associate with a mild foot shock. In addition to freezing, the animals ran, jumped, stood on their hind legs and stopped their usual reward-seeking behavior in response to the cue. Crucially, these reactions were absent when the rats were exposed to sound cues not associated with pain. Overall, these experiments demonstrate that Pavlovian conditioning can elicit a full range of fear-related behaviors beyond freezing. Understanding the neural activity behind these diverse responses could lead to more targeted therapies and interventions addressing the various ways stress and anxiety manifest in people.