Cause of Concussion With Persisting Symptoms Is Associated With Long-Term Recovery and Symptom Type, Duration, and Number in a Longitudinal Cohort of 600 Patients.

It is important for patients and clinicians to know the potential for recovery from concussion as soon as possible after injury, especially in patients who do not recover completely in the first month and have concussion with persisting concussion symptoms (C+PCS). We assessed the association between the causes of concussion and recovery from C+PCS in a consecutive retrospective and prospective cohort of 600 patients referred to the Canadian Concussion Center (CCC) at Toronto Western Hospital. Data were obtained from clinical records and follow-up questionnaires and not from a standardized database. A novel method was used to assess long-term recovery, and multi-variable Cox proportional hazards models were used to assess relationships between cause of concussion and time to recovery. We examined the subsequent recovery of patients who had not recovered after at least one month from the time of concussion. Patients were grouped into the following four causes: sports and recreation (S&R, n = 312, 52%); motor vehicle collisions (MVC, n = 103, 17%); falls (n = 100, 17%); and being struck by an object including violence (SBOV, n = 85, 14%). The MVC group had the highest percentage of females (75.7%), the oldest participants (median: 40.0 [interquartile range (IQR):30.5-49.0] years), the most symptoms (median:11.0 [IQR:8.5-15.0]), and the longest symptom duration (median: 28.0 [IQR:12.0-56.00] months). In contrast, the S&R group had the highest percentage of males (58.1%), the youngest participants (median:20.0 [IQR:17.0-30.0] years), the best recovery outcome, and shortest symptom duration (median:22.0 [IQR:8.0-49.5] months). Significant differences among the four causes included age (p < 0.001), sex (p < 0.001), number of previous concussions (p < 0.001), history of psychiatric disorders (p = 0.002), and migraine (p = 0.001). Recovery from concussion was categorized into three groups: (1) Complete Recovery occurred in only 60 (10%) patients with median time 8.0 (IQR:3.5-18.0) months and included 42 S&R, 7 MVC, 8 falls, and 3 SBOV; (2) Incomplete Recovery occurred in 408 (68.0%) patients with persisting median symptom time of 5.0 (IQR:2.0-12.0) months; and (3) Unknown Recovery occurred in 132 (22.0%) patients and was because of lack of follow-up. In summary, the cause of C+PCS was associated with the type, number, and duration of symptoms and time required for recovery, although all causes of C+PCS produced prolonged symptoms in a large percentage of patients, which emphasizes the importance of concussions as a public health concern necessitating improved prevention and treatment strategies.

Identifying metabolic adaptations characteristic of cardiotoxicity using paired transcriptomics and metabolomics data integrated with a computational model of heart metabolism.

Improvements in the diagnosis and treatment of cancer have revealed long-term side effects of chemotherapeutics, particularly cardiotoxicity. Here, we present paired transcriptomics and metabolomics data characterizing in vitro cardiotoxicity to three compounds: 5-fluorouracil, acetaminophen, and doxorubicin. Standard gene enrichment and metabolomics approaches identify some commonly affected pathways and metabolites but are not able to readily identify metabolic adaptations in response to cardiotoxicity. The paired data was integrated with a genome-scale metabolic network reconstruction of the heart to identify shifted metabolic functions, unique metabolic reactions, and changes in flux in metabolic reactions in response to these compounds. Using this approach, we confirm previously seen changes in the p53 pathway by doxorubicin and RNA synthesis by 5-fluorouracil, we find evidence for an increase in phospholipid metabolism in response to acetaminophen, and we see a shift in central carbon metabolism suggesting an increase in metabolic demand after treatment with doxorubicin and 5-fluorouracil.

A Novel Method for Assessing Risk-Adjusted Diagnostic Coding Specificity for Depression Using a U.S. Cohort of over One Million Patients.

Depression is a prevalent and debilitating mental health condition that poses significant challenges for healthcare providers, researchers, and policymakers. The diagnostic coding specificity of depression is crucial for improving patient care, resource allocation, and health outcomes. We propose a novel approach to assess risk-adjusted coding specificity for individuals diagnosed with depression using a vast cohort of over one million inpatient hospitalizations in the United States. Considering various clinical, demographic, and socioeconomic characteristics, we develop a risk-adjusted model that assesses diagnostic coding specificity. Results demonstrate that risk-adjustment is necessary and useful to explain variability in the coding specificity of principal (AUC = 0.76) and secondary (AUC = 0.69) diagnoses. Our approach combines a multivariate logistic regression at the patient hospitalization level to extract risk-adjusted probabilities of specificity with a Poisson Binomial approach at the facility level. This method can be used to identify healthcare facilities that over- and under-specify diagnostic coding when compared to peer-defined standards of practice.

A polydiolcitrate-MoS2 composite for 3D printing Radio-opaque, Bioresorbable Vascular Scaffolds.

Implantable polymeric biodegradable devices, such as biodegradable vascular stents or scaffolds, cannot be fully visualized using standard X-ray-based techniques, compromising their performance due to malposition after deployment. To address this challenge, we describe composites of methacrylated poly(1,12 dodecamethylene citrate) (mPDC) and MoS2 nanosheets to fabricate novel X-ray visible radiopaque and photocurable liquid polymer-ceramic composite (mPDC-MoS2). The composite was used as an ink with micro continuous liquid interface production (µCLIP) to fabricate bioresorbable vascular scaffolds (BVS). Prints exhibited excellent crimping and expansion mechanics without strut failures and, importantly, required X-ray visibility in air and muscle tissue. Notably, MoS2 nanosheets displayed physical degradation over time in a PBS environment, indicating the potential for producing bioresorbable devices. mPDC-MoS2 is a promising bioresorbable X-ray-visible composite material suitable for 3D printing medical devices, particularly vascular scaffolds or stents, that require non-invasive X-ray-based monitoring techniques for implantation and evaluation. This innovative composite system holds significant promise for the development of biocompatible and highly visible medical implants, potentially enhancing patient outcomes and reducing medical complications.

Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.

Drug repositioning seeks to leverage existing clinical knowledge to identify alternative clinical settings for approved drugs. However, repositioning efforts fail to demonstrate improved success rates in late-stage clinical trials. Focusing on 11 approved kinase inhibitors that have been evaluated in 139 repositioning hypotheses, we use data mining to characterize the state of clinical repurposing. Then, using a simple experimental correction with human serum proteins in in vitro pharmacodynamic assays, we develop a measurement of a drug's effective exposure. We show that this metric is remarkably predictive of clinical activity for a panel of five kinase inhibitors across 23 drug variant targets in leukemia. We then validate our model's performance in six other kinase inhibitors for two types of solid tumors: non-small cell lung cancer (NSCLC) and gastrointestinal stromal tumors (GISTs). Our approach presents a straightforward strategy to use existing clinical information and experimental systems to decrease the clinical failure rate in drug repurposing studies.

Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses.

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that several metabolic pathways exhibit sex differences including glycolysis, fatty acid metabolism, nucleotide metabolism, and xenobiotics metabolism. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we find several subsystems with differential expression overlap with the sex-altered pathways such as fatty acid metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the pentose phosphate pathway and other metabolic pathways. These results suggest potential sex differences in the contribution of the pentose phosphate pathway to oxidative stress, and we recommend further research into how these reactions respond to hepatotoxic pharmaceuticals.

Metabolic modeling of sex-specific tissue predicts mechanisms of differences in toxicological responses.

Male subjects in animal and human studies are disproportionately used for toxicological testing. This discrepancy is evidenced in clinical medicine where females are more likely than males to experience liver-related adverse events in response to xenobiotics. While previous work has shown gene expression differences between the sexes, there is a lack of systems-level approaches to understand the direct clinical impact effect of these differences. Here, we integrate gene expression data with metabolic network models to characterize the impact of transcriptional changes of metabolic genes in the context of sex differences and drug treatment. We used Tasks Inferred from Differential Expression (TIDEs), a reaction-centric approach to analyzing differences in gene expression, to discover that androgen, ether lipid, glucocorticoid, tryptophan, and xenobiotic metabolism have more activity in the male liver, and serotonin, melatonin, pentose, glucuronate, and vitamin A metabolism have more activity in the female liver. When TIDEs is used to compare expression differences in treated and untreated hepatocytes, we see little response in those sex-altered subsystems, and the largest differences are in subsystems related to lipid metabolism. Finally, using sex-specific transcriptomic data, we create individual and averaged male and female liver models and find differences in the import of bile acids and salts. This result suggests that the sexually dimorphic behavior of the liver may be caused by differences in enterohepatic recirculation, and we suggest an investigation into sex-specific microbiome composition as an avenue of further research. Author Summary: Male-bias in clinical testing of drugs has led to a disproportionate number of hepatotoxic events in women. Previous works use gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex; however, when comparing these subsystems with those pathways altered by hepatotoxic agents, we find little overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 human cell metabolic model. In these models we find a difference in flux for the import of bile acids and salts, suggesting a potential difference in enterohepatic circulation. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.

A webinar series to educate applicants about the UK academic foundation programme: a longitudinal cross-sectional study.

BACKGROUND: The UK academic foundation programme (AFP) is a competitive programme for medical graduates and forms the initial stage of the integrated clinical academic pathway. The application is complex and targeted education is beneficial. As online technologies improve, virtual medical education is becoming more common. Currently, webinar education, particularly that of webinar series, are poorly evidenced. An online course was created to investigate the acceptability and effectiveness of webinars for medical education. METHODS: A six-part, one-hour sessional webinar course was developed following a focus group with academic foundation doctors. A pre- and post-course cross-sectional questionnaire study evaluated participant demographics, webinar opinion and self-rated understanding of the AFP via Google Form (Google, USA). Where applicable a five-point Likert scale (1-Strongly disagree to 5-strongly agree) was utilised and analysis using non-parametric paired statistical analysis. RESULTS: Medical students (n=303) from 35 UK universities completed the pre-course questionnaire. Most students had not received targeted education on the AFP. They rated webinars useful for education (mean=4.2 s.d. 0.7). After the course, participants (n=66) expressed it was significantly convenient (mean=4.7), effective (mean=4.7) and suitably interactive (mean=4.4) (p<0.001 compared to neutral). Participants preferred short sessions over multiple days to the concept of a full-day event (mean=4.6 vs 3.1, p<0.001). Paired analysis of participants completing both forms (n=47) demonstrates a significant increase in self-rated understanding of AFP content, portfolio building, application process, acute clinical scenarios, interview technique and overall confidence in acquiring an AFP post (p<0.001). Follow-up identified 43 participants who completed the course were successful in their AFP application. This represents 7.8% of all successful AFP applicants in 2021. CONCLUSIONS: This study evidences an accessible and effective webinar series for AFP education. Comprehensive webinar courses for similar topics and demographics may provide valuable utility in the provision of future medical education. TRIAL REGISTRATION: Ethics requirements were waived for this study by Bristol University Ethics Committee. All participants in this study consented for anonymous use of their data. As such the trial is not registered.

Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity.

We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF6 motif (where M is either RuII or OsII) with an appended C16 fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C16 OsII nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism.

Synthesis and disassembly of an organometallic polymer comprising redox-active Co4S4 clusters and Janus biscarbene linkers.

Here, we show for the first time that main-chain organometallic polymers (MCOPs) can be prepared from Janus N-heterocyclic carbene (NHC) linkers and polynuclear cluster nodes. The crosslinked framework Co4S4-MCOP is synthesized via ligand displacement reactions and undergoes reversible electron transfer in the solid state. Discrete molecular cluster species can be excised from the framework by digesting the solid in solutions of excess monocarbene. Finally, we demonstrate a synthetic route to monodisperse framework particles via coordination modulation.

Acute effects of axial loading on postural control during walking and turning in people with multiple sclerosis: A pilot study.

BACKGROUND: Impaired sensory integration is heavily involved in gait control and accentuates fall risk in individuals with multiple sclerosis (MS). While axial loading has been found beneficial, little is known about the effect of non-specific axial loads on gait parameters and mobility tasks in those with MS. RESEARCH QUESTION: What are the effects of non-specific axial loading via weighted vests on walking and turning in those with MS. METHODS: Twelve participants with MS and eleven age- and gender-matched healthy controls participated in a cross-sectional study. All participants completed five trials of continuous walking with turns wearing weighted vests at 0%, 2%, 4%, 5%, and then 0% of their body weight. Gait parameters were measured using wireless inertial sensors. A 2 (group) x 5 (vest weight) multivariate analysis of variance (MANOVA) was performed to determine any significant differences between groups and across weighted vests for each gait variable. Post-hoc analysis and paired t-tests with corresponding effect sizes were also conducted. RESULTS: A significant between groups main effect was found for group (F (6100) = 14.74, p = .000) in multiple gait parameters (p < 0.05), although no significant main effect was found for weighted vest. Within group analyses indicated significantly increased cadence and gait speed across varying weighted vests for both MS and control groups (p < 0 >05). Increased vest weight from 0%PRE to 2% also had large effect on shortening double support time and increasing stride length in the MS group. SIGNIFICANCE: This study provided preliminary evidence that non-specific axial loads of varying weights appear to improve certain gait parameters. As such, this modality may offer mobility benefit and serve as an accessible home-based intervention alternative aimed at improving walking in individuals with MS.

Interim Foundation Year One (FiY1) and preparedness for foundation year 1: A national survey of UK foundation doctors.

BACKGROUND: Induction programmes aim to ease the transition from medical student to doctor. The interim foundation year 1 (FiY1) placement, introduced in the first COVID-19 wave, provided experience in advance of the Foundation Year 1 (FY1) start in August; providing more time and enhanced responsibilities than traditional induction programmes. This study examines the effects of the FiY1 placement on anxiety levels and preparedness for FY1. METHODS: This was a descriptive cross-sectional study using data from four cohorts of FY1s who completed the online National FY1 induction survey from 2017 to 2020 (n = 4766). Questions evaluated self-reported preparedness and anxiety levels. Differences in preparedness and anxiety levels of FiY1 and non-FiY1 participants in 2020, and the 2017-2019 participants (non-FiY1 controls), were evaluated. RESULTS: FiY1s in 2020 reported higher self-reported preparedness (79%) than non-FiY1s (54%) in 2020 (p = <0.001) and the control 2017-2019 cohort (63.8%) (p < 0.001). Fewer FiY1s experienced pathological anxiety (29.3% versus 40.8% for non-FiY1s; p = 0.001). CONCLUSION: Time spent in an FiY1 role is associated with an increase in self-perceptions of preparedness and a reduction in anxiety. These data indicate that time spent in an FiY1 role may have utility in further improving the transition period from medical school to FY1.

Synthesis, structure and anticancer properties of new biotin- and morpholine-functionalized ruthenium and osmium half-sandwich complexes.

Ruthenium (Ru) and osmium (Os) complexes are of sustained interest in cancer research and may be alternative to platinum-based therapy. We detail here three new series of ruthenium and osmium complexes, supported by physico-chemical characterizations, including time-dependent density functional theory, a combined experimental and computational study on the aquation reactions and the nature of the metal-arene bond. Cytotoxic profiles were then evaluated on several cancer cell lines although with limited success. Further investigations were, however, performed on the most active series using a genetic approach based on RNA interference and highlighted a potential multi-target mechanism of action through topoisomerase II, mitotic spindle, HDAC and DNMT inhibition.

Mapping the Landscape of Surgical Registries in the United Kingdom: A Review According to the SWiM Methodology.

BACKGROUND: Well-designed surgical registries are essential for high-quality patient centred evaluation of implantable devices and surgical procedures. The importance of registries was highlighted in the recent Cumberlege report that detailed important innovation failures such as the use of vaginal mesh. Many surgical registries exist, but it is currently unclear how different registries are funded, governed, designed, and how their databases are hosted and utilised. There is therefore a need to understand the variation and characteristics of existing surgical registries to identify limitations and make recommendations for improvement. This work aims to understand the characteristics and heterogeneity in the design, governance, and function of existing surgical registries in the United Kingdom (UK). METHODS: Existing surgical registries will be identified using multiple data sources including surgical society websites; search engine review; a targeted search of the Medline and Embase databases and expert knowledge. The data identified were reviewed following the synthesis without meta-analysis (SWiM) methodology. This information will be gathered from sources in the public domain only to fully understand registry transparency for professionals and the public. Details of each registry including disease area/condition/device evaluated; types of outcomes collected; governance, consent, and oversight; linkage to other datasets and funding will be extracted using a standardised data extraction tool. Characteristics of identified registries will be summarised into a narrative review. DISSEMINATION: Findings will be presented at national and international conferences and published in peer-reviewed journals. Results will be presented to key stakeholders including surgeons, methodologists, trialists, regulators, data managers and patients to provide an up-to-date description of the current state of surgical registries in the UK. This work will inform a consensus process to agree how the design of new and existing registries can be optimised to support high quality research to benefit patients and the NHS. HIGHLIGHTS: Well-designed surgical registries are essential for high-quality patient centred evaluation of implantable devices and surgical proceduresPresently there is limited understanding on how these registries are designed, governed, what data they collect and how this data is utilised for research.This review aims to map the landscape of surgical registries in the UK, and understand how they are optimised for research.

Bicycling-related concussions leading to postconcussion syndrome in adults.

BACKGROUND: Concussions among adult bicyclists are common, but little is known about the long-term effects of the consequences of these concussions such as postconcussion syndrome (PCS) including its occurrence, clinical features and recovery potential. Indeed, our study is the first to examine PCS due to bicycling in any age group. OBJECTIVES: We examined patient demographics, concussion mechanisms and persistent symptoms as factors leading to PCS in adults and the potential for recovery. METHODS: We conducted a retrospective chart review of 28 patients age 18 or older who sustained a concussion while bicycling and were referred to the Canadian Concussion Centre for management of PCS. RESULTS: Eighteen patients (64.3%) fell from their bicycles due to loss of control, attempts to avoid a crash or collision with an object. Eight patients (28.6%) were struck by a motor vehicle, and two patients (7.1%) were injured by collision with another bicycle. The mean duration of PCS was 23.7 months and at the time of the last follow-up, 23 (82.1%) patients had failed to recover completely. Patients with one or more previous concussions had a significantly longer duration of PCS (p=0.042). Bicycling concussions resulted in a greater mean duration of PCS (23.7 months) than a comparison group of patients with PCS due to collision sports (16.1 months) (p=0.07). CONCLUSION: Adults who sustain bicycling-related concussions and develop PCS often have long-lasting symptoms; greater attention should be given to prevention strategies such as improved bicycling infrastructure and safer bicycling practices to reduce concussions in adult bicyclists.

The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning.

Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.