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Objective: To determine differences in glucose control and cardiovascular disease risk factors following three weeks of added soda, 100% fruit juice, or water in apparently healthy, college-aged adults. Participants: Thirty-six adults (18 males; 18 females) between the ages of 18 and 30 years of age. Methods: A 3-arm randomized controlled parallel-arm trial; at baseline and after three weeks consuming the assigned beverage, participants completed glucose control and cardiovascular disease risk factor assessments. Results: There were no significant differences between beverage conditions for glucose control or cardiovascular disease risk factors (ps > 0.05). There were no significant changes in caloric intake or differences in caloric intake between conditions, p = 0.17. p Conclusions: In healthy, young adults, under free-living conditions, short-term consumption of two commercially packaged servings of SBs did not lead to significant glucose control or cardiovascular disease risk factor changes, indicating potential compensation and/or resilience to negative short-term effects.

Abstract Background Musculoskeletal injuries are a common occurrence in sport. The goal of sport injury epidemiology is to study these injuries at a population level to inform their prevention and treatment. Main body This review provides an overview of musculoskeletal sport injuries and the musculoskeletal system from a biological and epidemiologic perspective, including injury mechanism, categorizations and types of sport injuries, healing, and subsequent injuries. It is meant to provide a concise introductory substantive background of musculoskeletal sport injuries for epidemiologists who may not have formal training in the underlying anatomy and pathophysiology. Conclusion An understanding of sport injuries is important for researchers in sport injury epidemiology when determining how to best define and assess their research questions and measures.

In recent years, a large focus has been placed on managing training load for injury prevention. To minimise injuries, training recommendations should be based on research that examines causal relationships between load and injury risk. While observational studies can be used to estimate causal effects, conventional methods to study the relationship between load and injury are prone to bias. The target trial framework is a valuable tool that requires researchers to emulate a hypothetical randomised trial using observational data. This framework helps to explicitly define research questions and design studies in a way that estimates causal effects. This article provides an overview of the components of the target trial framework as applied to studies on load and injury and describes various considerations that should be made in study design and analyses to minimise bias.

Abstract Background A stroke frequently results in impaired performance of activities of daily life. Many of these are highly dependent on effective coordination between the two arms. In the context of bimanual movements, cyclic rhythmical bilateral arm coordination patterns can be classified into two fundamental modes: in-phase (bilateral homologous muscles contract simultaneously) and anti-phase (bilateral muscles contract alternately) movements. We aimed to investigate how patients with left (LHS) and right (RHS) hemispheric stroke are differentially affected in both individual-limb control and inter-limb coordination during bilateral movements. Methods We used kinematic measurements to assess bilateral coordination abilities of 18 chronic hemiparetic stroke patients (9 LHS; 9 RHS) and 18 age- and sex-matched controls. Using KINARM upper-limb exoskeleton system, we examined individual-limb control by quantifying trajectory variability in each hand and inter-limb coordination by computing the phase synchronization between hands during anti- and in-phase movements. Results RHS patients exhibited greater impairment in individual- and inter-limb control during anti-phase movements, whilst LHS patients showed greater impairment in individual-limb control during in-phase movements alone. However, LHS patients further showed a swap in hand dominance during in-phase movements. Conclusions The current study used individual-limb and inter-limb kinematic profiles and showed that bilateral movements are differently impaired in patients with left vs. right hemispheric strokes. Our results demonstrate that both fundamental bilateral coordination modes are differently controlled in both hemispheres using a lesion model approach. From a clinical perspective, we suggest that lesion side should be taken into account for more individually targeted bilateral coordination training strategies. Trial registration: the current experiment is not a health care intervention study.

Abstract Background Individuals with non-small cell lung cancer (NSCLC) are burdened by long-lasting symptoms (e.g., dyspnea and fatigue) post-treatment. These symptoms often reduce physical activity levels and increase the risk of functional decline. Though we have previously proposed cluster-set resistance training to mitigate symptom burden in lung cancer, there is currently no data on the feasibility or acceptability of this mode of exercise in cancer. Therefore, the purpose of this study was to investigate the feasibility and acceptability of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC stages I–III (i.e., early stage). Methods This study aimed to recruit individuals with NSCLC stages I–III post-treatment to participate in 8 weeks of home-based resistance training, 3 days per week. The program included supervised sessions in the participants’ homes and virtual supervision via videoconferencing. The primary outcome measure of feasibility was evaluated through recruitment, retention, and intervention fidelity (i.e., proportion of exercise completed, relative to what was prescribed). Intervention acceptability (i.e., ease and quality of virtual delivery, level of difficulty, and home-based approach) was assessed using a 4-point Likert-type scale from “strongly disagree” to “strongly agree”. Results Fourteen participants were recruited over a 6-month period, with 11 completing the intervention (2 withdrew due to unrelated illness, 1 withdrew due to requiring active treatment), yielding a retention rate of 79%. Characteristics of the participants who completed the intervention (n = 11) were as follows: mean age: 71 ± 10 years, mean BMI: 29.1 ± 6.5, and average time since diagnosis was 62 ± 51 months. Of completers, 27% were male, and 36% were Black; 10 were stage I (91%), and one was stage II (9%). Mean session attendance was 86.4 ± 9.5%. Mean intervention fidelity was 83.1 ± 13.1%. With regard to acceptability, > 90% of participants positively rated all aspects of the intervention delivery. No adverse events related to exercise were recorded. Conclusions The hybrid delivery of a home-based resistance exercise program for individuals previously treated for early-stage NSCLC was found to be safe and feasible. Adaptations to the program for future interventions are required, particularly surrounding resistance exercise programming, and intervention delivery with home visits. Trial registration ClinicalTrials.gov: NCT05014035 . Registered January 20, 2021.

Abstract Boron (B) isotopes are widely used in the Earth sciences to trace processes ranging from slab recycling in the mantle to changes in ocean pH and atmospheric CO2. Boron isotope analysis is increasingly achieved by multi‐collector inductively coupled plasma mass spectrometry, which requires separation of B from the sample matrix. Traditional column chromatography methods for this separation have a well‐established track record but are time consuming and prone to contamination from airborne blank. Here, we present an extensive array of tests that establish a novel method for B purification using a batch method. We discuss the key controls and limitations on sample loading, matrix removal and B elution including sample volume, ionic strength, buffer to acid ratio and elution volume, all of which may also help optimize column‐based methods. We find consistent, low procedural blanks of 10 ± 16 pg and excellent reproducibility: 10 ng NIST RM 8301 foram [8301f] yields 14.58 ± 0.11‰ 2SD n = 15; 2.5 ng 8301f yields 14.60 ± 0.19‰ 2SD, n = 31; and overall long term 2SD on n = 218 samples pooling different sample sizes yields 14.62 ± 0.21‰ 2SD. This method also offers significant advantages in throughput, allowing the processing of 24 samples in ∼5 hr. This boron batch method thus provides a fast, reproducible, low‐blank method for purification of boron for high precision isotopic analyses.

Abstract Boron isotope ratios (δ11B) are used across the Earth Sciences and are increasing analyzed by Multi‐Collector Inductively Coupled Plasma Mass Spectrometry (MC‐ICPMS). Accurate δ11B MC‐ICPMS analysis requires boron purification from the sample matrix using ion‐exchange column chromatography. However, the traditional gravity‐drip column method is time‐consuming and prone to airborne contamination due to its long duration and open resin surface. To address these issues, we designed a novel, simple, and reliable column chromatography technique called “peri‐columns.” This method uses a peristaltic pump to generate vacuum on a commonly used column set up. This method uses sealed collection beakers and does not require solutions to pass through pump tubing, minimizing contamination. The duration is reduced by eight‐fold, processing 12 samples in just 1.5 hr. It also yields low and consistent total procedural blanks, averaging 11 pg. The efficiency and efficacy of this method were tested by repeated boron purification from calcium carbonate and high‐sodium matrices with international and in‐house reference materials. The results matched those obtained using the gravity column method and fell within our laboratory long‐term and international certified values. The mean δ11B and 2SD (standard deviation) of repeatedly processed NIST 8301f were 14.57 ± 0.26‰ (n = 31), NIST 8301c was 24.19 ± 0.33‰ (n = 10), STAiG‐F1 was 16.20 ± 0.26‰ (n = 13), and seawater was 39.52 ± 0.32‰ (n = 10). All the components of our techniques are commercially available, and it is easily adaptable to other laboratories and isotope systems.

Abstract New, open access tools have been developed to validate ionospheric models in terms of technologically relevant metrics. These are ionospheric errors on GPS 3D position, HF ham radio communications, and peak F‐region density. To demonstrate these tools, we have used output from Sami is Another Model of the Ionosphere (SAMI3) driven by high‐latitude electric potentials derived from Active Magnetosphere and Planetary Electrodynamics Response Experiment, covering the first available month of operation using Iridium‐NEXT data (March 2019). Output of this model is now available for visualization and download via https://sami3.jhuapl.edu. The GPS test indicates SAMI3 reduces ionospheric errors on 3D position solutions from 1.9 m with no model to 1.6 m on average (maximum error: 14.2 m without correction, 13.9 m with correction). SAMI3 predicts 55.5% of reported amateur radio links between 2–30 MHz and 500–2,000 km. Autoscaled and then machine learning “cleaned” Digisonde NmF2 data indicate a 1.0 × 1011 el. m3 median positive bias in SAMI3 (equivalent to a 27% overestimation). The positive NmF2 bias is largest during the daytime, which may explain the relatively good performance in predicting HF links then. The underlying data sources and software used here are publicly available, so that interested groups may apply these tests to other models and time intervals.

Abstract Introduction Targeted lung cancer screening is effective in reducing lung cancer and all‐cause mortality according to major trials in the United Kingdom and Europe. However, the best ways of implementing screening in local communities requires an understanding of the population the programme will serve. We undertook a study to explore the views of those potentially eligible for, and to identify potential barriers and facilitators to taking part in, lung screening, to inform the development of a feasibility study. Methods Men and women aged 45–70, living in urban and rural Scotland, and either self‐reported people who smoke or who recently quit, were invited to take part in the study via research agency Taylor McKenzie. Eleven men and 14 women took part in three virtual focus groups exploring their views on lung screening. Focus group transcripts were transcribed and analysed using thematic analysis, assisted by QSR NVivo. Findings Three overarching themes were identified: (1) Knowledge, awareness and acceptability of lung screening, (2) Barriers and facilitators to screening and (3) Promoting screening and implementation ideas. Participants were largely supportive of lung screening in principle and described the importance of the early detection of cancer. Emotional and psychological concerns as well as system‐level and practical issues were discussed as posing barriers and facilitators to lung screening. Conclusions Understanding the views of people potentially eligible for a lung health check can usefully inform the development of a further study to test the feasibility and acceptability of lung screening in Scotland. Patient or Public Contribution The LUNGSCOT study has convened a patient advisory group to advise on all aspects of study development and implementation. Patient representatives commented on the focus group study design, study materials and ethics application, and two representatives read the focus group transcripts.

Abstract Background Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland. Methods We used Arksey and O’Malley’s scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases. Results Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening, Enthusiasm for lung screening, Barriers to lung screening, and Facilitators or ways of promoting uptake of lung screening. Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation. Conclusions Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

Abstract Data accurately representing the population distribution at the subnational level within countries is critical to policy and decision makers for many applications. Call data records (CDRs) have shown great promise for this, providing much higher temporal and spatial resolutions compared to traditional data sources. For CDRs to be integrated with other data and in order to effectively inform and support policy and decision making, mobile phone user must be distributed from the cell tower level into administrative units. This can be done in different ways and it is often not considered which method produces the best representation of the underlying population distribution. Using anonymised CDRs in Namibia between 2011 and 2013, four distribution methods were assessed at multiple administrative unit levels. Estimates of user density per administrative unit were ranked for each method and compared against the corresponding census-derived population densities, using Kendall’s tau-b rank tests. Seasonal and trend decomposition using Loess (STL) and multivariate clustering was subsequently used to identify patterns of seasonal user variation and investigate how different distribution methods can impact these. Results show that the accuracy of the results of each distribution method is influenced by the considered administrative unit level. While marginal differences between methods are displayed at “coarser” level 1, the use of mobile phone tower ranges provided the most accurate results for Namibia at finer levels 2 and 3. The use of STL is helpful to recognise the impact of the underlying distribution methods on further analysis, with the degree of consensus between methods decreasing as spatial scale increases. Multivariate clustering delivers valuable insights into which units share a similar seasonal user behaviour. The higher the number of prescribed clusters, the more the results obtained using different distribution methods differ. However, two major seasonal patterns were identified across all distribution methods, levels and most cluster numbers: (a) units with a 15% user decrease in August and (b) units with a 20–30% user increase in December. Both patterns are likely to be partially linked to school holidays and people going on vacation and/or visiting relatives and friends. This study highlights the need and importance of investigating CDRs in detail before conducting subsequent analysis like seasonal and trend decomposition. In particular, CDRs need to be investigated both in terms of their area and population coverage, as well as in relation to the appropriate distribution method to use based on the spatial scale of the specific application. The use of inappropriate methods can change observed seasonal patterns and impact the derived conclusions.

Abstract Technological advancements are dramatically changing the landscape of therapeutic development. The convergence of advances in computing power, analytical methods, artificial intelligence, novel digital health tools, and cloud‐based platforms has the potential to power an exponential acceleration of evidence generation. For regulatory agencies responsible for evidence evaluation and oversight of medical products, these advances present both promises and challenges. Ultimately, realizing the translation and impact of these innovations that could potentially enhance therapeutic development and improve the health of individuals and the public will require a nimble and responsive regulatory approach. Supporting an adaptive policy‐making infrastructure that is poised to address novel regulatory considerations, creating a workforce to ensure relevant expertise, and fostering more diverse collaborations with a broader group of stakeholders are steps toward the goal of modernizing the regulatory ecosystem. This article outlines approaches that can help provide the flexibility and tools needed to foster innovation, while ensuring the safety and effectiveness of medical products.

Abstract Background Symptom burden remains a critical concern for individuals with non-small cell lung cancer (NSCLC) following the completion of treatment. The most common symptom clusters, dyspnea (shortness of breath) and fatigue, can contribute to physical decline, reductions in quality of life, and a higher risk of comorbidities and mortality. Dyspnea is a primary limiter of exercise capacity in individuals with lung cancer, resulting in exercise avoidance and an accelerated physical decline. As such, designing resistance training with cluster sets to mitigate symptoms of dyspnea and fatigue may result in improved exercise tolerance. Thus, maintaining the exercise stimulus via cluster sets, combined with improved tolerance of the exercise, could result in the maintenance of physical function and quality of life. The purpose of this study is to investigate the feasibility and preliminary efficacy of a hybrid-delivery home-based cluster-set resistance training program in individuals with NSCLC. Methods Individuals with NSCLC (n = 15), within 12 months of completion of treatment, will be recruited to participate in this single-arm feasibility trial. Participants will complete 8 weeks of home-based resistance training designed to minimize dyspnea and fatigue. The hybrid delivery of the program will include supervised sessions in the participants’ home and virtual supervision via video conferencing. The primary outcome of feasibility will be quantified by recruitment rates, retention, acceptability, and intervention fidelity. Exploratory outcomes (dyspnea, fatigue, quality of life, physical function, and body composition) will be assessed pre- and post-intervention. Discussion This study will provide important data on the feasibility of delivering this intervention and inform procedures for a future randomized controlled trial. Trial registration Record not yet public

Aim: T-helper cells could play an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), a common B-cell neoplasm. Although CLL cells can present soluble antigens targeted from the B-cell receptor to T-helper cells via major histocompatibility complex (MHC) class II, antigens recognized by some CLL cells may be encountered in a particulate form. Here the ability of CLL cells to internalize and present anti-immunoglobulin M (IgM) beads as a model for the interaction of CLL cells with particulate antigens was investigated. Methods: The effect of anti-IgM beads on antigen presentation pathways was analyzed using RNA-seq and internalization of anti-IgM beads by primary CLL cells was investigated using confocal microscopy and flow cytometry. Antigen presentation was investigated by analyzing activation of a T-cell line expressing a T-cell receptor specific for a peptide derived from mouse κ light chains after incubating CLL cells with a mouse κ light chain-containing anti-IgM monoclonal antibody. Kinase inhibitors were used to characterize the pathways mediating internalization and antigen presentation. Results: Stimulation of surface IgM of CLL cells increased expression of the antigen presentation machinery and CLL cells were able to phagocytose anti-IgM beads. Internalization of anti-IgM beads was associated with MHC class II-restricted activation of cognate T-helper cells. Antigen presentation by CLL cells was dependent on activity of spleen tyrosine kinase (SYK) and phosphatidylinositol 3-kinase delta (PI3Kδ) but was unaffected by inhibitors of Bruton’s tyrosine kinase (BTK). Conclusions: CLL cells can internalize and present antigen from anti-IgM beads. This capacity of CLL cells may be particularly important for recruitment of T-cell help in vivo in response to particulate antigens.

Performing endovascular medical interventions safely and efficiently requires a diverse set of skills that need to be practised in dedicated training sessions. Here, we used multimodal magnetic resonance (MR) imaging to determine the structural and functional plasticity and core skills associated with skill acquisition. A training group learned to perform a simulator-based endovascular procedure, while a control group performed a simplified version of the task; multimodal MR images were acquired before and after training. Using a well-controlled interaction design, we found strong multimodal evidence for the role of the intraparietal sulcus (IPS) in endovascular skill acquisition that is in line with previous work implicating the structure in visuospatial transformations including simple visuo-motor and mental rotation tasks. Our results provide a unique window into the multimodal nature of rapid structural and functional plasticity of the human brain while learning a multifaceted and complex clinical skill. Further, our results provide a detailed description of the plasticity process associated with endovascular skill acquisition and highlight specific facets of skills that could enhance current medical pedagogy and be useful to explicitly target during clinical resident training.

Abstract Due to the increasing complexity of diseases in the aging population and rapid progress in catheter-based technology, the demands on operators’ skills in conducting endovascular interventions (EI) has increased dramatically, putting more emphasis on training. However, it is not well understood which factors influence learning and performance. In the present study, we examined the ability of EI naïve medical students to acquire basic catheter skills and the role of pre-existing cognitive ability and manual dexterity in predicting performance. Nineteen medical students practised an internal carotid artery angiography during a three-day training on an endovascular simulator. Prior to the training they completed a battery of tests. Skill acquisition was assessed using quantitative and clinical performance measures; the outcome measures from the test battery were used to predict the learning rate. The quantitative metrics indicated that participants’ performance improved significantly across the training, but the clinical evaluation revealed that participants did not significantly improve on the more complex part of the procedure. Mental rotation ability (MRA) predicted quantitative, but not clinical performance. We suggest that MRA tests in combination with simulator sessions could be used to assess the trainee’s early competence level and tailor the training to individual needs.

Advances in translational science require innovative solutions, and engagement of productive transdisciplinary teams play a critical role. While various forms of scientific meetings have long provided venues for sharing scientific findings and generating new collaborations, many conferences lack opportunities for active discussions. We describe the use of an Un-Meeting to foster innovative translational science teams through engaged discussions across multidisciplinary groups addressing a shared theme. The Un-Meeting was delivered by the University of Rochester Center for Leading Innovation and Collaboration, the national coordinating center for the National Institutes of Health Clinical and Translational Science Awards (CTSA) program. This pilot CTSA program Un-Meeting focused on engaging translational scientists, policy-makers, community members, advocates, and public health professionals to address the opioid crisis. The participant-driven format leveraged lightning talks, attendee-led idea generation, and extensive breakout discussions to foster multidisciplinary networking. Results indicated participation by a broad set of attendees and a high level of networking during the meeting. These results, coupled with the growth of the Un-Meeting across the CTSA Consortium, provide practices and models to potentially advance team and translational science. While future work will further assess the impact of Un-Meetings, this format presents a promising approach to enhance translational science.

The cerebellum's involvement in cognitive, affective and motor functions is mediated by connections to different regions of the cerebral cortex. A distinctive feature of cortico-cerebellar loops that has been demonstrated in the animal work is a topographic organization that is preserved across its corticopontine, pontocerebellar, and cerebello-thalmo-cortical segments. Here we used tractography derived from diffusion imaging data to characterize the connections between the pons and the individual lobules of the cerebellum and generate a parcellation of the pons and middle cerebellar peduncle based on the pattern of connectivity. We identified a rostral to caudal gradient in the pons, similar to that observed in the animal work, such that rostral regions were preferentially connected to cerebellar lobules involved in non-motor, and caudal regions with motor regions. These findings advance our fundamental understanding of the cerebellum, and the parcellations we generated provide context for future research into the pontocerebellar tract's involvement in health and disease.

The ∼74 ka Toba eruption was one of the largest volcanic events of the Quaternary. There is much interest in determining the impact of such a large event, particularly on the climate and hominid populations at the time. Although the Toba eruption has been identified in both land and marine archives as the Youngest Toba Tuff, its precise place in the ice core record is ambiguous. Several volcanic sulfate signals have been identified in both Antarctic and Greenland ice cores and span the Toba eruption 40Ar/39Ar age uncertainty. Here, we measure sulfur isotope compositions in Antarctic ice samples from the Dome C (EDC) and Dronning Maud Land (EDML) ice cores at high temporal resolution across 11 of these potential Toba sulfate peaks to identify candidates with sulfur mass-independent fractionation (S-MIF), indicative of an eruption whose plume reached altitudes at or above the stratospheric ozone layer. Using this method, we identify several candidate sulfate peaks that contain stratospheric sulfur. We further narrow down potential candidates based on the isotope signatures by identifying sulfate peaks that are due to a volcanic event at tropical latitudes. In one of these sulfate peaks at 73.67 ka, we find the largest ever reported magnitude of S-MIF in volcanic sulfate in polar ice, with a Δ33S value of −4.75 ‰. As there is a positive correlation between the magnitude of the S-MIF signal recorded in ice cores and eruptive plume height, this could be a likely candidate for the Toba super-eruption, with a plume top height in excess of 45 km. These results support the 73.7±0.3 ka (1σ) 40Ar/39Ar age estimate for the eruption, with ice core ages of our candidates with the largest magnitude S-MIF at 73.67 and 73.74 ka. Finally, since these candidate eruptions occurred on the transition into Greenland Stadial 20, the relative timing suggests that Toba was not the trigger for the large Northern Hemisphere cooling at this time although we cannot rule out an amplifying effect.

Background Colorectal cancer (CRC) is the second most diagnosed cancer in men and women and second most common cause of cancer death in Australia; Australia’s CRC incidence and mortality are among the world’s highest. The Australian National Bowel Cancer Screening Program began in 2006; however, only 33% of those approached for the first time by the Program between 2018 and 2019 returned the kit. Of the 5.7 million kits sent during this period, only 44% were returned. Our aim was to identify practices and features of national bowel cancer screening programs in countries with similar programs but higher screening participation, to identify potential interventions for optimising Australian CRC screening participation. Methods We searched published and grey literature for CRC screening programs reporting at least 50% screening participation using postal invitation and free return of iFOBT home kits. Interviews were conducted with cancer registry staff and academic researchers, focused on participant and practitioner engagement in screening. Results National programs in Netherlands, Scotland, Denmark, and Finland reported over 50% screening participation rates for all invitation rounds. Shared characteristics include small populations within small geographic areas relative to Australia; relatively high literacy; a one-sample iFOBT kit; national registration systems for population cancer screening research; and screening program research including randomised trials of program features. Conclusions Apart from the one-sample kit, we identified no single solution to persistent Australian low uptake of screening. Research including randomised trials within the program promises to increase participation. Impact This screening program comparison suggests that within-program intervention trials will lead to increased Australian screening participation.

Abstract Electrical stimulation of the cervical spinal cord is gaining traction as a therapy following spinal cord injury; however, it is difficult to target the cervical motor region in a rodent using a non-penetrating stimulus compared with direct placement of intraspinal wire electrodes. Penetrating wire electrodes have been explored in rodent and pig models and, while they have proven beneficial in the injured spinal cord, the negative aspects of spinal parenchymal penetration (e.g., gliosis, neural tissue damage, and obdurate inflammation) are of concern when considering therapeutic potential. We therefore designed a novel approach for epidural stimulation of the rat spinal cord using a wireless stimulation system and ventral electrode array. Our approach allowed for preservation of mobility following surgery and was suitable for long term stimulation strategies in awake, freely functioning animals. Further, electrophysiology mapping of the ventral spinal cord revealed the ventral approach was suitable to target muscle groups of the rat forelimb and, at a single electrode lead position, different stimulation protocols could be applied to achieve unique activation patterns of the muscles of the forelimb.

Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.

The proliferation of digital technologies and the application of sophisticated data analysis techniques are increasingly viewed as having the potential to transform translational research and precision medicine. While digital technologies are rapidly applied in innovative ways to develop new diagnostics and therapies, the ultimate approval and adoption of these emerging methods presents several scientific and regulatory challenges. To better understand and address these regulatory science gaps, a working group of the Clinical and Translational Science Awards Program convened the Regulatory Science to Advance Precision Medicine Forum focused on digital health, particularly examining gaps in the use, validation, and interpretation of data from sensors that collect and tools that analyze digital biomarkers. The key findings and recommendations provided here emerged from the Forum and include the need to enhance areas related to data standards, data quality and validity, knowledge management, and building trust between all stakeholders.

The striatum is a major subcortical connection hub that has been heavily implicated in a wide array of motor and cognitive functions. Here, we developed a normative multimodal, data-driven microstructural parcellation of the striatum using non-negative matrix factorization (NMF) based on multiple magnetic resonance imaging-based metrics (mean diffusivity, fractional anisotropy, and the ratio between T1- and T2-weighted structural scans) from the Human Connectome Project Young Adult dataset (n = 329 unrelated participants, age range: 22–35, F/M: 185/144). We further explored the biological and functional relationships of this parcellation by relating our findings to motor and cognitive performance in tasks known to involve the striatum as well as demographics. We identified 5 spatially distinct striatal components for each hemisphere. We also show the gain in component stability when using multimodal versus unimodal metrics. Our findings suggest distinct microstructural patterns in the human striatum that are largely symmetric and that relate mostly to age and sex. Our work also highlights the putative functional relevance of these striatal components to different designations based on a Neurosynth meta-analysis.

Little is known about the experiences of those hospitalized during the COVID-19 pandemic in Canada. Our aims were to (a) report on the experiences, (b) compare with historical results, and (c) assess for potential monthly differences of patients hospitalized in the early months of the COVID-19 across Alberta. A random sample of adults was surveyed within 6 weeks of discharge from 93 hospitals, using a modified version of the Canadian Patient Experiences Survey – Inpatient Care (CPES-IC). Discharges from April to September 2020 comprised the “during COVID-19 pandemic” cohort, while April to September 2019 formed the historical one. Results were reported as percent in “top box”, indicative of the most positive answer choice. Odds of reporting a “top box” response were calculated while controlling for demographic and clinical features. In total, 23,412 surveys (11,344 during COVID-19, 12,068 historical) were obtained. Those hospitalized during COVID-19 had higher odds of “top box” ratings on 17 of 39 questions examined, and lower odds on 2 questions (information about the admission process, inclusion of family/friends in care decisions). The remaining 20 questions showed no difference between the 2 cohorts. Our results indicate that respondents hospitalized during the early months of the pandemic had experiences that were largely better or comparable to pre-pandemic. This speaks to the dedication and resilience of staff who provided care during challenging circumstances. Our findings may assist in mitigating fears among those who are hesitant to seek medical care during future pandemics or public health emergencies, including subsequent waves of COVID-19.

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private partnerships have developed to identify new modes of controlling leishmaniasis. Most of these collaborative efforts have relied upon the small molecule synthetic compound libraries held by industry, but the number of New Chemical Entities (NCE) identified and entering development as antileishmanials has been very low. In light of this, here we describe a public-private effort to identify natural products with activity against Leishmania mexicana, a causative agent of cutaneous leishmanaisis (CL). Utilising Hypha Discovery's fungal extract library which is rich in small molecule (

Abstract: Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell–like CLL (n-CLL), memory B-cell–like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.

Background:. Surviving critical illness often creates a lasting psychological impact, including depression, anxiety, and post-traumatic stress. Memories of frightening and delusional experiences are the largest potentially modifiable risk factor, but currently, there is no proven intervention to improve these inciting factors. Psychological support based on positive suggestion is a psychotherapeutic approach that can be provided even to patients in altered cognitive states and is therefore a viable psychotherapy intervention throughout the ICU stay. Traditional ICU care team members have limited time and training to provide such psychological support to patients. Doulas are trained supportive companions who have been effectively used to provide patient advocacy and emotional support in other clinical settings and may address this need. Our aim was to train and implement a psychological support based on positive suggestion program for the critically ill using doulas, and measure acceptance of this intervention through stakeholder feedback. Methods:. Doula training included three objectives: an introduction to ICU practice structure and policies; education about fundamental aspects of critical care conditions and procedures; and didactic and hands-on learning experiences in effective use of psychological support based on positive suggestion in the critically ill. Doulas were evaluated at the end of their training and during subsequent clinical activities using competency-based assessments as well as through survey-based questions and interviews with key stakeholders. Results:. The ICU doulas performed psychological support based on positive suggestion on 43 critically ill patients in the ICU setting. Stakeholder feedback from nurses, patients, and patient families was positive. The majority (28/32) of surveyed bedside ICU nurses reported that the doulas’ involvement was helpful for both patients and nurses alike. All interviewed family members offered positive comments about the ICU doula presence and of the 40 patients who recalled the intervention 37 found it comforting. Conclusions:. Our program successfully trained two doulas to work effectively in the ICU setting performing patient-centered psychological support based on positive suggestion interventions. Their training improved their skill sets and was reported as beneficial by patients, families, and critical care nursing. This training program offers a proof of concept that could be applied in other medical centers, bringing doulas more commonly into the ICU practice to help humanize the experience for patients, families, and medical teams.

This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2–24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20–24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2–24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2–12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.

It is well established that sex differences exist in the manifestation of vascular diseases. Arterial stiffness (AS) has been associated with changes in cerebrovascular reactivity (CVR) and cognitive decline in aging. Specifically, older adults with increased AS show a decline on executive function (EF) tasks. Interestingly, the relationship between AS and CVR is more complex, where some studies show decreased CVR with increased AS, and others demonstrate preserved CVR despite higher AS. Here, we investigated the possible role of sex on these hemodynamic relationships. Acquisitions were completed in 48 older adults. Pseudo-continuous arterial spin labeling (pCASL) data were collected during a hypercapnia challenge. Aortic pulse wave velocity (PWV) data was acquired using cine phase contrast velocity series. Cognitive function was assessed with a comprehensive neuropsychological battery, and a composite score for EF was calculated using four cognitive tests from the neuropsychological battery. A moderation model test revealed that sex moderated the relationship between PWV and CVR and PWV and EF, but not between CVR and EF. Together, our results indicate that the relationships between central stiffness, cerebral hemodynamics and cognition are in part mediated by sex.

Objectives The Social Appearance Anxiety Scale (SAAS) is a 16-item questionnaire developed to evaluate fear of appearance-based evaluation by others. The primary objective of this research was to investigate the existence of differential item functioning (DIF) for the 16 SAAS items, comparing patients who completed the SAAS in English and French, either to confirm that scores are comparable or provide guidance on calculating comparable scores. A secondary research objective was to investigate the existence of DIF based on sex and disease status. A tertiary research objective was to assess DIF related to language, sex, and disease status on the recently developed SAAS-5.Design This was a cross-sectional analysis using baseline data from patients enrolled in the Scleroderma Patient-centred Intervention Network (SPIN).Setting SPIN patients included in the present study were enrolled at 43 centres in Canada, USA, UK, France and Australia, with questionnaires completed in April 2014 to July 2019.Participants 1640 SPIN patients completed the SAAS in French (n=600) or English (n=1040).Primary and secondary measures The SAAS was collected along with demographic and disease characteristics.Results Six items were identified with statistically significant language-based DIF, four with sex-based DIF and one with disease type-based DIF. However, factor scores before and after accounting for DIF were similar (Pearson correlation >0.99), and individual score differences were small. This was true for both the full and shortened versions of the SAAS.Conclusion SAAS and SAAS-5 scores are comparable across language, sex, and disease-type, despite small differences in how patients respond to some items.

Abstract Microneedles (MNs) offer a rapid method of transdermal drug delivery through penetration of the stratum corneum. However, commercial translation has been limited by fabrication techniques unique to each drug. Herein, a broadly applicable platform is explored by drug‐loading via swelling effect of a hydrogel MN patch. A range of small molecule hydrophilic, hydrophobic, and biomacromolecule therapeutics demonstrate successful loading and burst release from hydrogel MNs fabricated from methacrylated hyaluronic acid (MeHA). The post‐fabrication drug loading process allows MeHA MN patches with drug loadings of 10 μg cm−2. Additional post‐fabrication processes are explored with dendrimer bioadhesives that increase work of adhesion, ensuring stable fixation on skin, and allow for additional drug loading strategies.

The mechanism of (CAG)n repeat generation, and related expandable repeat diseases in non-dividing cells, is currently understood in terms of a DNA template-based DNA repair synthesis process involving hairpin stabilized slippage, local error-prone repair via MutSβ (MSH2–MSH3) hairpin protective stabilization, then nascent strand extension by DNA polymerases-β and -δ. We advance a very similar slipped hairpin-stabilized model involving MSH2–MSH3 with two key differences: the copying template may also be the nascent pre-mRNA with the repair pathway being mediated by the Y-family error-prone enzymes DNA polymerase-η and DNA polymerase-κ acting as reverse transcriptases. We argue that both DNA-based and RNA-based mechanisms could well be activated in affected non-dividing brain cells in vivo. Here, we compare the advantages of the RNA/RT-based model proposed by us as an adjunct to previously proposed models. In brief, our model depends upon dysregulated innate and adaptive immunity cascades involving AID/APOBEC and ADAR deaminases that are known to be involved in normal locus-specific immunoglobulin somatic hypermutation, cancer progression and somatic mutations at many off-target non-immunoglobulin sites across the genome: we explain how these processes could also play an active role in repeat expansion diseases at RNA polymerase II-transcribed genes.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses.

Neuronal polarity established in developing neurons ensures proper function in the mature nervous system. As functionally distinct cellular compartments, axons and dendrites often require different subsets of proteins to maintain synaptic transmission and overall order. Although neurons in the mature CNS do not regenerate throughout life, their interactions with their extracellular environment are dynamic. The axon remains an overall protected area of the neuron where only certain proteins have access throughout the lifespan of the cell. This is in comparison to the somatodendritic compartment, where although it too has a specialised subset of proteins required for its maintenance, many proteins destined for the axonal compartment must first be trafficked through the former. Recent research has shown that axonal proteins contain specific axon-targeting motifs that permit access to the axonal compartment as well as downstream targeting to the axonal membrane. These motifs target proteins to the axonal compartment by a variety of mechanisms including: promoting segregation into axon-targeted secretory vesicles, increasing interaction with axonal kinesins and enhancing somatodendritic endocytosis. In this review, we will discuss axon-targeting motifs within the context of established neuron trafficking mechanisms. We will also include examples of how these motifs have been applied to target proteins to the axonal compartment to improve both tools for the study of axon biology, and for use as potential therapeutics for axonopathies.

Rapidly advancing technology often pulls the regulatory field along as it evolves to incorporate new concepts, better tools, and more finely honed equipment. When the area impacted by the technological advancement is regulated by the Food and Drug Administration (FDA), a gap develops between the technology and the guidelines that govern its application. Subsequently, there are challenges in determining appropriate regulatory pathways for evolving products at the initial research and developmental stages. Myriad factors necessitate several rounds of iterative review and the involvement of multiple divisions within the FDA. To better understand the regulatory science issues roiling around the area of additive manufacturing of medical products, a group of experts, led by a Clinical and Translational Science Award working group, convened the Regulatory Science to Advance Precision Medicine at the Fall Forum to discuss some of the current regulatory science roadblocks.

Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.