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Abstract Background Chronic pain, regardless of its type, is a significant risk factor for suicide. However, not all individuals with chronic pain also experience suicidal thoughts and behaviors. Better characterization of clinical risk profiles and comorbidities across the medical spectrum among people with chronic pain who die by suicide is urgently needed to aid treatment and prevention strategies. Methods This case–control study leverages population-based data from the Utah Suicide Mortality Risk Study. Specifically, we identify clinical phenotypes from diagnostic data that differentiate between individuals that died by suicide with chronic pain diagnoses (N = 1,410) and living control individuals who also had chronic pain diagnoses (N = 4,664). Medical diagnostic codes were aggregated via phecodes to perform a phenotype-based phenome-wide association study. Using multivariable logistic regression analysis adjusting for covariates and multiple testing, differences in 1,727 common clinical phenotypes (phecodes) were assessed between suicide deaths and controls with chronic pain diagnoses. Models were also stratified by sex. Results Chronic pain diagnoses were nearly three times more prevalent in individuals who died by suicide compared with those who did not. Sixty-five phecodes were significantly overrepresented among suicide deaths with chronic pain diagnoses compared with controls with chronic pain diagnoses. Utah suicide deaths with chronic pain had significantly more psychiatric diagnoses (mood disorders, anxiety disorders, attention deficit hyperactivity disorder, posttraumatic stress disorder, personality disorders, schizophrenia/psychosis, substance use related traits and prior overdoses, and diagnoses related to previous suicidal thoughts and behaviors) in addition to insomnia and specific pain related diagnoses compared to Utah controls with chronic pain (odds ratios ranged from 1.40–7.10). Twenty-five phecodes were overrepresented in controls with chronic pain compared to suicides. These were related to preventative care, cancer, obesity and other conditions (odds ratios ranged from 0.16–0.73). Sex-specific analyses largely replicated the combined analyses, yet the strength of the association was stronger for women with phecodes related to prior self-harm. Conclusions Results identified multiple clinical comorbidities with chronic pain that differentiate suicide deaths from living control individuals with a history of diagnosed chronic pain. Our findings may help discern individuals with chronic pain who may be at greater risk for suicide death.

Abstract Background Reliability of echocardiographic calculations for stroke volume and mitral regurgitant fraction (RFMR) are affected by observer variability and lack of a gold standard. Variability is used to calculate critical change values (CCVs) that are thresholds representing real change in a measure not associated with observer variability. Hypothesis Observed intra‐ and interobserver accuracy and variability in healthy dogs help model CCV for RFMR. Animals Reliability cohort of 34 healthy dogs; allometric scaling cohort of 99 dogs with heart disease and 25 healthy dogs. Methods Accuracy, variability, and CCV of 2 observers using geometric and flow‐based echocardiography were prospectively compared against a standard of RFMR = 0% and extrapolated across a range of expected RFMR values in the reliability cohort partly derived from cardiac dimensions predicted by the allometric cohort. Results Accuracy of methods to determine RFMR in descending order was 4‐chamber bullet (Bullet4CH), mitral inflow, cube formula, and Simpson's method of disks. Intraobserver variability was relatively high. The CCV for RFMR ranged from 28% to 88% and was inversely related to RFMR when extrapolated for use in affected dogs. For both observers, the Bullet4CH method had the lowest intraobserver CCV (Operator 1:28%, Operator 2:41%). Interobserver strength of agreement was low with intraclass correlation coefficients ranging from 0.210 to 0.413. Conclusions and Clinical Importance Echocardiographic volumetric methods used to calculate stroke volume and RFMR have low accuracy and high variability in healthy dogs. Extrapolation of observed CCV to a range of expected RFMR suggests observers and methods are not interchangeable and variability might hinder routine clinical usage. Individual observers should be aware of their own variability and CCV.

Abstract Background Persons (henceforth, women) who have hypertensive disorders of pregnancy (HDP) are at risk of premature cardiovascular disease (CVD). While largely preventable through lifestyle management, many women and clinicians are unaware of the risk. Based on prior research, we developed a question prompt tool (QPT) on preventing and managing CVD after HDP. The purpose of this study was to refine QPT design. Methods We recruited Canadian women who had HDP and clinicians who might care for them using multiple strategies, conducted telephone interviews with consenting participants, and used qualitative description and inductive content analysis to derive themes. Results We interviewed 21 women who varied in HDP type, CVD status, years since HDP pregnancy, age, geography and ethno-cultural group; and 21 clinicians who varied in specialty (midwife, nurse practitioner, family physician, internist, obstetrician, cardiologist), geography and years in practice. Participating women and clinicians agreed on needed improvements: more instructions, lay and gender-neutral language, links to additional information, more space for answers, graphic appeal, and both print and electronic format. Both groups identified similar barriers: clinicians lack time/willingness, and low language/health literacy and access to technology among women; enablers: translated, credible source/endorser, culturally relevant, organized by health trajectory stages; and likely benefits: raise awareness, empower women, encourage them to adopt healthy lifestyle. Women desired exposure to the QPT before or during pregnancy, while clinicians recommended waiting until postpartum to avoid overwhelming women. Similarly, most women said the QPT should be available through multiple avenues to empower them for health self-advocacy, while clinicians thought they should introduce the QPT to women, and decide when and which questions to address. To mitigate reluctance, clinicians recommended self-directed educational materials accompany the QPT. Conclusions We will use this information to refine QPT design and plan for future evaluation. If found to be effective and widely disseminated, the QPT could improve awareness and communication about this issue, and may reduce CVD risk in many women who have hypertensive pregnancies. Ongoing research is needed to more fully understand how QPTs support patient-clinician communication, and how to alert and prime both patients and clinicians to use QPTs.

Abstract Background Reciprocal exchanges of metabolites between phytoplankton and bacteria influence the fitness of these microorganisms which ultimately shapes the productivity of marine ecosystems. Recent evidence suggests that plant growth-promoting hormones may be key metabolites within mutualistic phytoplankton-bacteria partnerships, but very little is known about the diversity of plant growth-promoting hormones produced by marine bacteria and their specific effects on phytoplankton growth. Here, we aimed to investigate the capacity of marine bacteria to produce 7 plant growth-promoting hormones and the effects of these hormones on Actinocyclus sp. growth. Results We examined the plant growth-promoting hormone synthesis capabilities of 14 bacterial strains that enhance the growth of the common diatom Actinocyclus. Plant growth-promoting hormone biosynthesis was ubiquitous among the bacteria tested. Indeed all 14 strains displayed the genomic potential to synthesise multiple hormones, and mass-spectrometry confirmed that each strain produced at least 6 out of the 7 tested plant growth-promoting hormones. Some of the plant growth-promoting hormones identified here, such as brassinolide and trans-zeatin, have never been reported in marine microorganisms. Importantly, all strains produced the hormone indole-3 acetic acid (IAA) in high concentrations and released it into their surroundings. Furthermore, indole-3 acetic acid extracellular concentrations were positively correlated with the ability of each strain to promote Actinocyclus growth. When inoculated with axenic Actinocyclus cultures, only indole-3 acetic acid and gibberellic acid enhanced the growth of the diatom, with cultures exposed to indole-3 acetic acid exhibiting a two-fold increase in cell numbers. Conclusion Our results reveal that marine bacteria produce a much broader range of plant growth-promoting hormones than previously suspected and that some of these compounds enhance the growth of a marine diatom. These findings suggest plant growth-promoting hormones play a large role in microbial communication and broaden our knowledge of their fuctions in the marine environment. Video Abstract

China is the single largest state-based international actor that is a major threat to the continued hegemony of the United States’ unipolar order. As such, a campaign of obstructive foreign policy is being waged against China through the obstructive marketing of China as a sinister threat and unreliable actor against the ‘rules-based order.’ By attempting to undermine China’s soft power potential, it is hoped that China’s global rise can be constrained and contained. Drawing on an integrative type of literature review, this article examines attempts at ‘knowledge production’ through geopolitically subjective interpretations and representations by the U.S. and its allies of the modern type of geopolitically-influenced international conflicts - hybrid warfare. In the English language imagination, hybrid warfare is a politically charged and loaded term that assumes ill intent by the user upon the intended victim. According to the research estimates by foreign experts, the current foreign policy of international activities by China displays a hybrid character. The country is publicly accused of carrying out operations in the economic, cybernetic, geographical, geopolitical, psychological, information and ideological spaces. Currently, the notion of “Chinese hybrid warfare” is starting to become an increasingly popular mass communicated trope. However, the aggravation of Sino-American relations against the backdrop of the South China Sea, the Taiwan issue and the Russian special military operation gives us an opportunity to predict that China will increasingly be projected as an increasingly dangerous source of hybrid threat in the Western-centric discourse to contain its global rise and by default to try to preserve US global hegemony through a negative information campaign.

Abstract Background Transaminase and creatinine elevations have been well described in adults treated with remdesivir for COVID-19. It is hypothesized that a similar safety profile exists in children with COVID-19 treated with remdesivir, but available data are limited, especially in children

Abstract Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identify an inflammation and therapy-enriched tumor state we term basal-to-inflammatory transition. Basal-to-inflammatory transition signature correlates with poor overall patient survival in many epithelial tumors. Basal-to-squamous cell carcinoma transition and basal-to-inflammatory transition occur in adjacent but distinct regions of a single tumor: basal-to-squamous cell carcinoma transition arises within the core tumor nodule, while basal-to-inflammatory transition emerges from a specialized inflammatory environment defined by a tumor-associated TREM1 myeloid signature. TREM1 myeloid-derived cytokines IL1 and OSM induce basal-to-inflammatory transition in vitro and in vivo through NF-κB, lowering sensitivity of patient basal cell carcinoma explant tumors to Smoothened inhibitor treatment. This work deepens our knowledge of the heterogeneous local tumor microenvironment and nominates basal-to-inflammatory transition as a drug-resistant but targetable tumor state driven by a specialized inflammatory microenvironment.

Abstract Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1’s function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases.

Abstract Transformer-based large language models (LLMs) are very suited for biological sequence data, because of analogies to natural language. Complex relationships can be learned, because a concept of "words" can be generated through tokenization. Training the models with masked token prediction, they learn both token sequence identity and larger sequence context. We developed methodology to interrogate model learning, which is both relevant for the interpretability of the model and to evaluate its potential for specific tasks. We used DNABERT, a DNA language model trained on the human genome with overlapping k-mers as tokens. To gain insight into the model′s learning, we interrogated how the model performs predictions, extracted token embeddings, and defined a fine-tuning benchmarking task to predict the next tokens of different sizes without overlaps. This task evaluates foundation models without interrogating specific genome biology, it does not depend on tokenization strategies, vocabulary size, the dictionary, or the number of training parameters. Lastly, there is no leakage of information from token identity into the prediction task, which makes it particularly useful to evaluate the learning of sequence context. We discovered that the model with overlapping k-mers struggles to learn larger sequence context. Instead, the learned embeddings largely represent token sequence. Still, good performance is achieved for genome-biology-inspired fine-tuning tasks. Models with overlapping tokens may be used for tasks where a larger sequence context is of less relevance, but the token sequence directly represents the desired learning features. This emphasizes the need to interrogate knowledge representation in biological LLMs.

Background/Objective: Atypical femur fractures (AFFs) caused by long-term bisphosphonate use are associated with high rates of delayed healing and nonunion. Case Report: A 64-year-old woman with osteopenia on alendronate for 15 years sustained a displaced left AFF following a fall from standing height. Imaging showed an acute displaced transverse diaphyseal left femur fracture with lateral cortical thickening and beaking. She underwent an open reduction and internal fixation with insertion of a cephalomedullary nail placed in compression mode, utilizing a novel technique involving intraoperative removal of the endosteal hypertrophied cortical bone at the fracture site. Alendronate was stopped and teriparatide was initiated postoperatively. Radiographs at 3.5 months postsurgery showed evidence of normal fracture union with mature callus formation. Discussion: AFFs caused by prolonged bisphosphonate use have a high rate of delayed healing and nonunion due to abnormal bone remodeling. Use of teriparatide postoperatively has been shown to reduce healing time in small observational studies in surgically treated patients. Our case demonstrates an expedited healing time of 3.5 months using teriparatide combined with a novel surgical technique involving removal of a portion of the abnormally remodeled bone and placement of an intramedullary nail in compression mode. Conclusion: Our case demonstrates an expedited healing time of 3.5 months compared to the average reported healing time for AFF of 10.7 months, supporting the use of the combination of teriparatide and a novel surgical technique.

Abandoned mine drainage treatment ponds could have contrasting effects on the reproductive success of birds living in the vicinity. The ponds and associated vegetation may, like any other body of freshwater, provide beneficial habitats for the insects that the birds use to feed their young; or instead, the ponds may act as an ecological trap, attracting the birds to a habitat that is poor in quality and negatively impacting their productivity. We monitored nests of an aerial insectivore, the Tree Swallow (Tachycineta bicolor), to determine whether the distance between the ponds and the nests affected various reproductive parameters including clutch size, hatch rate, number of nestlings, nestling size and mass, number of fledglings, fledging rate, and fledge date. Data were collected over two breeding seasons (2022 and 2023) from a swallow population in southwestern Pennsylvania, USA. We found that the nests closest to the treatment ponds had significantly more nestlings and fledglings, earlier fledge dates, and a better fledging rate when compared to nests that were more distant from the ponds. However, all these parameters were well below previously published values, which suggests that the mine drainage ponds provide good nesting habitats relative to what is available in the region but that they do not represent high-quality habitats for this species overall.

Abstract Durable factor VIII expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus-mediated gene therapy. Trials with initially normal factor VIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable expression inadequate to restore normal hemostasis. Here we demonstrate that male mice recapitulate expression-level-dependent loss of factor VIII levels due to declines in vector copy number. We show that an enhanced function factor VIII variant (factor VIII-R336Q/R562Q), resistant to activated protein C-mediated inactivation, normalizes hemostasis at below-normal expression without evidence of prothrombotic risk in male hemophilia A mice. These data support that factor VIII-R336Q/R562Q may restore normal factor VIII function at low levels of expression to permit durability using low vector doses to minimize dose-dependent adeno-associated virus toxicities. This work informs the mechanism of factor VIII durability after gene transfer and supports that factor VIII-R336Q/R562Q may safely overcome current hemophilia A gene therapy limitations.

ABSTRACT Herpes simplex virus-1 (HSV-1) establishes a latent infection in peripheral neurons and periodically reactivates in response to a stimulus to permit transmission. In vitro models using primary neurons are invaluable to studying latent infection because they use bona fide neurons that have undergone differentiation and maturation in vivo. However, culture conditions in vitro should remain as close to those in vivo as possible. This is especially important when considering minimizing cell stress, as it is a well-known trigger of HSV reactivation. We recently developed an HSV-1 model system that requires neurons to be cultured for extended lengths of time. Therefore, we sought to refine culture conditions to optimize neuronal health and minimize secondary effects on latency and reactivation. Here, we demonstrate that culturing primary neurons under conditions closer to physiological oxygen concentrations (5% oxygen) results in cultures with features consistent with reduced stress. Furthermore, culture in these lower oxygen conditions diminishes the progression to full HSV-1 reactivation despite minimal impacts on latency establishment and earlier stages of HSV-1 reactivation. We anticipate that our findings will be useful for the broader microbiology community as they highlight the importance of considering physiological oxygen concentration in studying host-pathogen interactions.IMPORTANCEEstablishing models to investigate host-pathogen interactions requires mimicking physiological conditions as closely as possible. One consideration is the oxygen concentration used for in vitro tissue culture experiments. Standard incubators do not regulate oxygen levels, exposing cells to oxygen concentrations of approximately 18%. However, cells within the body are exposed to much lower oxygen concentrations, with physiological oxygen concentrations in the brain being 0.55%–8% oxygen. Here, we describe a model for herpes simplex virus 1 (HSV-1) latent infection using neurons cultured in 5% oxygen. We show that culturing neurons in more physiological oxygen concentrations improves neuronal health to permit long-term studies of virus-cell interactions and the impact on reactivation.

Intradiscal drug delivery is a promising strategy for treating intervertebral disk degeneration (IVDD). Local degenerative processes and intrinsically low fluid exchange are likely to influence drug retention. Understanding their connection will enable the optimization of IVDD therapeutics. Release and retention of an inactive hydrophilic fluorine-19 labeled peptide (19F-P) as model for regenerative peptides was studied in a whole IVD culture model by measuring the 19F-NMR (nuclear magnetic resonance) signal in culture media and IVD tissue extracts. In another set-up, noninvasive near-infrared imaging was used to visualize IR-780, as hydrophobic small molecular drug model, retention upon injection into healthy and degenerative caudal IVDs in a rat model of disk degeneration. Furthermore, IR-780-loaded degradable polyester amide microspheres (PEAM) were injected into healthy and needle pricked degenerative IVDs, subcutaneously, and in knee joints with and without surgically-induced osteoarthritis (OA). Most 19F-P was released from the IVD after 7 days. IR-780 signal intensity declined over a 14-week period after bolus injection, without a difference between healthy and degenerative disks. IR-780 signal declined faster in the skin and knee joints compared to the IVDs. IR-780 delivery by PEAMs enhanced disk retention beyond 16 weeks. Moreover, in degenerated IVDs the IR-780 signal was higher over time than in healthy IVDs while no difference between OA and healthy joints was noted. We conclude that the clearance of peptides and hydrophobic small molecules from the IVD is relatively fast. These results illustrate that development of controlled release formulations should take into account the target anatomical location and local (patho)biology.

Objectives Little prior research investigated how to promote physical activity (PA), which can reduce cancer risk, to immigrant women. The overall aim of the current study was to pilot test education session feasibility. The objectives were to assess participation in, satisfaction with and potential impact of the education session, knowledge needed to refine the education session prior to a future trial.Design Pre–post multiple-methods comparative cohort,Setting Canadian immigrant settlement agencies recruited intervention and control women.Participants Intervention: 60 baseline, 53 education (49 virtual group, 4 video only), 1 month (43 virtual, 4 video), 6 months (38 virtual, 4 video), 37% African black; control: 41, 32% African black.Results Among intervention women, PA knowledge increased significantly from baseline at 1 (p

Renal physiology is considered one of the most challenging medical disciplines to understand and to teach. Eight academic nephrologists have come together to produce a podcast devoted to helping learners at any level improve their understanding of this difficult topic. Using Dr Burton D. Rose’s classic textbook: Clinical Physiology of Acid-Base and Electrolyte Disorders, the podcast faculty systematically attack each chapter of the book in a didactic yet fun-flowing interactive discussion. This education model is unique and helps demystify complex topics.

Vaccines have historically played a pivotal role in controlling epidemics. Effective vaccines for viruses causing significant human disease, e.g., Ebola, Lassa fever, or Crimean Congo hemorrhagic fever virus, would be invaluable to public health strategies and counter-measure development missions. Here, we propose coverage metrics to quantify vaccine-induced CD8+ T cell-mediated immune protection, as well as metrics to characterize immuno-dominant epitopes, in light of human genetic heterogeneity and viral evolution. Proof-of-principle of our approach and methods are demonstrated for Ebola virus, SARS-CoV-2, and Burkholderia pseudomallei (vaccine) proteins.

Abstract Objectives To explore how to reach immigrant women through community agencies to raise awareness of the role of physical activity (PA) in reducing cancer risk. Study design Qualitative description. Methods We conducted semi-structured telephone interviews with immigrant women and community agency managers to discuss the ideal design of an education session on PA and cancer risk, and identified themes using content analysis. Results Participants included 22 women (6 African or Caribbean Black, 4 Chinese, 3 Filipino, 5 Indian, 4 Pakistani) and 16 agency managers from across Canada. Women were not familiar with Canada’s PA guidelines, and few were aware that PA reduces the risk of cancer. All expressed interest in education about PA and cancer. Diverse women and managers expressed similar preferences for education session design including content (e.g. PA amount/type), format (e.g. in person preferred but virtual more practical), personnel (external expert plus agency staff), cultural tailoring (e.g. translated supplemental take home information) and reinforcing (e.g. follow-up with participants) strategies. Women and managers identified few barriers to participating in education sessions, chiefly, that women lacked time due to work and family responsibilities; and noted several enablers of participation (e.g. emphasize social aspect, provide gift cards or recreation centre passes). Conclusions We generated insight on the ideal characteristics of a community-based education session that could raise awareness among immigrant women of the importance of PA in reducing cancer risk. Further research is needed to assess the feasibility and impact of PA education sessions designed based on these findings.

Abstract Background Rate control (RC; meanHRHolter ≤ 125 bpm) increases survival in dogs with atrial fibrillation (AF). The mechanisms remain unclear. Hypothesis/Objectives Investigate echocardiographic and biomarker differences between RC and non‐RC (NRC) dogs. Determine if changes post‐anti‐arrhythmic drugs (AAD) predict successful RC in subsequent Holter monitoring. Evaluate if early vs late RC affects survival. Animals Fifty‐two dogs with AF. Methods Holter‐derived mean heart rate, echocardiographic and biomarker variables from dogs receiving AAD were analyzed prospectively at each re‐evaluation and grouped into RC or NRC. The primary endpoint was successful RC. Between group comparisons of absolute values, magnitude of change from admission to re‐evaluations and end of study were performed using Mann‐Whitney tests or unpaired t‐tests. Logistic regression explored variables associated with inability to achieve RC at subsequent visits. Kaplan‐Meier survival analysis was used to compare survival time of early vs late RC. Results At visit 2, 11/52 dogs were RC; at visit 3, 14/52 were RC; and at visit 4, 4/52 were RC. At the end of study, 25/52 remained NRC. At visit 2, both groups had increased cardiac dimensions, but NRC dogs had larger dimensions; biomarkers did not differ. At the end of study, RC showed decreased cardiac dimensions and end‐terminal pro‐brain natriuretic peptide (NT‐proBNP) compared with NRC. No variables were useful at predicting RC success in subsequent visits. Survival analysis found no differences between early vs late RC. Conclusions and Clinical Importance The RC dogs had decreased cardiac dimensions and NT‐proBNP, suggesting HR‐mediated reverse‐remodeling might benefit survival, even with delayed RC achievement. Pursuit of RC is crucial despite initial failures.

Abstract There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed—direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer—Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16—known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.

Abstract Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two male mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

Abstract Background A growing number of older adults (ages 65+) live with Type 1 diabetes. Simultaneously, technologies such as continuous glucose monitoring (CGM) have become standard of care. There is thus a need to understand better the complex dynamics that promote use of CGM (and other care innovations) over time in this age group. Our aim was to adapt methods from systems thinking, specifically a participatory approach to system dynamics modeling called group model building (GMB), to model the complex experiences that may underlie different trajectories of CGM use among this population. Herein, we report on the feasibility, strengths, and limitations of this methodology. Methods We conducted a series of GMB workshops and validation interviews to collect data in the form of questionnaires, diagrams, and recordings of group discussion. Data were integrated into a conceptual diagram of the “system” of factors associated with uptake and use of CGM over time. We evaluate the feasibility of each aspect of the study, including the teaching of systems thinking to older adult participants. We collected participant feedback on positive aspects of their experiences and areas for improvement. Results We completed nine GMB workshops with older adults and their caregivers (N = 33). Each three-hour in-person workshop comprised: (1) questionnaires; (2) the GMB session, including both didactic components and structured activities; and (3) a brief focus group discussion. Within the GMB session, individual drawing activities proved to be the most challenging for participants, while group activities and discussion of relevant dynamics over time for illustrative (i.e., realistic but not real) patients yielded rich engagement and sufficient information for system diagramming. Study participants liked the opportunity to share experiences with peers, learning and enhancing their knowledge, peer support, age-specific discussions, the workshop pace and structure, and the systems thinking framework. Participants gave mixed feedback on the workshop duration. Conclusions The study demonstrates preliminary feasibility, acceptability, and the value of GMB for engaging older adults about key determinants of complex health behaviors over time. To our knowledge, few studies have extended participatory systems science methods to older adult stakeholders. Future studies may utilize this methodology to inform novel approaches for supporting health across the lifespan.

Abstract Background In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM). Hypothesis/Objectives To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance. Animals Twelve neurologically affected QH foals and the dams. Methods Genomic DNA was isolated and pedigrees were manually constructed. Results All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma‐glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0–18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance. Conclusions and Clinical Importance EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs

Abstract Background The ability to perform transvenous temporary cardiac pacing (TV‐TP) is critical to stabilize horses with symptomatic bradyarrhythmias. Reports of successful TV‐TP in horses are limited, and only briefly describe short‐term pacing. Objective To describe temporary, medium‐term (24 h) transvenous right ventricular pacing in awake horses using a bipolar torque‐directed pacing catheter. Animals Six healthy adult institutional teaching horses. Methods Prospective experimental study with 2 immediately successive TV‐TP lead placements in each horse with a target location of the RV apex. One placement was performed primarily with echocardiographic guidance and 1 primarily with fluoroscopic guidance. In all placements, corresponding images were obtained with both imaging modalities. Horses were then paced for 24 h, unrestricted in a stall with continuous telemetric ECG monitoring. Echocardiographically determined lead position, episodes of pacing failure in the preceding 6 h, and pacing thresholds were recorded every 6 h. Pacing failure was defined as a period of loss of capture longer than 20 s. Results Pacing leads were placed with both guidance methods and maintained for 24 h with no complications. Two horses with leads angled caudally in the right ventricular apex had no pacing failure, the remaining 4 horses had varying degrees of loss of capture. Leads located in the right ventricular apex had longer time to pacing failure and lower capture thresholds P

Abstract Background Differentiation of the subclinical phases of myxomatous mitral valve disease (MMVD) in dogs relies heavily on echocardiography. Focused cardiac ultrasonography (FCU) is a point‐of‐care technique that can assess heart size. Hypothesis/Objectives Veterinary students trained in FCU can differentiate dogs with subclinical MMVD based on left ventricular (LV) and left atrial (LA) dimensions. Animals Forty‐eight dogs with subclinical MMVD. Methods Veterinary students were trained to measure LV dimension and LA‐to‐aortic root dimension ratio (LA : Ao) using FCU. Dogs were categorized into 2 cohorts based on whether or not the LV normalized internal diastolic dimension was ≥1.7 and LA : Ao was ≥1.6. Agreement between FCU and echocardiographic studies performed by cardiologists was evaluated. Results One‐hundred and forty‐six FCU examinations were performed by 58 veterinary students on 48 dogs. Overall agreement between students and cardiologists was moderate (Fleiss' kappa, 0.54; 95% confidence interval [CI], 0.39‐0.69; P

Auditory hallucinations (AH) are the most common symptom of psychosis. The voices people hear make comments that are benign or even encouraging, but most often voices are threatening and derogatory. Negative AH are often highly distressing and contribute to suicide risk and violent behavior. Biological mechanisms underlying the valence of voices (i.e., positive, negative, neutral) are not well delineated. In the current study, we examined whether AH voice valence was associated with increased activation of the Defensive Motivational System, as indexed by central and autonomic system response to unpleasant stimuli. Data were evaluated from two studies that used a common symptom rating instrument, the Psychotic Symptom Rating Scale (PSY-RATS), to measure AH valence. Participants included outpatients diagnosed with SZ. Tasks included: Study 1: Trier Social Stress Task while heart rate was recorded via electrocardiography (N = 27); Study 2: Passive Viewing Task while participants were exposed to pleasant, unpleasant, and neutral images from the International Affective Picture System (IAPS) library while eye movements, pupil dilation, and electroencephalography were recorded (N = 25). Results indicated that negative voice content was significantly associated with: 1) increased heart rate during an acute social stressor, 2) increased pupil dilation to unpleasant images, 3) higher neural reactivity to unpleasant images, and 4) a greater likelihood of having bottom-up attention drawn to unpleasant stimuli. Findings suggest that negative AH are associated with greater Defensive Motivational System activation in terms of central and autonomic nervous system response.

BackgroundOsteoarthritis is more prevalent and severe among women than among men, but women are less likely to access early diagnosis and first-line management, particularly racialized immigrant women. Previous research advocated for greater access to culturally safe osteoarthritis information for both diverse women and health care professionals. The internet can reduce disparities by facilitating access to health information, but online materials can vary in quality. ObjectiveThis study aimed to assess the quality and cultural safety of online osteoarthritis materials for persons affected by osteoarthritis and health care professionals. MethodsContent analysis was used to describe publicly available materials on osteoarthritis first-line management developed by Canadian organizations for affected persons or health care professionals. Searching, screening, and data extraction were performed in triplicate. We identified materials by searching Google, MEDLINE, and references of osteoarthritis-relevant guidelines and policies, and consulting our research team and collaborators. We assessed quality using DISCERN (University of Oxford) and a compiled framework for affected persons and health care professionals. We compiled frameworks to assess cultural safety. We derived an overall score, categorized as low (

This study explores the pedagogical impacts of the infection control measures implemented in Norwegian kindergartens after the Covid-19 lockdown in the spring of 2020. The data is based on a survey study with three repeated measures following kindergartens from the first week of reopening in April, continuing until June. Reflexive thematic analysis is used in the analysis of data from answers to open questions. The themes generated were: (1) limited time to prepare, (2) concerns about the unknown, (3) structuring the kindergartens according to the guidelines, (4) securing a safe place for children within the new rules and routines; (5) closer relationships but reduced child democracy, (6) spending time more time outside and in nature, and (7) reduced collaboration and information flow. Framed by a crisis management perspective and the concepts of structural and process quality, we discuss what we can learn from the kindergartens’ experiences in the spring of 2020.

BackgroundMicro- and nanoplastics (MNPs) are emerging pollutants of concern with ubiquitous presence in global ecosystems. MNPs pose potential implications for human health; however, the health impacts of MNP exposures are not yet understood. Recent evidence suggests that MNPs can cross the placental barrier, underlying the urgent need to understand their impact on reproductive health and development. ObjectiveThe Actionable eUropean ROadmap for early-life health Risk Assessment of micro- and nanoplastics (AURORA) project will investigate MNP exposures and their biological and health effects during pregnancy and early life, which are critical periods due to heightened vulnerability to environmental stressors. The AURORA project will enhance exposure assessment capabilities for measuring MNPs, MNP-associated chemicals, and plastic additives in human tissues, including placenta and blood. MethodsIn this interdisciplinary project, we will advance methods for in-depth characterization and scalable chemical analytical strategies, enabling high-resolution and large-scale toxicological, exposure assessment, and epidemiological studies. The AURORA project performs observational studies to investigate determinants and health impacts of MNPs by including 800 mother-child pairs from 2 existing birth cohorts and 110 women of reproductive age from a newly established cohort. This will be complemented by toxicological studies using a tiered-testing approach and epidemiological investigations to evaluate associations between maternal and prenatal MNP exposures and health perturbations, such as placental function, immune-inflammatory responses, oxidative stress, accelerated aging, endocrine disruption, and child growth and development. The ultimate goal of the AURORA project is to create an MNP risk assessment framework and identify the remaining knowledge gaps and priorities needed to comprehensively assess the impact of MNPs on early-life health. ResultsIn the first 3 years of this 5-year project (2021-2026), progress was made toward all objectives. This includes completion of recruitment and data collection for new and existing cohorts, development of analytical methodological protocols, and initiation of the toxicological tiered assessments. As of September 2024, data analysis is ongoing and results are expected to be published starting in 2025. ConclusionsAs plastic pollution increases globally, it is imperative to understand the impact of MNPs on human health, particularly during vulnerable developmental stages such as early life. The contributions of the AURORA project will inform future risk assessment. International Registered Report Identifier (IRRID)DERR1-10.2196/63176

Objectives Immigrant and sexually/gender-diverse women (henceforth, women) face inequities in access to and quality of care. As a result, many seek health information from community agencies perceived as culturally safe. We aimed to generate knowledge on capacity needed for culturally safe community agency health promotion.Design Theoretical rapid review.Data sources Studies identified in MEDLINE, EMBASE, CINAHL, PsycINFO, Sociological Abstracts, Cochrane Library and the Joanna Briggs Institute Database of Systematic Reviews.Eligibility criteria Studies published in 2013 or later on health promotion for ethnoculturally, sexually and gender-diverse women led by community agencies (eg, settlement, cultural, support and faith).Data extraction/synthesis We extracted data on study characteristics, cultural tailoring, implementation with the Reach Effectiveness Adoption Implementation framework and health promotion capacity with the New South Wales framework.Results We included 19 studies published from 2017 to 2023. Most focused on health promotion to African or Latin American persons in faith-based organisations. Few studies focused solely on women, and no studies focused on or included 2SLGBTQ women. Few studies described cultural tailoring beyond the use of participants’ first language. Training of community health workers (CHWs) to deliver health promotion education, and CHW in-person group training of health promotion participants on a wide range of topics resulted in improved knowledge, self-efficacy, intention to modify behaviour, behaviour change and health outcomes. A few studies yielded some insight into what community agencies need to enable health promotion: dedicated funding and personnel, training in healthcare issues, space and partnerships with academic and healthcare organisations.Conclusions This study confirmed and enhanced our understanding of the health promotion role of community agencies and identified gaps that can inform future research on how to achieve culturally safe community agency health promotion for diverse women.

IntroductionCancer patients may have increased risk for adverse cardiac events, but our understanding of cardiovascular risk in thymic cancer patients is not clear. We sought to characterize baseline cardiometabolic risk factors before thymic cancer diagnosis and the potential association between cancer treatment and subsequent cardiac events.MethodsThis was a retrospective cohort study evaluating patients with thymic cancer from 2003 to 2020 compared to age- and sex-matched controls without cancer. Baseline cardiovascular risk factors, cancer characteristics, and incidence of cardiac events were collected from the health information exchange. Multivariable regression was used to examine the impact of cardiovascular risk factors and cancer therapies.ResultsWe compared 296 patients with pathology-confirmed thymic cancer to 2,960 noncancer controls. Prior to cancer diagnosis, thymic cancer patients (TCPs) had lower prevalence of hypertension, dyslipidemia, and diabetes mellitus and similar rates of obesity, tobacco use, and pre-existing cardiovascular disease (CVD) compared to controls. After diagnosis, high-risk TCPs (>2 cardiovascular risk factors or pre-existing CVD) had higher risk for cardiac events (HR 3.73, 95% CI 2.88–4.83, p

Abstract Background Women are disproportionately impacted by osteoarthritis (OA) but less likely than men to access OA care, particularly racialized women. One way to reduce inequities is through policies that can influence healthcare services. We examined how OA-relevant policies in Canada address equitable, person-centred OA care for women. Methods We used content analysis to extract data from English-language OA-relevant documents referred to as policies or other synonymous terms published in 2000 or later identified by searching governmental and other web sites. We used summary statistics to describe policy characteristics, person-centred care using McCormack’s six-domain framework, and mention of OA prevalence, barriers and strategies to improve equitable access to OA care among women. Results We included 14 policies developed from 2004 to 2021. None comprehensively addressed all person-centred care domains, and few addressed individual domains: enable self-management (50%), share decisions (43%), exchange information (29%), respond to emotions (14%), foster a healing relationship (0%) and manage uncertainty (0%). Even when mentioned, content offered little guidance for how to achieve person-centred OA care. Few policies acknowledged greater prevalence of OA among women (36%), older (29%) or Indigenous persons (29%) and those of lower socioeconomic status (14%); or barriers to OA care among those of lower socioeconomic status (50%), in rural areas (43%), of older age (37%) or ethno-cultural groups (21%), or women (21%). Four (29%) policies recommended strategies for improving access to OA care at the patient (self-management education material in different languages and tailored to cultural norms), clinician (healthcare professional education) and system level (evaluate OA service equity, engage lay health leaders in delivering self-management programs, and offer self-management programs in a variety of formats). Five (36%) policies recommended research on how to improve OA care for equity-seeking groups. Conclusions Canadian OA-relevant policies lack guidance to overcome disparities in access to person-centred OA care for equity-seeking groups including women. This study identified several ways to strengthen policies. Ongoing research must identify the needs and preferences of equity-seeking persons with OA, and evaluate the impact of various models of service delivery, knowledge needed to influence OA-relevant policy.

Abstract Background Human Papillomavirus-associated oropharyngeal cancer (HPV-OPC) incidence is increasing among men in the United States. Poor dental health has previously been associated with risk of head and neck cancers, oral HPV infection, and persistence but it is not understood whether dental health is associated with outcomes. We sought to determine the association of dental health with progression free survival and overall mortality among men with an HPV-OPC. Methods A cross sectional study of men diagnosed with HPV-OPC between 2014–2020 at Moffitt Cancer Center in Tampa, FL was conducted. Dental records were abstracted for assessment of dental fitness prior to cancer treatment. Five dental factors including number of teeth lost, pocket depth, gingival score, loss of attachment, and bone loss were individually examined. Risk factor and outcome data were collected from a patient risk questionnaire and medical record. Using item response theory, an overall dental fitness score from five dental factors was developed in which missing data were multiply imputed. Cox proportional hazards model was used to assess whether dental factors were associated with progression-free survival or overall mortality. Results Among 206 HPV-OPC cases, median follow-up was 3.4 years (IQR: 2.4–4.4) during which 40 cases involved progression or mortality and 25 deaths occurred. Overall dentition was significantly associated with progression free survival (p = 0.04) and with overall survival (p = 0.03) though findings were not significant after adjustment for age at diagnosis, stage, and smoking history (p = 0.146 and p = 0.120, respectively). A pocket depth of 7 mm or more was associated with overall survival (HR: 5.21; 95% CI: 1.43—19.11) and this remained significant after adjustment for confounding (aHR: 4.14; 95% CI: 1.72—16.26). Conclusions Among men diagnosed with an HPV-associated OPC in the US, worse dental health was associated with reduced progression free survival and overall survival, but not after adjustment for confounders. Further studies are needed to examine whether dental health is associated with other prognostic factors and subsequent treatment-related outcomes.

Abstract Background Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a poor prognosis. Doxorubicin is part of standard curative therapy for TNBC, but chemotherapy resistance remains an important clinical challenge. Bocodepsin (OKI-179) is a small molecule class I histone deacetylase (HDAC) inhibitor that promotes apoptosis in TNBC preclinical models. The purpose of this study was to investigate the combination of bocodepsin and doxorubicin in preclinical TNBC models and evaluate the impact on terminal cell fate, including apoptosis and senescence. Methods TNBC cell lines were treated with doxorubicin and CellTiter-Glo was used to assess proliferation and determine doxorubicin sensitivity. Select cell lines were treated with OKI-005 (in vitro version of bocodepsin) and doxorubicin and assessed for proliferation, apoptosis as measured by Annexin V/PI, and cell cycle by flow cytometry. Immunoblotting was used to assess changes in mediators of apoptosis, cell cycle arrest, and senescence. Senescence was measured by the senescence-associated β-galactosidase assay. An MDA-MB-231 xenograft in vivo model was treated with bocodepsin, doxorubicin, or the combination and assessed for inhibition of tumor growth. shRNA knockdown of p53 was performed in the CAL-51 cell line and proliferation, apoptosis and senescence were assessed in response to combination treatment. Results OKI-005 and doxorubicin resulted in synergistic antiproliferative activity in TNBC cells lines regardless of p53 mutation status. The combination led to increased apoptosis and decreased senescence. In vivo, the combination resulted in increased tumor growth inhibition compared to either single agent. shRNA knock-down of p53 led to increased doxorubicin-induced senescence that was decreased with the addition of OKI-005 in vitro. Conclusion The addition of bocodepsin to doxorubicin resulted in synergistic antiproliferative activity in vitro, improved tumor growth inhibition in vivo, and promotion of apoptosis which makes this a promising combination to overcome doxorubicin resistance in TNBC. Bocodepsin is currently in clinical development and has a favorable toxicity profile compared to other HDAC inhibitors supporting the feasibility of evaluating this combination in patients with TNBC.

Abstract Carnitine is required to transport fatty acid across the mitochondrial membrane to undergo beta oxidation. In addition to disorders of fatty acid metabolism, a relative carnitine deficiency has been reported in pulmonary arterial hypertension (PAH). Here we performed an observational study in which food and supplement consumption were collected in an observation period followed by open label administration of a carnitine supplement to determine feasibility of increasing plasma carnitine levels in humans PAH. We confirmed that relative carnitine deficiency in PAH is not due to reduced dietary consumption and that plasma levels of carnitine can be increased in PAH patients with supplementation that is well tolerated.

Summary: Background: Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. Methods: We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment. Findings: Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis. Interpretation: Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments. Funding: German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.

Abstract Public health concerns about recent viral epidemics have motivated researchers to seek novel ways to understand pathogen infection in native, wildlife hosts. With its deep history of tools and perspectives for understanding the abundance and distribution of organisms, ecology can shed new light on viral infection dynamics. However, datasets allowing deep explorations of viral communities from an ecological perspective are lacking. We sampled 1086 bats from two, adjacent Puerto Rican caves and tested them for infection by herpesviruses, resulting in 3131 short, viral sequences. Using percent identity of nucleotides and a machine learning algorithm (affinity propagation), we categorized herpesviruses into 43 operational taxonomic units (OTUs) to be used in place of species in subsequent ecological analyses. Herpesvirus metacommunities demonstrated long‐tailed rank frequency distributions at all analyzed levels of host organization (i.e., individual, population, and community). Although 13 herpesvirus OTUs were detected in more than one host species, OTUs generally exhibited host specificity by infecting a single core host species at a significantly higher prevalence than in all satellite species combined. We describe the natural history of herpesvirus metacommunities in Puerto Rican bats and suggest that viruses follow the general law that communities comprise few common and many rare species. To guide future efforts in the field of viral ecology, hypotheses are presented regarding mechanisms that contribute to these patterns.

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), a member of the RGK family of Ras-like GTPases, is implicated in Huntington’s disease and Long QT Syndrome and is highly expressed in the brain and endocrine cells. We examine the evolutionary history of Rem2 identified in various mammalian species, focusing on the role of purifying selection and coevolution in shaping its sequence and protein structural constraints. Our analysis of Rem2 sequences across 175 mammalian species found evidence for strong purifying selection in 70% of non-invariant codon sites which is characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2’s role in the regulation of neuronal development and function. We inferred epistatic effects in 50 pairs of codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences which revealed the dynamics of how substitutions that change the gene sequence of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and gene - interactions that have shaped the sequence and structure of the Rem2 protein, we gain a stronger understanding of its biological and functional constraints.

Background: Chronic cough (CC) affects about 10% of adults, but opioid use in CC is not well understood. Objectives: To determine the use of opioid-containing cough suppressant (OCCS) prescriptions in patients with CC using electronic health records. Design: Retrospective cohort study. Methods: Through retrospective analysis of Midwestern U.S. electronic health records, diagnoses, prescriptions, and natural language processing identified CC – at least three medical encounters with cough, with 56–120 days between first and last encounter – and a ‘non-chronic cohort’. Student’s t -test, Pearson’s chi-square, and zero-inflated Poisson models were used. Results: About 20% of 23,210 patients with CC were prescribed OCCS; odds of an OCCS prescription were twice as great in CC. In CC, OCCS drugs were ordered in 38% with Medicaid insurance and 15% with commercial insurance. Conclusion: Findings identify an important role for opioids in CC, and opportunity to learn more about the drugs’ effectiveness.

Introduction: Young sexual minority men (SMM) bear the greatest burden of anal human papillomavirus (HPV) infections. We assessed anal HPV genotype discordance between the Linear Array (LA) and SPF10 PCR-DEIA-LiPA25 (LiPA25). Methods: Discordance was assessed between LA and LiPA25 using self-collected anal swabs from 120 SMM aged 18–29 who were recruited in 2014–2016. Multiple-type infection was explored as a potential confounder of testing agreement, along with clinical and behavioral factors such as HIV status, syphilis status, incarceration history, health insurance coverage, having 3 or more sex partners in the past 6 months, and co-infection with HPV-16. Results: Significant discordance was found for HPV-6, -11, -16, -31, -42, -54, and -59. Exploratory analyses suggest higher prevalence of genotype discordance in those living with HIV, those with 3 or more sex partners, and those who were positive for 4 or more HPV types. Conclusions: Our results highlight the importance of HPV detection methods which may inform different interpretations of research assessing anal HPV natural history among SMM at highest risk for HPV.

Abstract Background Poor natriuresis is a potential marker of diuretic resistance in dogs with acute congestive heart failure (CHF) but little is known about the relationship between urine sodium concentration (uNa) and frequency of successful decongestion. Supplemental O2 is a common treatment in dogs with severe CHF. The time from start to discontinuation of supplemental O2 therapy (DCSO2) typically reflects the time course and ease of decongestion. Hypothesis/Objectives Urine Na concentration after IV administration of furosemide will be correlated with duration of treatment with supplemental O2 (timeO2) and the cumulative frequency of successful DCSO2 during hospitalization. Animals Fifty‐one dogs with acute CHF. Methods Retrospective observational single center study. Results Dogs with low uNa had significantly longer mean timeO2 than dogs with high uNa (uNa

Adrenocortical carcinoma (ACC) is a rare malignant tumor originating in the adrenal cortex and characterized by poor 5-year survival. It occurs with a frequency of 2–4 cases per 2 million in the population. Women are more frequently affected than men and it is mostly detected in the fourth and fifth decades. In the most of cases, the cancerogenesis occurs sporadically because of gene driver mutations in somatic adrenocortical cells, in other cases it can be found as part of a genetically determined syndrome such as Li–Fraumeni syndrome or Wermer's syndrome (multiple endocrine adenomatosis type I). ACC most frequently happens occurs without symptoms in the initial stages leading to poor diagnoses. Because of this lack of early detection, the tumor is not considered malignant reducing the benefits of further treatment. Sometimes the fact that the resected tumor is indeed adrenocortical carcinoma becomes clear only after recurrence, or after the appearance of metastases. We present a case of adrenocortical carcinoma in a 46-year-old woman who went to the doctor in 1.5 year after symptoms were manfested. This clinical case illustrates the consequences of late diagnosis of a malignant tumor. We would like to emphasize the importance of timely detection of a neoplasm, using all of the potential of laboratory-instrumental and genomic analysis. Due to low oncological awareness, our patient was slow to seek medical help, which in turn led not only to metastases, but also to complications in the cardiovascular system.

The South American fruit fly Anastrepha fraterculus (Wiedmann) has a vast range extending from northern Mexico, through Central America, to South America where it is an extremely polyphagous pest of wild and cultivated fruits. It is a complex of cryptic species currently composed of eight recognised morphotypes: “Mexican”, “Venezuelan”, “Andean”, “Peruvian”, “Ecuadorian”, and the three Brazilian morphotypes “Brazilian-1”, “Brazilian-2”, and “Brazilian-3”. Molecular markers that can identify the member species of the complex are crucial for the implementation of effective pest control measures, such as the sterile insect technique. The object of this study was to evaluate the use of the internal transcribed spacer 2 (ITS2) sequence for discriminating several members of the A. fraterculus cryptic species complex (Mexican, Peruvian, and Brazilian-1) and a related species, Anastrepha schultzi Blanchard. The analysis highlighted significant genetic differentiation between the evaluated morphotypes, allowed their discrimination within the A. fraterculus cryptic species complex, and provided new insights into their genetic relationships. The ITS2 marker provides a basis for the development of taxonomic keys for the discrimination of the cryptic taxa within the A. fraterculus cryptic species complex. ITS2 also represents an important marker for the poorly studied species A. schultzi.

Abstract Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions.

Abstract Background Individuals with an increased body mass index (BMI) (≥ 30 kg/m2) experience higher rates of perinatal mental health disorders than individuals with BMI

Abstract Background Women are more likely to develop osteoarthritis (OA), and have greater OA pain and disability compared with men, but are less likely to receive guideline-recommended management, particularly racialized women. OA care of diverse women, and strategies to improve the quality of their OA care is understudied. The purpose of this study was to explore strategies to overcome barriers of access to OA care for diverse women. Methods We conducted qualitative interviews with key informants and used content analysis to identify themes regarding what constitutes person-centred OA care, barriers of OA care, and strategies to support equitable timely access to person-centred OA care. Results We interviewed 27 women who varied by ethno-cultural group (e.g. African or Caribbean Black, Chinese, Filipino, Indian, Pakistani, Caucasian), age, region of Canada, level of education, location of OA and years with OA; and 31 healthcare professionals who varied by profession (e.g. family physician, nurse practitioner, community pharmacist, physio- and occupational therapists, chiropractors, healthcare executives, policy-makers), career stage, region of Canada and type of organization. Participants within and across groups largely agreed on approaches for person-centred OA care across six domains: foster a healing relationship, exchange information, address emotions, manage uncertainty, share decisions and enable self-management. Participants identified 22 barriers of access and 18 strategies to overcome barriers at the patient- (e.g. educational sessions and materials that accommodate cultural norms offered in different languages and formats for persons affected by OA), healthcare professional- (e.g. medical and continuing education on OA and on providing OA care tailored to intersectional factors) and system- (e.g. public health campaigns to raise awareness of OA, and how to prevent and manage it; self-referral to and public funding for therapy, greater number and ethno-cultural diversity of healthcare professionals, healthcare policies that address the needs of diverse women, dedicated inter-professional OA clinics, and a national strategy to coordinate OA care) levels. Conclusions This research contributes to a gap in knowledge of how to optimize OA care for disadvantaged groups including diverse women. Ongoing efforts are needed to examine how best to implement these strategies, which will require multi-sector collaboration and must engage diverse women.

Abstract Background A precision medicine approach in type 2 diabetes requires the identification of clinical and biological features that are reproducibly associated with differences in clinical outcomes with specific anti-hyperglycaemic therapies. Robust evidence of such treatment effect heterogeneity could support more individualized clinical decisions on optimal type 2 diabetes therapy. Methods We performed a pre-registered systematic review of meta-analysis studies, randomized control trials, and observational studies evaluating clinical and biological features associated with heterogenous treatment effects for SGLT2-inhibitor and GLP1-receptor agonist therapies, considering glycaemic, cardiovascular, and renal outcomes. After screening 5,686 studies, we included 101 studies of SGLT2-inhibitors and 75 studies of GLP1-receptor agonists in the final systematic review. Results Here we show that the majority of included papers have methodological limitations precluding robust assessment of treatment effect heterogeneity. For SGLT2-inhibitors, multiple observational studies suggest lower renal function as a predictor of lesser glycaemic response, while markers of reduced insulin secretion predict lesser glycaemic response with GLP1-receptor agonists. For both therapies, multiple post-hoc analyses of randomized control trials (including trial meta-analysis) identify minimal clinically relevant treatment effect heterogeneity for cardiovascular and renal outcomes. Conclusions Current evidence on treatment effect heterogeneity for SGLT2-inhibitor and GLP1-receptor agonist therapies is limited, likely reflecting the methodological limitations of published studies. Robust and appropriately powered studies are required to understand type 2 diabetes treatment effect heterogeneity and evaluate the potential for precision medicine to inform future clinical care.

Abstract Introduction Women are disproportionately impacted by osteoarthritis (OA) but less likely than men to access early diagnosis and management, or experience OA care tailored through person-centred approaches to their needs and preferences, particularly racialized women. One way to support clinicians in optimizing OA care is through clinical guidelines. We aimed to examine the content of OA guidelines for guidance on providing equitable, person-centred care to disadvantaged groups including women. Methods We searched indexed databases and websites for English-language OA-relevant guidelines published in 2000 or later by non-profit organizations. We used manifest content analysis to extract data, and summary statistics and text to describe guideline characteristics, person-centred care (PCC) using a six-domain PCC framework, OA prevalence or barriers by intersectional factors, and strategies to improve equitable access to OA care. Results We included 36 OA guidelines published from 2003 to 2021 in 8 regions or countries. Few (39%) development panels included patients. While most (81%) guidelines included at least one PCC domain, guidance was often brief or vague, few addressed exchange information, respond to emotions and manage uncertainty, and none referred to fostering a healing relationship. Few (39%) guidelines acknowledged or described greater prevalence of OA among particular groups; only 3 (8%) noted that socioeconomic status was a barrier to OA care, and only 2 (6%) offered guidance to clinicians on how to improve equitable access to OA care: assess acceptability, availability, accessibility, and affordability of self-management interventions; and employ risk assessment tools to identify patients without means to cope well at home after surgery. Conclusions This study revealed that OA guidelines do not support clinicians in caring for diverse persons with OA who face disadvantages due to intersectional factors that influence access to and quality of care. Developers could strengthen OA guidelines by incorporating guidance for PCC and for equity that could be drawn from existing frameworks and tools, and by including diverse persons with OA on guideline development panels. Future research is needed to identify multi-level (patient, clinician, system) strategies that could be implemented via guidelines or in other ways to improve equitable, person-centred OA care. Patient or public contribution This study was informed by a team of researchers, collaborators, and thirteen diverse women with lived experience, who contributed to planning, and data collection, analysis and interpretation by reviewing study materials and providing verbal (during meetings) and written (via email) feedback.