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Abstract Background Colorectal cancer (CRC) is globally the third most prevalent cancer and a leading cause of cancer-related deaths. In Alberta, Canada, a significant portion of CRC diagnoses occur following emergency department (ED) presentations. Gaps remain in understanding patient’s perspectives on CRC diagnosis after an ED visit. The aim of this study was to examine the experiences and perspectives of a group of patients diagnosed with CRC subsequent to an ED visit in Alberta and their close contacts. Methods We conducted a qualitative study using in-depth, semi-structured interviews with patients diagnosed with CRC after an ED visit at the Rockyview General Hospital, Calgary, and their close contacts, from November 2022 to June 2023. Interviews focused on symptom recognition, healthcare interactions, and the decision-making process leading to an ED visit. They were conducted in-person or over the phone, and analysed using thematic analysis. Results Eighteen participants (12 patients and 6 close contacts) were interviewed, revealing four main themes: (1) variability in symptom recognition and interpretation; (2) inconsistencies in primary care consultations; (3) factors influencing decision-making leading to an ED visit; and (4) recommendations for expedited diagnosis outside of EDs. Conclusion The findings highlight the complexity of the diagnostic journey for CRC patients in Alberta, pointing to significant gaps in symptom recognition and response by patients and healthcare providers. Improved diagnostic protocols and targeted support for healthcare providers, as well as approaches to address systemic delays may help streamline the diagnostic journey. Future research should focus on exploring innovative interventions to address the identified barriers to timely CRC diagnosis.

Abstract Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric “RCR-complex”. We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called “R78C”, combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

ObjectivesEarly removal of chest tubes reduces pain and morbidity. This study aimed to remove chest tubes immediately after robotic pulmonary resection with complete thoracic lymphadenectomy by administering ice cream to rule out chylothorax.MethodsThis quality improvement study utilized prospectively gathered data from one thoracic surgeon. Patients were given 3.6 fl oz of ice cream in the recovery room within 1 h after their operation. Chest tubes were removed within 4 h if there was no chylous drainage and air leak on the digital drainage system.ResultsFrom January 2022 to August 2023, 343 patients underwent robotic pulmonary resection with complete thoracic lymphadenectomy. The median time to ingest the ice cream was 1.5 h after skin closure. The incidence of chylothorax was 0.87% (3/343). Two patients were diagnosed with chylothorax after consuming ice cream within 4 h of surgery. One patient, whose chest tube remained in place due to an air leak, had a chylothorax diagnosed on postoperative day 1 (POD1). All three patients were discharged home on POD1 with their chest tubes in place, adhering to a no-fat, medium-chain triglyceride diet. All chylothoraces resolved within 6 days. None of the remaining patients developed chylothorax postoperatively with a minimum follow-up period of 90 days.ConclusionsProviding ice cream to patients after pulmonary resection and complete thoracic lymphadenectomy is an effective and reliable technique to rule out chylothorax early in the postoperative period and facilitates early chest tube removal. Further studies are needed to ensure that this simple, inexpensive test is reproducible.

Abstract Background A shortage of healthcare providers, particularly in primary care and mental health, exists in the predominately rural state of Idaho. There are also barriers to retaining healthcare providers to work in rural and remote communities. Limited research using U.S. samples has explored factors that may affect the retention of healthcare providers in rural areas. Additionally, due to differences between communities, it is important to conduct community-level investigations to better understand how these factors may affect retention in rural areas. Therefore, the purpose of this study was to explore factors affecting healthcare provider retention in a rural community in Northern Idaho. Methods A modified version of the Nursing Community Apgar Questionnaire (NCAQ) was completed by 30 healthcare providers in a rural and frontier community in Northern Idaho to assess factors influencing healthcare provider retention. Factors were classified into classes including geographic, economic, scope of practice, medical support, and facility and community support classes. Retention factors were assessed on their perceived importance to retention as well as whether they were perceived as an advantage or challenge to retention based on Likert scales. A “Community Apgar” score was also created by combining the importance and advantage/challenge factors. Results Overall, items in the medical support group had the highest importance of any other class and included factors such as nursing workforce. Additionally, the facility and community support class, which included factors such as televideo support, was rated the highest advantage class and had the highest Apgar score, indicating it contained the factor that healthcare providers identified as the most important advantage (i.e., medical reference resources). Conclusion Our study identified multiple factors that healthcare providers deemed as important advantages or disadvantages to retaining healthcare providers in rural areas. Overall, facility and community support factors were found to have the highest advantage in the retention of rural providers. Rural healthcare organizations looking to increase healthcare provider retention should target retention efforts towards these factors. Additional research should also be conducted on other rural samples across the U.S. to make comparisons of findings.

Abstract Spreading depolarizations (SDs) are widely recognized as a major contributor to the progression of tissue damage from ischemic stroke even if blood flow can be restored. They are characterized by negative intracortical waveforms of up to -20 mV, propagation velocities of 3 - 6 mm/min, and massive disturbance of membrane ion homeostasis. High-density, micro-electrocorticographic (μECoG) epidural electrodes and custom, DC-coupled, multiplexed amplifiers, were used to continuously characterize and monitor SD and µECoG cortical signal evolution in awake, moving rats over days. This highly innovative approach can define these events over a large brain surface area (~ 3.4 × 3.4 mm), extending across the boundaries of the stroke, and offers sufficient electrode density (60 contacts total per array for a density of 5.7 electrodes / mm2) to measure and determine the origin of SDs in relation to the infarct boundaries. In addition, spontaneous ECoG activity can simultaneously be detected to further define cortical infarct regions. This technology allows us to understand dynamic stroke evolution and provides immediate cortical functional activity over days. Further translational development of this approach may facilitate improved treatment options for acute stroke patients.

Abstract Organic matter in extraterrestrial samples is a complex material that might have played an important role in the delivery of prebiotic molecules to the early Earth. We report here on the identification of nitrogen-containing compounds such as amino acids and N-heterocycles within the recent observed meteorite fall Winchcombe by high-spatial resolution spectroscopy techniques. Although nitrogen contents of Winchcombe organic matter are low (N/C ~ 1–3%), we were able to detect the presence of these compounds using a low-noise direct electron detector. These biologically relevant molecules have therefore been tentatively found within a fresh, minimally processed meteorite sample by high spatial resolution techniques conserving the overall petrographic context. Carbon functional chemistry investigations show that sizes of aromatic domains are small and that abundances of carboxylic functional groups are low. Our observations demonstrate that Winchcombe represents an important addition to the collection of carbonaceous chondrites and still preserves pristine extraterrestrial organic matter.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca2+) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca2+-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca2+ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca2+ to protect the heart from cardiac remodeling. Methods and results: The Mitochondrial Ca2+ uniporter (MCU), the main mitochondrial Ca2+ uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2−/−-MCUCKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2−/−-MCUCKO hearts. Live-cell imaging identified altered Ca2+ handling and increased oxidative stress in CASQ2−/−-MCUCKO myocytes. The activation status of Ca2+-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2−/−-MCUCKO model. RNAseq identified changes in the transcriptome of the CASQ2−/−-MCUCKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression. Conclusions: We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca2+ uptake is crucial for preventing pathological cardiac remodeling in CPVT.

Background. Variation in donation after circulatory death (DCD) organ recovery and liver transplant practices exist among transplant centers. This study aimed to evaluate these practices among centers in the United States. Methods. Scientific Registry of Transplant Recipients data were accessed to identify centers that performed liver transplantation in 2021 and 2022. Surveys were sent to transplant centers that consistently performed ≥5 DCD liver transplants per year. Results. DCD liver transplants were performed by 95 centers (65.1%) of the 146 liver transplant centers in the United States. Survey results were recorded from 42 centers that consistently performed ≥5 DCD liver transplants per year, with a 59.5% response rate. Withdrawal-to-asystole and agonal time were used to define donor warm ischemia time (WIT) in 16% and 84% centers, respectively. Fifty-six percent of the centers did not use oxygen saturation to define donor WIT. Systolic blood pressure cutoffs used to define agonal time varied between 50 and 80 mm Hg, donor age cutoffs ranged between 55 and 75 y, and cold ischemia times varied between 4 and 10 h. Seventy-six percent of centers used normothermic machine perfusion for DCD liver transplantation. Conclusions. This study highlights the wide variation in use, recovery, and definition of donor WIT. Using national data to rigorously define best practices will encourage greater utilization of this important donor resource.

IntroductionMany loci segregate alleles classified as “genetic diseases” due to their deleterious effects on health. However, some disease alleles have been reported to show beneficial effects under certain conditions or in certain populations. The beneficial effects of these antagonistically pleiotropic alleles may explain their continued prevalence, but the degree to which antagonistic pleiotropy is common or rare is unresolved. We surveyed the medical literature to identify examples of antagonistic pleiotropy to help determine whether antagonistic pleiotropy appears to be rare or common.ResultsWe identified ten examples of loci with polymorphisms for which the presence of antagonistic pleiotropy is well supported by detailed genetic or epidemiological information in humans. One additional locus was identified for which the supporting evidence comes from animal studies. These examples complement over 20 others reported in other reviews.DiscussionThe existence of more than 30 identified antagonistically pleiotropic human disease alleles suggests that this phenomenon may be widespread. This poses important implications for both our understanding of human evolutionary genetics and our approaches to clinical treatment and disease prevention, especially therapies based on genetic modification.

It is imperative for individuals to exhibit flexible behaviour according to ecological context, such as available resources or predation threat. Manipulative studies on responses to threat often focus on behaviour in the presence of a single indicator for the potential of predation, whereas in the wild perception of threat will probably be more nuanced. Here, we examine the collective behaviour of eastern mosquitofish (Gambusia holbrooki) subject to five differing threat scenarios relating to the presence and hunger state of a jade perch (Scortum barcoo). Across threat scenarios, groups exhibit unique behavioural profiles that differ in the durations that particular collective states are maintained, the probability of transitions between states, the size and duration of persistence of spatially defined subgroups, and the patterns of collective order of these subgroups. Under the greatest level of threat, subgroups of consistent membership persist for longer durations. Group-level behaviours, and their differences, are interconnected with differences in estimates of the underlying rules of interaction thought to govern collective motion. The responses of the group are shown to be specific to the details of a potential threat, rather than a binary response to the presence or absence of some form of threat.

Summary: To investigate the phosphorylation-based signaling and protein changes occurring early in epileptogenesis, the hippocampi of mice treated with pilocarpine were examined by quantitative mass spectrometry at 4 and 24 h post-status epilepticus at vast depth. Hundreds of posttranscriptional regulatory proteins were the major early targets of increased phosphorylation. At 24 h, many protein level changes were detected and the phosphoproteome continued to be perturbed. The major targets of decreased phosphorylation at 4 and 24 h were a subset of postsynaptic density scaffold proteins, ion channels, and neurotransmitter receptors. Many proteins targeted by dephosphorylation at 4 h also had decreased protein abundance at 24 h, indicating a phosphatase-mediated weakening of synapses. Increased translation was indicated by protein changes at 24 h. These observations, and many additional indicators within this multiomic resource, suggest that early epileptogenesis is characterized by signaling that stimulates both growth and a homeostatic response that weakens excitability.

Abstract Acute hyperbaric O2 (HBO) therapy after spinal cord injury (SCI) can reduce inflammation and increase neuronal survival. To our knowledge, it is unknown if these benefits of HBO require hyperbaric vs. normobaric hyperoxia. We used a C4 lateralized contusion SCI in adult male and female rats to test the hypothesis that the combination of hyperbaria and 100% O2 (i.e. HBO) more effectively mitigates spinal inflammation and neuronal loss, and enhances respiratory recovery, as compared to normobaric 100% O2. Experimental groups included spinal intact, SCI no O2 therapy, and SCI + 100% O2 delivered at normobaric pressure (1 atmosphere, ATA), or at 2- or 3 ATA. O2 treatments lasted 1-h, commenced within 2-h of SCI, and were repeated for 10 days. The spinal inflammatory response was assessed with transcriptomics (RNAseq) and immunohistochemistry. Gene co-expression network analysis showed that the strong inflammatory response to SCI was dramatically diminished by both hyper- and normobaric O2 therapy. Similarly, both HBO and normobaric O2 treatments reduced the prevalence of immunohistological markers for astrocytes (glial fibrillary acidic protein) and microglia (ionized calcium binding adaptor molecule) in the injured spinal cord. However, HBO treatment also had unique impacts not detected in the normobaric group including upregulation of an anti-inflammatory cytokine (interleukin-4) in the plasma, and larger inspiratory tidal volumes at 10-days (whole body-plethysmography measurements). We conclude that normobaric O2 treatment can reduce the spinal inflammatory response after SCI, but pressured O2 (i.e., HBO) provides further benefit.

Background: Few data on maternal-infant hair cortisol are available from HIV high-burden settings. We evaluated maternal hair cortisol and its relationship with infant hair cortisol, perinatal stressors, and pregnancy outcomes in Kenya. Materials and Methods: We analyzed data from an HIV prevention trial (NCT03070600). Pregnant women without HIV were enrolled and followed through 9 months postpartum. We utilized hair samples collected at 6 weeks postpartum from mother-infant pairs to quantify hair cortisol concentrations (HCC) reflecting cortisol levels over the prior ?3 months. HCC was measured by enzyme immunoassay. We tested whether mean maternal HCC was associated with infant HCC, stressors, and/or birth outcomes using linear regression. Results: Overall, 153 women had HCC available at 6 weeks postpartum. Median maternal age was 25 years (Interquartile range [IQR] 22?30), median completed education was 12 years (IQR: 8?12), and 95% were married. Median birthweight was 3.4 kilograms (IQR: 3.1?3.7), 13% of women experienced preterm birth (PTB), and 2% of infants had low birthweight (LBW); 11% were small-for-gestational age (SGA). Median maternal HCC was 12.0?pg/mg (IQR: 6.3?20.4); and median infant HCC was 10.4?pg/mg (IQR: 5.5?23.7). Infant HCC was correlated with maternal HCC (r?=?0.498, p?0.001). Stressors associated with maternal HCC (p?

Objective: Chest tubes cause pain and morbidity. Methods: This is a quality initiative study and review of patients who underwent robotic pulmonary resection by 1 surgeon (R.J.C.). The goal was to remove chest tubes within 4 to 12 hours after robotic segmentectomy and lobectomy. Primary outcome was removal without the need for reinsertion, thoracentesis, or any morbidity due to early removal of the chest tube. Secondary outcomes were symptomatic pneumothorax, pleural effusion, chylothorax, subcutaneous emphysema, and chest tube reinsertion or thoracentesis within 60 days of surgery. Results: Between January 2018 and December 2022, 590 patients underwent robotic lobectomy or segmentectomy. Chest tubes were removed within 4 to 12 hours postoperatively in 63.5% of patients (375/590). In 2022, this was achieved in 91% after lobectomy (119/128) and 94% after segmentectomy (75/80). There were significantly more chest tubes removed within 4 to 12 hours postoperatively from 2020 to 2022 than pre-2020 (P

Objective: Chest tubes are frequently placed after thymectomy, without data to support this common practice. We report our experience in eliminating them after robotic thymectomy. Methods: This is a retrospective database review of patients who underwent robotic thymectomy performed by a single surgeon in which intraoperative chest tube insertion was not planned. Patient characteristics and postoperative outcomes are presented. Results: Between January 2018 and October 2022, 75 patients underwent robotic thymectomy performed by a single surgeon. Of those, 64 (85.3%) underwent a left-sided thoracic approach. The most common indication for resection was a suspicious anterior mediastinal mass. There were no conversions to an open operation. The median operative time was 72 minutes (range, 38-164 minutes), and the median estimated blood loss was 20 cc (range, 10-60 cc). Ten patients (13.3%) went home on the day of surgery, and all others (86.7%) were discharged on postoperative day 1. A chest tube was placed in 1 patient at time of closure because of a persistent air leak after extensive adhesiolysis from a prior thoracotomy; the tube was removed on the day of surgery after resolution of the air leak. No other patient required chest tube placement intraoperatively, immediately postoperatively, or within 60 days postoperation. Two patients underwent outpatient thoracentesis within 1 month postoperation for effusions. There were no 30- or 90-day mortality and no major morbidities. Conclusions: A chest tube after robotic thymectomy is not necessary in almost all patients and can be safely omitted. The dogmatic routine practice of chest tube placement should be questioned.

Abstract Transient brain insults including status epilepticus (SE) can initiate a process termed ‘epileptogenesis’ that results in chronic temporal lobe epilepsy. As a consequence, the entire tri-synaptic circuit of the hippocampus is fundamentally impaired. A key role in epileptogenesis has been attributed to the CA1 region as the last relay station in the hippocampal circuit and as site of aberrant plasticity, e.g. mediated by acquired channelopathies. The transcriptional profiles of the distinct hippocampal neurons are highly dynamic during epileptogenesis. Here, we aimed to elucidate the early SE-elicited mRNA signature changes and the respective upstream regulatory cascades in CA1. RNA sequencing of CA1 was performed in the mouse pilocarpine-induced SE model at multiple time points ranging from 6 to 72 h after the initial insult. Bioinformatics was used to decipher altered gene expression, signalling cascades and their corresponding cell type profiles. Robust transcriptomic changes were detected at 6 h after SE and at subsequent time points during early epileptogenesis. Major differentially expressed mRNAs encoded primarily immediate early and excitability-related gene products, as well as genes encoding immune signalling factors. Binding sites for the transcription factors Nfkb1, Spi1, Irf8, and two Runx family members, were enriched within promoters of differentially expressed genes related to major inflammatory processes, whereas the transcriptional repressors Suz12, Nfe2l2 and Rest were associated with hyperexcitability and GABA / glutamate receptor activity. CA1 quickly responds to SE by inducing transcription of genes linked to inflammation and excitation stress. Transcription factors mediating this transcriptomic switch represent targets for new highly selected, cell type and time window-specific anti-epileptogenic strategies.

Abstract Neuronal communication relies on the release of neurotransmitters from various populations of synaptic vesicles. Despite displaying vastly different release probabilities and mobilities, the reserve and recycling pool of vesicles co-exist within a single cluster suggesting that small synaptic biomolecular condensates could regulate their nanoscale distribution. Here, we performed a large-scale activity-dependent phosphoproteome analysis of hippocampal neurons in vitro and identified Tau as a highly phosphorylated and disordered candidate protein. Single-molecule super-resolution microscopy revealed that Tau undergoes liquid-liquid phase separation to generate presynaptic nanoclusters whose density and number are regulated by activity. This activity-dependent diffusion process allows Tau to translocate into the presynapse where it forms biomolecular condensates, to selectively control the mobility of recycling vesicles. Tau, therefore, forms presynaptic nano-biomolecular condensates that regulate the nanoscale organization of synaptic vesicles in an activity-dependent manner.

Abstract Background Fluoride is ubiquitous in the United States (US); however, data on biomarkers and patterns of fluoride exposure among US pregnant women are scarce. We examined specific gravity adjusted maternal urinary fluoride (MUFsg) in relation to sociodemographic variables and metal co-exposures among pregnant women in Los Angeles, California. Methods Participants were from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort. There were 293 and 490 women with MUFsg measured during first and third trimesters, respectively. An intra-class correlation coefficient examined consistency of MUFsg between trimesters. Kruskal–Wallis and Mann-Whitney U tests examined associations of MUFsg with sociodemographic variables. Covariate adjusted linear regression examined associations of MUFsg with blood metals and specific gravity adjusted urine metals among a subsample of participants within and between trimesters. A False Discovery Rate (FDR) correction accounted for multiple comparisons. Results Median (IQR) MUFsg was 0.65 (0.5) mg/L and 0.8 (0.59) mg/L, during trimesters one and three respectively. During both trimesters, MUFsg was higher among older participants, those with higher income, and White, non-Hispanic participants than Hispanic participants. MUFsg was also higher for White, non-Hispanic participants than for Black, non-Hispanic participants in trimester three, and for those with graduate training in trimester one. MUFsg was negatively associated with blood mercury in trimester one and positively associated with blood lead in trimester three. MUFsg was positively associated with various urinary metals, including antimony, barium, cadmium, cobalt, copper, lead, nickel, tin, and zinc in trimesters one and/or three. Conclusions MUFsg levels observed were comparable to those found in pregnant women in Mexico and Canada that have been associated with poorer neurodevelopmental outcomes. Lower urinary fluoride levels among Hispanic and non-Hispanic Black participants in MADRES compared to non-Hispanic White participants may reflect lower tap water consumption or lower fluoride exposure from other sources. Additional research is needed to examine whether MUFsg levels observed among pregnant women in the US are associated with neurodevelopmental outcomes.

Abstract Background To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood. Methods We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo. Results We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apc fl/fl mice in vivo. Conclusions Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

This study evaluates the R3THA™ assessment protocol (R3THA-AP™), a technology-supported testing module for personalized rehabilitation in children with cerebral palsy (CP). It focuses on the reliability and validity of the R3THA-AP in assessing hand and arm function, by comparing kinematic assessments with standard clinical assessments. Conducted during a 4-week summer camp, the study assessed the functional and impairment levels of children with CP aged 3–18. The findings suggest that R3THA is more reliable for children aged 8 and older, indicating that age significantly influences the protocol’s effectiveness. The results also showed that the R3THA-AP’s kinematic measurements of hand and wrist movements are positively correlated with the Box and Blocks Test Index (BBTI), reflecting hand function and dexterity. Additionally, the R3THA-AP’s accuracy metrics for hand and wrist activities align with the Melbourne Assessment 2’s Range of Motion (MA2-ROM) scores, suggesting a meaningful relationship between R3THA-AP data and clinical assessments of motor skills. However, no significant correlations were observed between the R3THA-AP and MA2’s accuracy and dexterity measurements, indicating areas for further research. These findings validate the R3THA-AP’s utility in assessing motor abilities in CP patients, supporting its integration into clinical practice.

Objective Map multimorbidity-weighted index (MWI) conditions to International Classification of Diseases, 10th Revision (ICD-10), expand the conditions and codes to develop a new ICD-10-coded MWI (MWI-ICD10) and updated MWI-ICD9, and assess their consistency.Design Population-based retrospective cohort.Setting Large medical centre between 2013 and 2017.Participants Adults ≥18 years old with encounters in each of 4 years (2013, 2014, 2016, 2017).Main outcome measures MWI conditions mapped to ICD-10 codes, and additional conditions and codes added to produce a new MWI-ICD10 and updated MWI-ICD9. We compared the prevalence of ICD-coded MWI conditions within the ICD-9 era (2013–2014), within the ICD-10 era (2016–2017) and across the ICD-9–ICD-10 transition in 2015 (washout period) among adults present in both sets of comparison years. We computed the prevalence and change in prevalence of conditions when using MWI-ICD10 versus MWI-ICD9.Results 88 175 adults met inclusion criteria. Participants were 60.8% female, 50.5% white, with mean age 54.7±17.3 years and baseline MWI-ICD9 4.47±6.02 (range 0–64.33). Of 94 conditions, 65 had

Objective Long-term chikungunya disease is characterised by persistent rheumatic symptoms following chikungunya virus infection. As there is no specific treatment available, affected individuals need strategies to adapt. However, research on these is scarce. This study aimed to explore which adaptive coping strategies are employed to manage persistent rheumatic symptoms in daily life.Setting The study was conducted in Curaçao.Design and participants An explorative qualitative study was conducted between September and October 2020, among a purposive sample of adults, 19 women and 4 men affected by long-term chikungunya disease. In-depth interviews were semi-structured and transcribed verbatim. The data were analysed using inductive thematic analysis.Results The disease duration for all participants ranged between 68 and 74 months (6 years). In narrating their experiences of coping with long-term chikungunya disease, four themes were identified: (1) learning to live with the disease; (2) resilience for dealing with pain; (3) maintaining positive self-image and attitude; and (4) coping through spirituality.Conclusion To live with long-term chikungunya disease with dignity in spite of physical pain and discomfort, participants tried to retain a sense of control of oneself and one’s lives, to not let the disease take over, focusing on the positive in their lives, and finding strength and remain hopeful. Interventions such as cognitive–behavioural therapy and mindfulness exercises may be effective in strengthening or regain affected individual’s sense of competence and control by fostering adaptive coping skills and resilience. Subsequently, these interventions may improve health-related quality of life when rheumatic symptoms persist following chikungunya virus infection.

Alcohol use is a risk factor for death and disability and is attributed to almost one-third of injury deaths globally. This highlights the need for interventions aimed at alcohol reduction, especially in areas with high rates of injury with concurrent alcohol use, such as Tanzania. The aim of this study is to create a culturally appropriate text messages as a booster to a brief negotiational intervention (BNI), to in the Emergency Department of the Kilimanjaro Christian Medical Centre, Moshi, Tanzania. Creation of text message boosters for an ED-based intervention expands the window of opportunity for alcohol use reduction in this high-risk population. The study followed a two-step approach to create the text message content in English and then translate and culturally adapt to Tanzanian Swahili. The culturalization process followed the World Health Organization's process of translation and adaptation of instruments. Translation, back translation, and qualitative focus groups were used for quality control to ensure text message content accuracy and cultural appropriateness. In total, nearly 50 text messages were initially developed in English, yet only 29 text messages were successfully translated and adapted; they were focused on the themes of Self-awareness, Goal setting and Motivation. We developed culturally appropriate text message boosters in Swahili for injury patients in Tanzania coupled with a BNI for alcohol use reduction. We found it important to evaluate content validation for interventions and measurement tools because the intended text message can often be lost in translation. The process of culturalization is critical in order to create interventions that are applicable and beneficial to the target population. Trial registration: Clinical Trials Registration Number: NCT02828267, NCT04535011.

Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that has a recognized role in cancer prevention as well as evidence to support its use as an adjuvant for cancer treatment. Importantly there has been an increasing number of studies contributing to the mechanistic understanding of aspirins’ anti-tumour effects and these studies continue to inform the potential clinical use of aspirin for both the prevention and treatment of cancer. This review focuses on the emerging role of aspirin as a regulator of metabolic reprogramming, an essential “hallmark of cancer” required to support the increased demand for biosynthetic intermediates needed for sustained proliferation. Cancer cells frequently undergo metabolic rewiring driven by oncogenic pathways such as hypoxia-inducible factor (HIF), wingless-related integration site (Wnt), mammalian target of rapamycin (mTOR), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB), which supports the increased proliferative rate as tumours develop and progress. Reviewed here, cellular metabolic reprogramming has been identified as a key mechanism of action of aspirin and include the regulation of key metabolic drivers, the regulation of enzymes involved in glycolysis and glutaminolysis, and altered nutrient utilisation upon aspirin exposure. Importantly, as aspirin treatment exposes metabolic vulnerabilities in tumour cells, there is an opportunity for the use of aspirin in combination with specific metabolic inhibitors in particular, glutaminase (GLS) inhibitors currently in clinical trials such as telaglenastat (CB-839) and IACS-6274 for the treatment of colorectal and potentially other cancers. The increasing evidence that aspirin impacts metabolism in cancer cells suggests that aspirin could provide a simple, relatively safe, and cost-effective way to target this important hallmark of cancer. Excitingly, this review highlights a potential new role for aspirin in improving the efficacy of a new generation of metabolic inhibitors currently undergoing clinical investigation.

Objective. This study aimed to describe and critically evaluate the COVID-19 vaccination program for high-risk children in Curacao and provide information about important factors such as parents’ vaccination hesitancy and effective strategies for communicating and delivering information about vaccination. Methods. This was a cross-sectional study. It was important to identify children aged 12–17 years who were at high risk of severe COVID-19 infection because of the limited medical facilities on the island; children considered to be at high risk were those with diseases such as obesity, hypertension or diabetes mellitus type 2. These children or their caregivers were invited by their pediatricians to be vaccinated as part of a program run by the Public Health Department of Curacao. These high-risk patients were vaccinated between 30 May 2021 and 25 February 2022 in designated child-friendly spaces, with a pediatrician present for guidance and reassurance. Children received the Pfizer-BioNTech COVID-19 vaccine at the recommended dose for their age. The primary outcome was a description and evaluation of the attendance for vaccination. The secondary outcomes were side effects after vaccination for the age groups 12–15 years and 16–17 years. Reasons for refusal or nonadherence were also registered. Results. Altogether 51% (24/47) of those aged 16–17 years who were invited were vaccinated compared with 42% (26/69) of those aged 12–15 years who were invited. Altogether, 46% of these high-risk children were vaccinated compared with 48% of children aged 12–17 years without risk factors. In our population, most patients did not experience any side effects and if they did, the side effects were mild. No cases of myocarditis or pericarditis were observed. A lack of trust in the vaccine and a lack of prioritization of vaccination when scheduling daily activities were important factors in refusal and nonadherence. Conclusions. To organize a successful vaccination program in a small community with limited resources for treating high-risk children it is crucial for medical professionals to provide reliable information. Public health initiatives should focus on assuaging parents’ fears about vaccines. In addition, ensuring there is good cooperation between doctors and the Public Health Department can help to make implementation successful. Finally, involving pediatricians and using dedicated areas for vaccinating children can help build trust with parents and caregivers.

In North America, some moose populations are declining, and meningeal worm (Parelaphostrongylus tenuis) infections may be contributing. Moose are aberrant hosts for meningeal worm and develop severe pathology whereas white-tailed deer (WTD) are definitive hosts that experience minimal pathology and spread parasite larvae into the environment. Analyses of harvested WTD heads confirmed meningeal worm in Western Manitoba, Canada including in areas where moose have experienced population declines and are currently of management concern. The prevalence of larval meningeal worm from WTD feces in these areas are unknown, particularly because the dorsal-spined larvae (DSL) are morphologically indistinguishable from muscle worm (Parelaphostrongylus andersoni). To assess transmission risk of DSL, we investigated the spatial and temporal variation of prevalence in WTD feces from four areas (two with historical moose population declines and two without) sampled across two summers. We predicted higher prevalence of DSL in areas where moose are of management concern and surveys have shown higher meningeal worm prevalence in WTD heads. Further, we expected to only recover meningeal worm, as muscle worm has only been reported from caribou in more northern areas of Manitoba. We collected WTD feces by transect sampling, used the Baermann technique to obtain larvae, and sequenced partial cytochrome oxidase 1 and internal transcribed spacer 2 genes to confirm species identity. Zero-inflated models revealed that DSL prevalence did not differ temporally but was higher in areas where moose are of management concern. Genetic analyses revealed that meningeal worm and muscle worm were both present in Western Manitoba and co-occurred in three areas. Our results reveal novel insights into the geographic distribution of muscle worm and emphasize the importance of DNA sequencing for DSL identification. We suggest that concern for moose populations is warranted given the increased risk of parasite infection in some management areas.

Abstract SARS-CoV-2 belongs to the family Coronaviridae which includes multiple human pathogens that have an outsized impact on aging populations. As a novel human pathogen, SARS-CoV-2 is undergoing continuous adaptation to this new host species and there is evidence of this throughout the scientific and public literature. However, most investigations of SARS-CoV-2 evolution have focused on large-scale collections of data across diverse populations and/or living environments. Here we investigate SARS-CoV-2 evolution in epidemiologically linked individuals within a single outbreak at a skilled nursing facility beginning with initial introduction of the pathogen. The data demonstrate that SARS-CoV-2 was introduced to the facility multiple times without establishing an interfacility transmission chain, followed by a single introduction that infected many individuals within a week. This large-scale introduction by a single genotype then persisted in the facility. SARS-CoV-2 sequences were investigated at both the consensus and intra-host variation levels. Understanding the variability in SARS-CoV-2 during transmission chains will assist in understanding the spread of this disease and can ultimately inform best practices for mitigation strategies.

Flavored e-cigarettes are a popular alternative to cigarette smoking; unfortunately, the extrapulmonary effects are not well-characterized. Human proximal tubule cells were cultured for 24 or 48 h with 0–1000 µM ethyl vanillin (ETH VAN) and cytotoxicity evaluated. Mitochondrial health was significantly diminished following 48 h of exposure, accompanied by significantly decreased spare capacity, coupling efficiency, and ATP synthase expression. ETH VAN at 24 h inhibited glycolysis. The endoplasmic reticulum (ER) stress marker C/EBP homologous protein (CHOP) was increased at 100 μM relative to 500–1000 μM. The downstream proapoptotic marker cleaved caspase-3 subsequently showed a decreasing trend in expression after 48 h of exposure. The autophagy biomarkers microtubule-associated proteins 1A/1B light chain 3 (LC3B-I and LC3B-II) were measured by Western blot. LC3B-II levels and the LC3B-II/LC3B-I ratio increased at 24 h, which suggested activation of autophagy. In contrast, by 48 h, the autophagy biomarker LC3B-II decreased, resulting in no change in the LC3B-II/LC3B-I ratio. Mitophagy biomarker PTEN-induced putative kinase 1 (PINK1) expression decreased after 48 h of exposure. The downstream marker Parkin was not significantly changed after 24 or 48 h. These findings indicate that the flavoring ETH VAN can induce energy pathway dysfunction and cellular stress responses in a renal model.

Current conceptualizations of dental caries etiology center primarily on the local role of sugar, starch, or other fermentable carbohydrates on tooth enamel demineralization—a well-established and empirically supported mechanism. However, in addition to this mechanism, studies dating back to the early 1900s point to an important systemic role of diet and nutrition, particularly from pasture-raised animal-source foods (ASF), in dental caries etiology and arrest. Findings from animal and human studies suggest that adherence to a diet high in calcium, phosphorus, fat-soluble vitamins A and D, and antioxidant vitamin C, as well as low in phytates, may contribute to arrest and reversal of dental caries, particularly among children. Furthermore, findings from observational and experimental studies of humans across the life-course suggest that fat-soluble vitamins A, D, and K2 may interact to protect against dental caries progression, even within a diet that regularly contains sugar. While these historic studies have not been revisited in decades, we emphasize the need for them to be reinvestigated and contextualized in the 21st century. Specifically, methodologically rigorous studies are needed to reinvestigate whether historical knowledge of systemic impacts of nutrition on dental health can help to inform current conceptualizations of dental caries etiology, prevention, and arrest.

Childhood overweight and obesity is a worldwide problem and to treat it parents’ detection has to be improved. The MapMe Body Image Scales (BIS) are a visual tool developed to improve parental perception of child weight in the United Kingdon (UK) based on British growth reference criteria. The aim of this study was to make a transcultural adaptation and validation of the MapMe BIS in Spain based on International Obesity Task Force (IOTF) cut offs A descriptive cross-sectional study was done. First, a translation and cultural adaptation was carried out. A total of 155 10–11-year-old children and their parents participated in this study. Children were measured to calculate their weight status, Body Mass Index (BMI), Body Fat Percentage (BFP) and Waist Circumference (WC), and their parents completed a purpose designed questionnaire about their perception and satisfaction of child’s body weight status using the adapted BIS. Test-retest reliability, criterion validity and concurrent validity of the adapted BIS were analyzed. This study shows that the adapted MapMe BIS has good psychometric properties and is a suitable visual scale to assess parental perception of weight status in 10 and 11-year-old children in Spain.

A recent meta-analysis reveals almost half of autistic individuals experience some form of victimization in their lifetime, including bullying and other forms of stigma. Research among caregivers of autistic individuals demonstrates that stigma can have a long-lasting impact on other aspects of a social identity, such as self-esteem, but less research has specifically examined this among autistic adults themselves, in spite of research suggesting these are likely constructs that contribute to the internalization of stigma and subsequent mental health consequences. The current study used a mixed method approach to assess the relation between stigma and several components of social identity and social functioning. More specifically, among 45 autistic young adults, three dimensions of self-reported stigma (discrimination, disclosure, and positive aspects) were examined in relation to self-esteem, self-efficacy, social satisfaction and adaptive social functioning. Quantitative analyses revealed higher reported discriminative and disclosure stigma were significantly associated with lower self-efficacy. Increased experience with all types of stigma were associated with lower social satisfaction. Greater reported disclosure stigma was also associated with lower self-esteem. Qualitative interviewing among eight autistic young adults helped to better understand the nature of stigma and the impact of these experiences. Thematic analysis of the qualitative data revealed that all of the participants experienced stigma in the form of exclusion or isolation and that a majority also experienced verbal bullying. Many of the negative interactions came from educators, peers, and family members. Most participants indicated that these stigmatizing interactions directly contributed to decreased social satisfaction, diminished self-efficacy, and lowered self-esteem. A greater understanding of the negative consequences of stigma can inform efforts to increase awareness and acceptance of autism.

Kainate receptors (KARs) are key regulators of neuronal excitability and synaptic transmission. KAR surface expression is tightly controlled in part by post-translational modifications (PTMs) of the GluK2 subunit. We have shown previously that agonist activation of GluK2-containing KARs leads to phosphorylation of GluK2 at S868, which promotes subsequent SUMOylation at K886 and receptor endocytosis. Furthermore, GluK2 has been shown to be palmitoylated. However, how the interplay between palmitoylation, phosphorylation and SUMOylation orchestrate KAR trafficking remains unclear. Here, we used a library of site-specific GluK2 mutants to investigate the interrelationship between GluK2 PTMs, and their impact on KAR surface expression. We show that GluK2 is basally palmitoylated and that this is decreased by kainate (KA) stimulation. Moreover, a non-palmitoylatable GluK2 mutant (C858/C871A) shows enhanced S868 phosphorylation and K886 SUMOylation under basal conditions and is insensitive to KA-induced internalisation. These results indicate that GluK2 palmitoylation contributes to stabilising KAR surface expression and that dynamic depalmitoylation promotes downstream phosphorylation and SUMOylation to mediate activity-dependent KAR endocytosis.

Background: Idaho, a predominately rural state, has a high prevalence of mental illness with minimal access to care. Barriers in diagnosis and treatment of pediatric behavioral health disorders could be mitigated with an accessible and effective specialty training program. Methods: A 10-session Project Extension for Community Health Outcomes (ECHO) series was designed to expand provider knowledge about pediatric behavioral health conditions and improve perceived clinical practice skills. Pre- and postseries evaluation surveys and individual session evaluations were used to assess the program. Results: A total of 148 individuals attended at least 1 of the 10 sessions. Participants reported high satisfaction with individual sessions and indicated that attendance positively impacted their knowledge and competency. Participants also reported that the knowledge and skills gained from the series would benefit more than half of their patients or clients. Conclusion: The short ECHO series appears to be a viable and valuable option to provide Idaho providers with effective specialty training that is well attended and well received.

Abstract Purpose To determine if the COVID‐19 pandemic has further exacerbated racial disparities in late‐stage presentation of breast, colorectal, lung, and prostate cancers. Methods We conducted a registry‐based retrospective study of patients with newly reported diagnoses of breast, colorectal, lung, and prostate cancers between March 2019–June 2019 (pre‐COVID‐19) and March 2020–June 2020 (early‐COVID‐19). We compared the volume of new diagnoses and stage at presentation according to race between both periods. Results During the study period, a total of 3528 patients had newly diagnosed cancer; 3304 of which had known disease stages and were included in the formal analyses. 467 (14.1%) were Blacks, and 2743 were (83%) Whites. 1216 (36.8%) had breast, 415 (12.6%) had colorectal, 827 (25%) had lung, and 846 (25.6%) had prostate cancers, respectively. The pre‐COVID‐19 period included 2120 (64.2%), and the early‐COVID‐19 period included 1184 (35.8%), representing a proportional 44.2% decline in the volume of new cases of breast, colorectal, lung, and prostate cancers, p

Abstract Proper wiring of the peripheral nervous system relies on neurotrophic signaling via nerve growth factor (NGF). NGF secreted by target organs (i.e. eye) binds to the TrkA receptor expressed on the distal axons of postganglionic neurons. Upon binding, TrkA is internalized into a signaling endosome and retrogradely trafficked back to the soma and into the dendrites to promote cell survival and postsynaptic maturation, respectively. Much progress has been made in recent years to define the fate of the retrogradely trafficked TrkA signaling endosome, yet it has not been fully characterized. Here we investigate extracellular vesicles (EVs) as a novel route of neurotrophic signaling. Using the mouse superior cervical ganglion (SCG) as a model, we isolate EVs derived from sympathetic cultures and characterize them using immunoblot assays, nanoparticle tracking analysis, and cryo-electron microscopy. Furthermore, using a compartmentalized culture system, we find that TrkA derived from endosomes originating in the distal axon can be detected on EVs secreted from the somatodendritic domain. In addition, inhibition of classic TrkA downstream pathways, specifically in somatodendritic compartments, greatly decreases TrkA packaging into EVs. Our results suggest a novel trafficking route for TrkA: it can travel long distances to the cell body, be packaged into EVs, and be secreted. Secretion of TrkA via EVs appears to be regulated by its own downstream effector cascades, raising intriguing future questions about novel functionalities associated with TrkA+ EVs.

Abstract Background The popular statistics-based Genome-wide association studies (GWAS) have provided deep insights into the field of complex disorder genetics. However, its clinical applicability to predict disease/trait outcomes remains unclear as statistical models are not designed to make predictions. This study employs statistics-free machine-learning (ML)-optimized polygenic risk score (PRS) to complement existing GWAS and bring the prediction of disease/trait outcomes closer to clinical application. Rheumatoid Arthritis (RA) was selected as a model disease to demonstrate the robustness of ML in disease prediction as RA is a prevalent chronic inflammatory joint disease with high mortality rates, affecting adults at the economic prime. Early identification of at-risk individuals may facilitate measures to mitigate the effects of the disease. Methods This study employs a robust ML feature selection algorithm to identify single nucleotide polymorphisms (SNPs) that can predict RA from a set of training data comprising RA patients and population control samples. Thereafter, selected SNPs were evaluated for their predictive performances across 3 independent, unseen test datasets. The selected SNPs were subsequently used to generate PRS which was also evaluated for its predictive capacity as a sole feature. Results Through robust ML feature selection, 9 SNPs were found to be the minimum number of features for excellent predictive performance (AUC > 0.9) in 3 independent, unseen test datasets. PRS based on these 9 SNPs was significantly associated with (P 0.9) of RA in the 3 unseen datasets. A RA ML-PRS calculator of these 9 SNPs was developed ( https://xistance.shinyapps.io/prs-ra/ ) to facilitate individualized clinical applicability. The majority of the predictive SNPs are protective, reside in non-coding regions, and are either predicted to be potentially functional SNPs (pfSNPs) or in high linkage disequilibrium (r2 > 0.8) with un-interrogated pfSNPs. Conclusions These findings highlight the promise of this ML strategy to identify useful genetic features that can robustly predict disease and amenable to translation for clinical application.

The biochemistry underlying seed coat darkening of lentil due to extended storage is limited. This study investigated the relationship between seed coat darkening over time during storage and changes in concentration of phenolic compounds (total phenolic compounds, total condensed tannins, proanthocyanidins and anthocyanins) in two red lentil cultivars (PBA Hallmark and PBA Jumbo2), stored at two grain moisture contents (10 and 14%, w/w) and two temperatures (4 and 35 °C) for 360 days. Seed coat darkening was only significant (p = 0.05) at high temperatures (35 °C) but not at low temperatures (4 °C), irrespective of grain moisture content and cultivar. The concentration of all phenolic compounds tested in this study reduced significantly (p = 0.05) throughout the study period, regardless of temperature and grain moisture treatments. The changes in seed coat brightness and redness followed a linear pattern, except for yellowness, where phenolic compounds initially reduced linearly and then remained constant thereafter. Darkening of seedcoat was only associated with the reduction in phenolic compounds tested in this study at 35 °C, and not at 4 °C. This suggests that seed coat darkening due to extended storage may not be directly linked to broad reductions in the groups of phenolic compounds or individual compounds assessed in this study. This information prompts further research to identify the actual biochemical processes that cause the darkening of seed coats during storage and assist in developing cultivars with stable seed coat colour by selecting and modifying such processes.

This article offers an examination of the lives of wives and partners of collegiate basketball coaches, employing the Bronfenbrenner Ecological model as a framework for analysis. While the world of sports coaching is routinely celebrated and scrutinized, the experiences and challenges faced by the wives and/or partners of these coaches remain relatively unexplored. This paper reviews the diverse systems influencing the lives of coaches’ partners and the need for holistic support mechanisms. By employing the Coaches’ Wives and Partners Adapted Bronfenbrenner Model as a conceptual framework, researchers, counselors and other helpers, and support networks can gain a deeper understanding of the complex dynamics at play and can offer more effective assistance to coaches’ partners as they navigate the unique challenges and opportunities associated with their role in the basketball world. Implications for the NCAA, universities/athletic departments, coaches, and coaches’ wives and partners are addressed.

This study presents an explanatory biophysical model developed and validated to simulate seed coat colour traits including CIE L*, a*, and b* changes over time for stored lentil cultivars PBA Hallmark, PBA Hurricane, PBA Bolt, and PBA Jumbo2 under diverse storage conditions. The model showed robust performance for all cultivars, with R2 values ≥ 0.89 and RMSE values ≤ 0.0019 for all seed coat colour traits. Laboratory validation at 35 °C demonstrated a high agreement (Lin’s Concordance Correlation Coefficient, CCC ≥ 0.82) between simulated and observed values of all colour traits for PBA Jumbo2 and strong agreement (CCC ≥ 0.81) for PBA Hallmark in brightness (CIE L*) and redness (CIE a*), but not in yellowness (CIE b*). At 15 °C, both cultivars exhibited moderate to weak agreement between simulated and observed values of all colour traits (CCC ≤ 0.47), as very little change was recorded in the observed values over the 360 days of storage. Bulk storage system validation for PBA Hallmark showed moderate performance (CCC ≥ 0.46) between simulated and observed values of all colour traits. Modelling to simulate changes in seed coat colour traits of lentils over time will equip growers and traders to make informed managerial decisions when storing lentils for long periods.

Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed.

Immunocompetence and reproduction are among the most important determinants of fitness. However, energetic and metabolic constraints create conflict between these two life-history traits. While many studies have explored the relationship between immune activity and reproductive fitness in birds and mammals inoculated with bacterial endotoxin, very few have focused on fish. Fish have been neglected in this area due, in part, to the claim that they are largely resistant to the immune effects of endotoxins. However, the present study suggests that they are susceptible to significant effects with respect to reproductive behaviour. Here, we examined the reproductive behaviour of male guppies following exposure to bacterial lipopolysaccharides (LPS) in comparison to that of male guppies in a control treatment. Additionally, we investigated the responses of females to these males. We show that although immune challenge does not suppress general activity in male guppies, it significantly reduces mating effort. While females showed no difference in general activity as a function of male treatments, they did exhibit reduced group cohesion in the presence of LPS-exposed males. We discuss this in the context of sickness behaviours, social avoidance of immune-challenged individuals and the effects of mounting an immune response on reproductive behaviour.

# Background The International Knee Document Committee Subjective Knee Form (IKDC-SKF) is a patient-reported outcome measure used in orthopedics and sports medicine. Further psychometric assessment is necessary to confirm measurement properties in a large, heterogenous sample. # Purpose The purpose of the study was to assess the psychometric properties of the IKDC-SKF in a large, heterogenous sample. # Study Design Cross-Sectional Study # Methods An exploratory factor analysis (EFA) was conducted to identify a sound latent structure and to assess internal consistency in a large sample of patients who underwent knee arthroscopy. A confirmatory factor analysis (CFA) was conducted to confirm structural validity. Multi-group invariance was conducted to assess factorial stability across sex and age groups, while longitudinal invariance procedures were performed to assess stability over time. # Results A 3-factor, 9-item IKDC-SKF short form was identified with EFA procedures. The model was confirmed with CFA (CFI = 0.983; TLI = 0.975; IFI = 0.983; RMSEA = 0.057), while a sound 2-factor, 6-item model was also identified (CFI = 1.0; TLI = 0.999; IFI = 1.0; RMSEA = 0.11). The 9-item IKDC-SKF short form was invariant across groups but not time; removal of a single item (i.e., 8-item IKDC-SKF short form) resulted in longitudinal invariance. The 6-item IKDC-SKF short form was invariant across groups and time. # Conclusion The 6-item, 8-item, and 9-item short form versions of the IKDC-SKF exceed contemporary fit recommendations and present as plausible alternatives to the IKDC-SKF with improved measurement properties, reduced scale response burden, and evidence of multi-group and longitudinal invariance. Further, the 6- and 8-item IKDC-SKF short forms may be used to assess group differences or change across time. # Level of evidence here Level 3

BackgroundMany individuals undergoing cancer treatment experience substantial financial hardship, often referred to as financial toxicity (FT). Those undergoing prostate cancer treatment may experience FT and its impact can exacerbate disparate health outcomes. Localized prostate cancer treatment options include: radiation, surgery, and/or active surveillance. Quality of life tradeoffs and costs differ between treatment options. In this project, our aim was to quantify direct healthcare costs to support patients and clinicians as they discuss prostate cancer treatment options. We provide the transparent steps to estimate healthcare costs associated with treatment for localized prostate cancer among the privately insured population using a large claims dataset.MethodsTo quantify the costs associated with their prostate cancer treatment, we used data from the Truven Health Analytics MarketScan Commercial Claims and Encounters, including MarketScan Medicaid, and peer reviewed literature. Strategies to estimate costs included: (1) identifying the problem, (2) engaging a multidisciplinary team, (3) reviewing the literature and identifying the database, (4) identifying outcomes, (5) defining the cohort, and (6) designing the analytic plan. The costs consist of patient, clinician, and system/facility costs, at 1-year, 3-years, and 5-years following diagnosis.ResultsWe outline our specific strategies to estimate costs, including: defining complex research questions, defining the study population, defining initial prostate cancer treatment, linking facility and provider level related costs, and developing a shared understanding of definitions on our research team.Discussion and next stepsAnalyses are underway. We plan to include these costs in a prostate cancer patient decision aid alongside other clinical tradeoffs.

Purpose: The feasibility of blinding applications for a medical physics residency program has yet to be demonstrated in the literature. We explore the application of an automated approach with human review and intervention to blind applications during the annual medical physics residency review cycle. Methods and Materials: Applications were blinded using an automated process and used for the first phase of residency review in the program. We retrospectively compared self-reported demographic and gender data with blinded and nonblinded cohorts from 2 sequential years of review from a medical physics residency program. Demographic data were analyzed comparing applicants with candidates selected to move to the next phase of the review process. Interrater agreement was also evaluated from the applicant reviewers. Results: We show the feasibility of blinding applications for a medical physics residency program. We observed no more than a 3% difference between the gender selection within the first phase of application review but greater differences when examining race and ethnicity between the 2 methods. The greatest difference was shown to be between Asian and White candidates, where there are statistical differences in the scores in the rubric categories of essay and overall impression. Conclusions: We suggest that each training program critically evaluate its selection criteria for potential sources of bias within the review process. We recommend further critical investigation of processes to promote equity and inclusion to ensure the methods and outcomes are aligned with the mission of the program. Finally, we recommend that the common application provide an option for blinding applications at the source so this can be an option to facilitate efforts for evaluating unconscious bias in the review process.

Abstract Background Amongst risk alleles associated with late-onset Alzheimer’s disease (AD), those that converged on the regulation of microglia activity have emerged as central to disease progression. Yet, how canonical amyloid-β (Aβ) and tau pathologies regulate microglia subtypes during the progression of AD remains poorly understood. Methods We use single-cell RNA-sequencing to profile microglia subtypes from mice exhibiting both Aβ and tau pathologies across disease progression. We identify novel microglia subtypes that are induced in response to both Aβ and tau pathologies in a disease-stage-specific manner. To validate the observation in AD mouse models, we also generated a snRNA-Seq dataset from the human superior frontal gyrus (SFG) and entorhinal cortex (ERC) at different Braak stages. Results We show that during early-stage disease, interferon signaling induces a subtype of microglia termed Early-stage AD-Associated Microglia (EADAM) in response to both Aβ and tau pathologies. During late-stage disease, a second microglia subtype termed Late-stage AD-Associated Microglia (LADAM) is detected. While similar microglia subtypes are observed in other models of neurodegenerative disease, the magnitude and composition of gene signatures found in EADAM and LADAM are distinct, suggesting the necessity of both Aβ and tau pathologies to elicit their emergence. Importantly, the pattern of EADAM- and LADAM-associated gene expression is observed in microglia from AD brains, during the early (Braak II)- or late (Braak VI/V)- stage of the disease, respectively. Furthermore, we show that several Siglec genes are selectively expressed in either EADAM or LADAM. Siglecg is expressed in white-matter-associated LADAM, and expression of Siglec-10, the human orthologue of Siglecg, is progressively elevated in an AD-stage-dependent manner but not shown in non-AD tauopathy. Conclusions Using scRNA-Seq in mouse models bearing amyloid-β and/or tau pathologies, we identify novel microglia subtypes induced by the combination of Aβ and tau pathologies in a disease stage-specific manner. Our findings suggest that both Aβ and tau pathologies are required for the disease stage-specific induction of EADAM and LADAM. In addition, we revealed Siglecs as biomarkers of AD progression and potential therapeutic targets.

Abstract Using exome sequencing for biomarker discovery and precision medicine requires connecting nucleotide-level variation with functional changes in encoded proteins. However, for functionally annotating the thousands of cancer-associated missense mutations, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and functional analysis is cost-prohibitive and inefficient. We describe parallel functional annotation (PFA) of large numbers of VUS using small cultures and crude extracts in 96-well plates. Using members of a histone methyltransferase family, we demonstrate high-throughput structural and functional annotation of cancer-associated mutations. By combining functional annotation of paralogs, we discovered two phylogenetic and clustering parameters that improve the accuracy of sequence-based functional predictions to over 90%. Our results demonstrate the value of PFA for defining oncogenic/tumor suppressor functions of histone methyltransferases as well as enhancing the accuracy of sequence-based algorithms in predicting the effects of cancer-associated mutations.