Perspectives of an NCI T32 Training Program Designed to Train a Diverse Workforce in Cancer Health Equity Research.

With cancer health disparities on the rise in the United States (USA), there is an increased need for novel approaches to address these challenges. One such approach that may help address these disparities is increasing diversity in the biomedical research workforce. The Cancer Health Equity and Career Development Program (CHECDP) embodies this approach by recruiting and training underrepresented minorities in cancer research to develop the skills and training needed to be competitive for independent research careers, thus diversifying the biomedical research workforce. The training model that CHECDP employs is unique with its funding through the NCI training mechanism, its strong institutional support, and its participant-driven curriculum. The curriculum includes educational, career, and leadership opportunities that are continuously evaluated for sustained impact. The program has been comprised of mostly under-represented minorities that have been propelled to independent careers with a high rate of funded career development awards. Our T32 program serves as a model of success for other programs seeking to diversify the biomedical research workforce and reduce cancer health disparities.

Variation in forest root image annotation by experts, novices, and AI.

BACKGROUND: The manual study of root dynamics using images requires huge investments of time and resources and is prone to previously poorly quantified annotator bias. Artificial intelligence (AI) image-processing tools have been successful in overcoming limitations of manual annotation in homogeneous soils, but their efficiency and accuracy is yet to be widely tested on less homogenous, non-agricultural soil profiles, e.g., that of forests, from which data on root dynamics are key to understanding the carbon cycle. Here, we quantify variance in root length measured by human annotators with varying experience levels. We evaluate the application of a convolutional neural network (CNN) model, trained on a software accessible to researchers without a machine learning background, on a heterogeneous minirhizotron image dataset taken in a multispecies, mature, deciduous temperate forest. RESULTS: Less experienced annotators consistently identified more root length than experienced annotators. Root length annotation also varied between experienced annotators. The CNN root length results were neither precise nor accurate, taking ~ 10% of the time but significantly overestimating root length compared to expert manual annotation (p = 0.01). The CNN net root length change results were closer to manual (p = 0.08) but there remained substantial variation. CONCLUSIONS: Manual root length annotation is contingent on the individual annotator. The only accessible CNN model cannot yet produce root data of sufficient accuracy and precision for ecological applications when applied to a complex, heterogeneous forest image dataset. A continuing evaluation and development of accessible CNNs for natural ecosystems is required.

Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity.

BACKGROUND: Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO and genome-wide association studies (GWAS) have highlighted the polygenicity of this adverse drug reaction. Polygenic scores (PGS), which integrate information from multiple genetic variants across the genome, offer a promising tool for the identification of individuals who are at higher risk for CIO. Integrating large-scale hearing loss GWAS data with single cell omics data holds potential to overcome limitations related to small sample sizes associated with CIO studies, enabling the creation of PGSs to predict CIO risk. RESULTS: We utilized a large-scale hearing loss GWAS and murine inner ear single nuclei RNA-sequencing (snRNA-seq) data to develop two polygenic scores: a hearing loss PGS (PGSHL) and a biologically informed PGS for CIO (PGSCIO). The PGSCIO included only variants which mapped to genes that were differentially expressed within cochlear cells that showed differential abundance in the murine snRNA-seq data post-cisplatin treatment. Evaluation of the association of these PGSs with CIO in our target CIO cohort revealed that PGSCIO demonstrated superior performance (P = 5.54 × 10- 5) relative to PGSHL (P = 2.93 × 10- 3). PGSCIO was also associated with CIO in our test cohort (P = 0.04), while the PGSHL did not show a significant association with CIO (P = 0.52). CONCLUSION: This study developed the first PGS for CIO using a large-scale hearing loss dataset and a biologically informed filter generated from cisplatin-treated murine inner ear snRNA-seq data. This innovative approach offers new avenues for developing PGSs for pharmacogenomic traits, which could contribute to the implementation of tailored therapeutic interventions. Further, our approach facilitated the identification of specific cochlear cells that may play critical roles in CIO. These novel insights will guide future research aimed at developing targeted therapeutic strategies to prevent CIO.

Input-specific localization of NMDA receptor GluN2 subunits in thalamocortical neurons.

Molecular and functional diversity among synapses is generated, in part, by differential expression of neurotransmitter receptors and their associated protein complexes. N-methyl-D-aspartate receptors (NMDARs) are tetrameric ionotropic glutamate receptors that most often comprise two GluN1 and two GluN2 subunits. NMDARs generate functionally diverse synapses across neuron populations through cell-type-specific expression patterns of GluN2 subunits (GluN2A - 2D), which have vastly different functional properties and distinct downstream signaling. Diverse NMDAR function has also been observed at anatomically distinct inputs to a single neuron population. However, the mechanisms that generate input-specific NMDAR function remain unknown as few studies have investigated subcellular GluN2 subunit localization in native brain tissue. We investigated NMDAR synaptic localization in thalamocortical (TC) neurons expressing all four GluN2 subunits. Utilizing super resolution imaging and knockout-validated antibodies, we revealed subtype- and input-specific GluN2 localization at corticothalamic (CT) versus sensory inputs to TC neurons in 4-week-old male and female C57Bl/6J mice. GluN2B was the most abundant postsynaptic subunit across all glutamatergic synapses followed by GluN2A and GluN2C, and GluN2D was localized to the fewest synapses. GluN2B was preferentially localized to CT synapses over sensory synapses, while GluN2A and GluN2C were more abundant at sensory inputs compared to CT inputs. Furthermore, postsynaptic scaffolding proteins PSD95 and SAP102 were preferentially localized with specific GluN2 subunits, and SAP102 was more abundant at sensory synapses than PSD95. This work indicates that TC neurons exhibit subtype- and input-specific localization of diverse NMDARs and associated scaffolding proteins that likely contribute to functional differences between CT and sensory synapses.

The Role of Mandatory Reporting, Perpetrator and Violence Type, and Alcohol Consumption in Undergraduates' Likelihood of Disclosing Sexual Violence.

It remains unclear if mandatory reporting (MR) of sexual violence (SV) in universities impacts student reports of SV. MR may deter students from disclosing SV under certain circumstances (e.g., alcohol, perpetrator). This study evaluated students' likelihood of reporting SV under MR policy across perpetrators, violence, and alcohol use. Female students received instructional manipulations describing either confidential or mandatory reporting policies before reading four vignettes describing SV. They rated their likelihood of reporting each vignette. Significant differences arose across vignettes, conditions, and alcohol consumption. This indicates MR can significantly decrease reporting likelihood in some cases, while alcohol consumption may increase the likelihood.

Use of cannulated screws in the treatment of unicondylar humeral condylar fractures in dogs.

OBJECTIVE: To describe unicondylar humeral fracture (UHF) repair using cannulated transcondylar screws, report postoperative fracture reduction, healing, and complication rates. STUDY DESIGN: Retrospective. ANIMALS: A total of 49 client owned dogs with UHF. METHODS: Surgical technique and approach (i.e., open, limited open, or minimally invasive) were recorded. Articular step defect (ASD) and gap (Gap) at the humeral condylar articular surface were measured on pre- and postoperative images and reported as percentages. Fracture healing was graded on follow-up radiographs. Functional outcome was based on client questionnaire over the phone. General linear models were used to assess the impact of surgical approach on %ASD, %Gap, whereas Cox regression was used to assess prognostic factors of full fracture healing. RESULTS: A total of 49 fractures repaired with a transcondylar screw with or without an antirotational pin(s) were included. Surgical approach did not have an impact on postoperative %ASD, %Gap or development of complications. The overall complication rate was 26% (11/42), with no revision surgery necessary. Of the dogs that encountered complications, 50% required pin and/or screw removal after fracture healing. For 29 dogs with a minimum of four-month owner telephone questionnaire follow-up, 90% reported no lameness and only three reported intermittent lameness. Achieving complete fracture healing was affected by increased postoperative %ASD (p = .033). CONCLUSION: The UHFs repaired by transcondylar cannulated screws had acceptable outcomes and fracture reduction with complication rates being similar regardless of the surgical approach. CLINICAL SIGNIFICANCE: Cannulated screws can be implanted with varying surgical approaches to successfully repair UHFs with comparable clinical outcome to previous reports.

Selective induction of senescence in cancer cells through near-infrared light treatment via mitochondrial modulation.

Photobiomodulation, utilising non-ionising light in the visible and near-infrared (NIR) spectrum, has been suggested as a potential method for enhancing tissue repair, reducing inflammation and possibly mitigating cancer-therapy-associated side effects. NIR light is suggested to be absorbed intracellularly, mainly by chromophores within the mitochondria. This study examines the impact of 734 nm NIR light on cellular senescence. Cancer (MCF7 and A549) and non-cancer (MCF10A and IMR-90) cell populations were subjected to 63 mJ/cm2 NIR-light exposure for 6 days. Senescence levels were quantified by measuring active senescence-associated beta-galactosidase. Exposure to NIR light significantly increases senescence levels in cancer (10.0%-203.2%) but not in non-cancer cells (p > 0.05). Changes in senescence were associated with significant modulation of mitochondrial homeostasis, including increased levels of reactive oxygen species (p < 0.05) and mitochondrial membrane potential (p < 0.05) post-NIR-light treatment. These results suggest that NIR light modulates cellular chemistry, arresting the proliferation of cancer cells via senescence induction while sparing non-cancer cells.

An original study assessing biomarker success rate in breast cancer recurrence biomarker research.

BACKGROUND: Breast cancer is the second most common cause of cancer mortality worldwide. Biomarker discovery has led to advances in understanding molecular phenotyping and thus has a great potential for precision management of this diverse disease. Despite increased interest in the biomarker field, only a small number of breast cancer biomarkers are known to be clinically useful. Therefore, it is very important to characterise the success rate of biomarkers in this field and study potential reasons for the deficit. We therefore aim to achieve quantitative characterisation of the biomarker translation gap by tracking the progress of prognostic biomarkers associated with breast cancer recurrence. METHODS: An electronic systematic search was conducted in Medline and Embase databases using keywords and mesh headings associated with breast cancer recurrence biomarkers (1940-2023). Abstracts were screened, and primary clinical studies involving breast cancer recurrence biomarkers were selected. Upon identification of relevant literature, we extracted the biomarker name, date of publication and journal name. All analyses were performed using IBM SPSS Statistics and GraphPad prism (La Jolla, California, USA). RESULTS: A total of 19,195 articles were identified, from which 4597 articles reported breast cancer biomarkers associated with recurrence. Upon data extraction, 2437 individual biomarkers were identified. Out of these, 23 are currently recommended for clinical use, which corresponds to only 0.94% of all discovered biomarkers. CONCLUSIONS: This study characterised for the first time the translational gap in the field of recurrence-related breast cancer biomarkers, indicating that only 0.94% of identified biomarkers were recommended for clinical use. This denotes an evident barrier in the biomarker research field and emphasises the need for a clearer route from biomarker discovery through to implementation.

Antibody and siRNA Nanocarriers to Suppress Wnt Signaling, Tumor Growth, and Lung Metastasis in Triple-Negative Breast Cancer.

The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular ß-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, we developed therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and ß-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell-specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress ß-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.

A Plasmodium falciparum genetic cross reveals the contributions of pfcrt and plasmepsin II/III to piperaquine drug resistance.

Piperaquine (PPQ) is widely used in combination with dihydroartemisinin as a first-line treatment against malaria. Multiple genetic drivers of PPQ resistance have been reported, including mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and increased copies of plasmepsin II/III (pm2/3). We generated a cross between a Cambodia-derived multidrug-resistant KEL1/PLA1 lineage isolate (KH004) and a drug-susceptible Malawian parasite (Mal31). Mal31 harbors a wild-type (3D7-like) pfcrt allele and a single copy of pm2/3, while KH004 has a chloroquine-resistant (Dd2-like) pfcrt allele with an additional G367C substitution and multiple copies of pm2/3. We recovered 104 unique recombinant parasites and examined a targeted set of progeny representing all possible combinations of variants at pfcrt and pm2/3. We performed a detailed analysis of competitive fitness and a range of PPQ susceptibility phenotypes with these progenies, including PPQ survival assay, area under the dose response curve, and a limited point IC50. We find that inheritance of the KH004 pfcrt allele is required for reduced PPQ sensitivity, whereas copy number variation in pm2/3 further decreases susceptibility but does not confer resistance in the absence of additional mutations in pfcrt. A deep investigation of genotype-phenotype relationships demonstrates that progeny clones from experimental crosses can be used to understand the relative contributions of pfcrt, pm2/3, and parasite genetic background to a range of PPQ-related traits. Additionally, we find that the resistance phenotype associated with parasites inheriting the G367C substitution in pfcrt is consistent with previously validated PPQ resistance mutations in this transporter.IMPORTANCEResistance to piperaquine, used in combination with dihydroartemisinin, has emerged in Cambodia and threatens to spread to other malaria-endemic regions. Understanding the causal mutations of drug resistance and their impact on parasite fitness is critical for surveillance and intervention and can also reveal new avenues to limiting the evolution and spread of drug resistance. An experimental genetic cross is a powerful tool for pinpointing the genetic determinants of key drug resistance and fitness phenotypes and has the distinct advantage of quantifying the effects of naturally evolved genetic variation. Our study was strengthened since the full range of copies of KH004 pm2/3 was inherited among the progeny clones, allowing us to directly test the role of the pm2/3 copy number on resistance-related phenotypes in the context of a unique pfcrt allele. Our multigene model suggests an important role for both loci in the evolution of this multidrug-resistant parasite lineage.

Enhancing Gene Co-Expression Network Inference for the Malaria Parasite Plasmodium falciparum.

BACKGROUND: Malaria results in more than 550,000 deaths each year due to drug resistance in the most lethal Plasmodium (P.) species P. falciparum. A full P. falciparum genome was published in 2002, yet 44.6% of its genes have unknown functions. Improving the functional annotation of genes is important for identifying drug targets and understanding the evolution of drug resistance. RESULTS: Genes function by interacting with one another. So, analyzing gene co-expression networks can enhance functional annotations and prioritize genes for wet lab validation. Earlier efforts to build gene co-expression networks in P. falciparum have been limited to a single network inference method or gaining biological understanding for only a single gene and its interacting partners. Here, we explore multiple inference methods and aim to systematically predict functional annotations for all P. falciparum genes. We evaluate each inferred network based on how well it predicts existing gene-Gene Ontology (GO) term annotations using network clustering and leave-one-out crossvalidation. We assess overlaps of the different networks' edges (gene co-expression relationships), as well as predicted functional knowledge. The networks' edges are overall complementary: 47-85% of all edges are unique to each network. In terms of the accuracy of predicting gene functional annotations, all networks yielded relatively high precision (as high as 87% for the network inferred using mutual information), but the highest recall reached was below 15%. All networks having low recall means that none of them capture a large amount of all existing gene-GO term annotations. In fact, their annotation predictions are highly complementary, with the largest pairwise overlap of only 27%. We provide ranked lists of inferred gene-gene interactions and predicted gene-GO term annotations for future use and wet lab validation by the malaria community. CONCLUSIONS: The different networks seem to capture different aspects of the P. falciparum biology in terms of both inferred interactions and predicted gene functional annotations. Thus, relying on a single network inference method should be avoided when possible. SUPPLEMENTARY DATA: Attached.

Local spatiotemporal dynamics of particulate matter and oak pollen measured by machine learning aided optical particle counters.

Conventional techniques for monitoring pollen currently have significant limitations in terms of labour, cost and the spatiotemporal resolution that can be achieved. Pollen monitoring networks across the world are generally sparse and are not able to fully represent the detailed characteristics of airborne pollen. There are few studies that observe concentrations on a local scale, and even fewer that do so in ecologically rich rural areas and close to emitting sources. Better understanding of these would be relevant to occupational risk assessments for public health, as well as ecology, biodiversity, and climate. We present a study using low-cost optical particle counters (OPCs) and the application of machine learning models to monitor particulate matter and pollen within a mature oak forest in the UK. We characterise the observed oak pollen concentrations, first during an OPC colocation period (6 days) for calibration purposes, then for a period (36 days) when the OPCs were distributed on an observational tower at different heights through the canopy. We assess the efficacy and usefulness of this method and discuss directions for future development, including the requirements for training data. The results show promise, with the derived pollen concentrations following the expected diurnal trends and interactions with meteorological variables. Quercus pollen concentrations appeared greatest when measured at the canopy height of the forest (20-30 m). Quercus pollen concentrations were lowest at the greatest measurement height that is above the canopy (40 m), which is congruent with previous studies of background pollen in urban environments. The attenuation of pollen concentrations as sources are depleted is also observed across the season and at different heights, with some evidence that the pollen concentrations persist later at the lowest level beneath the canopy (10 m) where catkins mature latest in the season compared to higher catkins.

The James A. Rand Young Investigator's Award: Keeping It Simple: Are all Musculoskeletal Infection Society Tests Useful to Diagnose Periprosthetic Joint Infection?

BACKGROUND: Current data evaluating the clinical value and cost-effectiveness of advanced diagnostic tests for periprosthetic joint infection (PJI) diagnosis, including alpha-defensin and synovial C-reactive protein (CRP), is conflicting. This study aimed to evaluate the adequacy of preoperative and intraoperative PJI workups without utilizing these tests. METHODS: This retrospective analysis identified all patients who underwent revision total knee or hip arthroplasty (rTKA and rTHA, respectively) for suspected PJI between 2018 and 2020 and had a minimum follow-up of 2 years. Perioperative data and lab results were collected, and cases were dichotomized based on whether they met the 2018 Musculoskeletal Infection Society (MSIS) criteria for PJI. In total, 204 rTKA and 158 rTHA cases suspected of PJI were reviewed. RESULTS: Nearly 100% of the cases were categorized as "infected" for meeting the 2018 MSIS criteria without utilization of alpha-defensin or synovial CRP (rTKA: n = 193, 94.6%; rTHA: n = 156, 98.7%). Most cases were classified as PJI preoperatively by meeting either the major MSIS or the combinational minor MSIS criteria of traditional lab tests (rTKA: n = 177, 86.8%; rTHA: n = 143, 90.5%). A subset of cases was classified as PJI by meeting combinational preoperative and intraoperative MSIS criteria (rTKA: 16, 7.8%; rTHA: 13, 8.2%). Only 3.6% of all cases were considered "inconclusive" using preoperative and intraoperative data. CONCLUSIONS: Given the high rate of cases satisfying PJI criteria during preoperative workup using our available tests, the synovial alpha-defensin and synovial CRP tests may not be necessary in the routine diagnostic workup of PJI. We suggest that the primary PJI workup process should be based on a stepwise algorithmic approach with the most economical testing necessary to determine a diagnosis first. The use of advanced, commercialized, and costly biomarkers should be utilized only when traditional testing is indeterminate.

Usability of the 4Ms Worksheet in the Emergency Department for Older Patients: A Qualitative Study.

Introduction: Older adults often have multiple comorbidities; therefore, they are at high risk for adverse events after discharge. The 4Ms framework-what matters, medications, mentation, mobility-has been used in acute and ambulatory care settings to identify risk factors for adverse events in older adults, although it has not been used in the emergency department (ED). We aimed to determine whether 1) use of the 4Ms worksheet would help emergency clinicians understand older adult patients' goals of care and 2) use of the worksheet was feasible in the ED. Methods: We conducted a qualitative, descriptive study among patients aged ≥60 years and emergency clinicians from January-June 2022. Patients were asked to fill out a 4Ms worksheet; following this, semi-structured interviews were conducted with patients and clinicians separately. We analysed data to create codes, which were divided into categories and sub-categories. Results: A total of 20 older patients and 19 emergency clinicians were interviewed. We identified two categories based on our aims: understanding patient goals of care (sub-categories: clinician/ patient concordance; understanding underlying goals of care; underlying goals of care discrepancy) and use of 4Ms Worksheet (sub-categories: worksheet to discussion discrepancy; challenges using worksheet; challenge completing worksheet before discharge). Rates of concordance between patient and clinician on main concern/goal of care and underlying goals of care were 82.4% and 15.4%, respectively. Conclusion: We found that most patients and emergency clinicians agreed on the main goal of care, although clinicians often failed to elicit patients' underlying goal(s) of care. Additionally, many patients preferred to have the interviewer fill out the worksheet for them. There was often discrepancy between what was written and what was discussed with the interviewer. More research is needed to determine the best way to integrate the 4Ms framework within emergency care.

Early Initiation of Ceftaroline-Based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia.

Purpose: Monotherapy with vancomycin or daptomycin remains guideline-based care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. Limited data support potential benefit of combination therapy with ceftaroline as initial therapy. We present an assessment of outcomes of patients initiated on early combination therapy for MRSA-B. Methods: This was a single-center, retrospective study of adult patients admitted with MRSA-B between July 1, 2017 and April 31, 2023. During this period, there was a change in institutional practice from routine administration of monotherapy to initial combination therapy for most patients with MRSA-B. Combination therapy included vancomycin or daptomycin plus ceftaroline within 72 hours of index blood culture and monotherapy was vancomycin or daptomycin alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were assessed. All outcomes were assessed using propensity score-weighted logistic regression. Results: Of 213 patients included, 118 received monotherapy (115 vancomycin, 3 daptomycin) and 95 received combination therapy with ceftaroline (76 vancomycin, 19 daptomycin). The mean time from MRSA-positive molecular diagnostic blood culture result to combination therapy was 12.1 hours. There was no difference between groups for the primary composite outcome (OR 1.58, 95% CI 0.60, 4.18). Time to microbiological cure was longer with combination therapy (mean difference 1.50 days, 95% CI 0.60, 2.41). Adverse event rates were similar in both groups. Conclusions: Early initiation of ceftaroline-based combination therapy did not improve outcomes for patients with MRSA-B in comparison to monotherapy therapy.

Membrane-Cloaked Nanoparticles for RNA Interference of ß-Catenin in Triple-Negative Breast Cancer.

There is an outstanding need for targeted therapies for triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. Since TNBC's rapid growth and metastasis are driven by hyperactive Wnt signaling, suppressing the key-pathway mediator ß-catenin through RNA interference may improve patient outcomes. However, small interfering ribonucleic acid (siRNA) molecules require a carrier to elicit targeted gene silencing. Here, we show that 4T1 cancer cell membrane wrapped poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) can deliver siRNA into TNBC cells, silence ß-catenin expression, and reduce the cells' tumorigenic qualities. Compared to unwrapped and nontargeted NPs, the cancer cell membrane wrapped nanoparticles (CCNPs) exhibit dramatically improved uptake by TNBC cells versus breast epithelial cells and greater gene silencing at mRNA and protein levels. Congruently, ß-catenin siRNA-loaded CCNPs significantly activate senescence in 2D cultured TNBC cells and reduce proliferation in 3D spheroids. This work advances the development of nucleic acid carriers for targeted RNA interference therapy.

Social and circadian rhythm dysregulation and suicide: A systematic review and meta-analysis.

This systematic review of 52 studies provides a quantitative synthesis of the empirical literature on social and circadian rhythm correlates of suicidal thoughts and behaviors (STB). Small-to-medium pooled effect sizes were observed for associations between evening chronotype and STB and suicidal ideation (SI), although the pooled effect size diminished when accounting for publication bias. Three studies employed longitudinal designs and suggested eveningness was predictive of future STB, with a small-to-medium effect size. Social rhythm irregularity was also a significant correlate of STB with pooled effect sizes in the medium range. Overall circadian rhythm disruption was not associated with STB, although certain circadian rhythm metrics, including mean daytime activity, circadian rhythm sleep-wake disorder diagnosis, and actigraphy-assessed amplitude were associated with STB. Pooled effect sizes for these indices were in the medium to large range. There is a need for additional longitudinal research on actigraphy-based circadian parameters and objective markers of circadian phase (i.e., dim-light melatonin onset) to gain a clearer understanding of associations of endogenous circadian function and STB beyond that which can be captured via self-report.

Cyclooxygenase inhibition does not blunt thermal hyperemia in skeletal muscle of humans.

Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. The cyclooxygenase pathway is active in skeletal muscle, is heat sensitive, and contributes to cutaneous thermal hyperemia in young healthy humans. Therefore, the purpose of this study was to test the hypothesis that cyclooxygenase inhibition would attenuate blood flow in the vastus lateralis muscle during localized heating. Twelve participants (6 women) were studied on two separate occasions: 1) time control (i.e., no ibuprofen); and 2) ingestion of 800 mg ibuprofen, a nonselective cyclooxygenase inhibitor. Experiments were randomized, counter-balanced, and separated by at least 10 days. Pulsed short-wave diathermy was used to induce unilateral deep heating of the vastus lateralis for 90 min, whereas the contralateral leg served as a thermoneutral control. Microdialysis was utilized to bypass the cutaneous circulation and directly measure local blood flow in the vastus lateralis muscle of each leg via the ethanol washout technique. Heat exposure increased muscle temperature and local blood flow (both P < 0.01 vs. baseline). However, the thermal hyperemic response did not differ between control and ibuprofen conditions (P ≥ 0.2). Muscle temperature slightly decreased for the thermoneutral leg (P < 0.01 vs. baseline), yet local blood flow remained relatively unchanged across time for control and ibuprofen conditions (both P ≥ 0.7). Taken together, our data suggest that inhibition of cyclooxygenase-derived vasodilator prostanoids does not blunt thermal hyperemia in skeletal muscle of young healthy humans.NEW & NOTEWORTHY Acute heat exposure increases skeletal muscle blood flow in humans. However, the mechanisms mediating this hyperemic response remain unknown. Using a pharmacological approach combined with microdialysis, we found that thermal hyperemia in the vastus lateralis muscle was well maintained despite the successful inhibition of cyclooxygenase. Our results suggest that cyclooxygenase-derived vasodilator prostanoids do not contribute to thermal hyperemia in skeletal muscle of young healthy humans.