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Jacalyn M GreenDepartment of Biochemistry, Midwestern University, IL, USAAbstract: In January 2012, glucarpidase (Voraxaze®) received approval from the US Food and Drug Administration for intravenous treatment of toxic plasma methotrexate concentrations due to impaired renal clearance. Methotrexate, an antifolate agent, has been used for over 60 years in the treatment of various cancers. High-dose methotrexate has been particularly useful in the treatment of leukemias and lymphomas. However, even with aggressive hydration and urine alkalinization, such regimens can lead to acute renal dysfunction, as indicated by decreases in urine production and concomitant increases in blood urea nitrogen and serum creatinine levels. Because methotrexate is largely excreted by the kidneys, this can greatly potentiate tissue damage. Toxic levels of blood methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase. Glucarpidase is a recombinant form of carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to form the amino acid glutamate and 2,4-diamino-N10-methylpteroic acid. Catabolites of methotrexate are much less toxic than the parent compound, and are primarily excreted by hepatic mechanisms. Glucarpidase has been available on a compassionate basis since the 1990s, and a variety of case reports and larger clinical trials have demonstrated the safety and efficacy of this drug in patients ranging in age from infants to the elderly and in a variety of races and ethnic groups. Glucarpidase should not be administered within 2 hours of leucovorin, because this agent is a reduced folate which competes with methotrexate for the enzyme and glucarpidase inactivates leucovorin. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective. Future applications of this enzyme in chemotherapy continue to be an active area of research.Keywords: glucarpidase, Voraxaze®, carboxypeptidase G2, methotrexate, antifolate, chemotherapy

Costimulation mediated by the CD28 receptor has been shown to play an important role in the development of a vigorous T cell immune response. Nevertheless, CD28-deficient mice can mount effective T cell-dependent immune responses. These data suggest that other costimulatory molecules may play a role in T cell activation. In a search for other costimulatory receptors on T cells, we have characterized a monoclonal antibody (mAb) that can costimulate T cells in the absence of accessory cells. Similar to CD28 antibodies, this mAb, R2/60, was found to synergize with T cell receptor engagement in inducing proliferation. Independent ligation of CD3 and the ligand recognized by R2/60 results in T cell proliferation, suggesting that the two molecules do not have to colocalize to activate the R2/60 costimulatory pathway. R2/60 does not react with CD28, and furthermore, R2/60 costimulates in a CD28-independent fashion since the mAb costimulates T cells from the CD28-deficient mice as well as wild-type mice. Expression cloning of the R2/60 antigen identified the ligand as murine CD43. Together, these data demonstrate that CD43 can serve as a receptor on T cells that can provide CD28-independent costimulation.

Objective: This study assessed treatment preferences among low-income Latino patients in public-sector primary care clinics and examined whether a collaborative care intervention that included patient education and allowed patients to choose between medication, therapy, or both would increase the likelihood that patients received preferred treatment.Methods: A total of 339 Latino patients with probable depressive disorders were recruited; participants completed a baseline conjoint analysis preference survey and were randomly assigned to receive the intervention or enhanced usual care. At 16 weeks, a patient survey assessed depression treatment received during the study period. Logistic regression models were constructed to estimate treatment preferences, examine patient characteristics associated with treatment preferences, and examine patient characteristics associated with a match between stated preference and actual treatment received.Results: The conjoint analysis preference survey showed that patients preferred counseling or counseling plus medication over antidepressant medication alone and that they preferred treatment in primary care over specialty mental health care, but they showed no significant preference for individual versus group treatment. Patients also indicated that individual education sessions, telephone sessions, transportation assistance, and family involvement were barrier reduction strategies that would enhance their likelihood of accepting treatment. Compared with patients assigned to usual care, those in the intervention group were 21 times as likely to receive preferred treatment. Among all participants, women, unemployed persons, those who spoke English, and those referred by providers were more likely to receive preferred treatment.Conclusions: Collaborative care interventions that include psychotherapy can increase the likelihood that Latino patients receive preferred care; however, special efforts may be needed to address preferences of working persons, men, and Spanish-speaking patients. [ABSTRACT FROM AUTHOR]

The current investigation examined the potential teleoanticipatory effect on perceptual response during repeated bouts of maximal sprint work. To determine the consistency of ratings of perceived exertion (RPE) increase during identical exercise bouts following variable recovery periods, 16 (8 men, 8 women) participants completed four separate trials of repeated maximal sprinting on 4 separate days utilizing different recovery periods. Following completion of the baseline trial, participants were given variable, counter-balanced recovery periods of 24, 48 and 72 hours, whereupon they repeated the intermittent exercise protocol. To determine the degree of similarity among trials, each individual's rate of RPE progression during each cycle of eight sprints throughout the recovery trials were compared to the rate of progression during the baseline exercise session. A series of 4 (trial) × 3 (cycle of sprints) repeated measures ANOVA were performed to identify significant main effects between trials and among cycles while session RPE was analyzed using one-way repeated measures ANOVA. Fisher's least significant difference post-hoc procedures were performed to identify where significant differences occurred when appropriate. Results revealed an inconsistency in the stability of RPE across repeated bouts of sprint exercise, with at least 50%of individuals having a substantial difference in RPE (i.e. ± 1 unit change) in at least one subsequent trial. These variations in perceptual responses were observed despite a concomitant stability of physiological and performance responses between sessions. Results suggest that rate of RPE increase correspond more closely to increased or decreased physiologic strain than to an anticipatory, feed-forward mechanism following variable recovery durations. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study evaluated an existing SNOMED-CT((R)) model for structured recording of heart murmur findings and compared it to a concept-dependent attributes model using content from SNOMED-CT. METHODS: The authors developed a model for recording heart murmur findings as an alternative to SNOMED-CT's use of Interprets and Has interpretation. A micro-nomenclature was then created to support each model using subset and extension mechanisms described for SNOMED-CT. Each micro-nomenclature included a partonomy of cardiac cycle timing values. A mechanism for handling ranges of values was also devised. One hundred clinical heart murmurs were recorded using purpose-built recording software based on both models. RESULTS: Each micro-nomenclature was extended through the addition of the same list of concepts. SNOMED role grouping was required in both models. All 100 clinical murmurs were described using each model. The only major differences between the two models were the number of relationship rows required for storage and the hierarchical assignments of concepts within the micro-nomenclatures. CONCLUSION: The authors were able to capture 100 clinical heart murmurs with both models. Requirements for implementing the two models were virtually identical. In fact, data stored using these models could be easily interconverted. There is no apparent penalty for implementing either approach. [ABSTRACT FROM AUTHOR]

Accessory molecule interactions can be critical in determining the outcome of a T cell's encounter with antigen. Cell adhesion proteins may augment T cell responses by facilitating TCR engagement of the antigen-MHC complex, while co-stimulatory molecules may deliver distinct signals that modulate T cell responsiveness. CD43 (leukosialin, sialophorin) has been suggested to influence cell activation by steric hindrance based upon the large size and glycosylation of the protein, as well as the relative abundance of the protein on the cell surface. In this paper we examine both in vitro and in vivo T cell-dependent responses in CD43-deficient mice. We demonstrate that T cells from CD43-deficient mice are hyper-responsive following both in vivo and in vitro activation, and that this is observed in response to not only TCR-CD3-mediated stimulation, but also following receptor-independent activation. This data suggests that mechanisms other than non-specific steric hindrance are important in the regulation of T cell activation by CD43. [ABSTRACT FROM PUBLISHER]

Transcranial magnetic stimulation (TMS) and electroencephalography (EEG) are non-invasive techniques used for neuromodulation and recording brain electrical activity, respectively. The integration of TMS-EEG has emerged as a valuable tool for investigating the complex mechanisms involved in age-related disorders, such as mild cognitive impairment (MCI) and Alzheimer's disease (AD). By systematically synthesizing TMS-EEG studies, this review aims to shed light on the neurophysiological mechanisms underlying MCI and AD, while also exploring the practical applications of TMS-EEG in clinical settings. PubMed, ScienceDirect, and PsychInfo were selected as the databases for this review. The 22 eligible studies included a total of 592 individuals with MCI or AD as well as 301 cognitively normal adults. TMS-EEG assessments unveiled specific patterns of corticospinal excitability, plasticity, and brain connectivity that distinguished individuals on the AD spectrum from cognitively normal older adults. Moreover, the TMS-induced EEG features were observed to be correlated with cognitive performance and the presence of AD pathological biomarkers. The comprehensive examination of the existing studies demonstrates that the combination of TMS and EEG has yielded valuable insights into the neurophysiology of MCI and AD. This integration shows great potential for early detection, monitoring disease progression, and anticipating response to treatment. Future research is of paramount importance to delve into the potential utilization of TMS-EEG for treatment optimization in individuals with MCI and AD., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Aging is a complex and diverse biological process characterized by progressive molecular, cellular, and tissue damage, resulting in a loss of physiological integrity and heightened vulnerability to pathology. This biological diversity corresponds with highly variable cognitive trajectories, which are further confounded by genetic and environmental factors that influence the resilience of the aging brain. Given this complexity, there is a need for neurophysiological indicators that not only discern physiologic and pathologic aging but also closely align with cognitive trajectories. Transcranial Magnetic Stimulation (TMS) may have utility in this regard as a non-invasive brain stimulation tool that can characterize features of cortical excitability. Particularly, as a proxy for central cholinergic function, short-afferent inhibition (SAI) dysfunction is robustly associated with cognitive deficits in the latter stages of Alzheimer's Disease and Related Dementia (ADRD). In this study, we evaluated SAI in healthy young adults and older adults who, though absent clinical diagnoses, were algorithmically classified as cognitively normal (CN) or cognitively impaired (CI) according to the Jak/Bondi actuarial criteria. We report that SAI is preserved in the Old-CN cohort relative to the young adults, and SAI is significantly diminished in the Old-CI cohort relative to both young and CN older adults. Additionally, diminished SAI was significantly associated with impaired sustained attention and working memory. As a proxy measure for central cholinergic deficits, we discuss the potential value of SAI for discerning physiological and pathological aging., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Competing Interests: We declare no competing interests.

Background: 16p11.2 proximal deletion and duplication syndromes (Break points 4-5) (593KB, Chr16; 29.6-30.2mb - HG38) are observed to have highly varied phenotypes, with a known propensity for lifelong psychiatric problems. This study aimed to contribute to a research gap by qualitatively exploring the challenges families with 16p11.2 deletion and duplication face by answering three research questions: (1) What are parents' perceptions of the ongoing support needs of families with children who have 16p11.2 living in the UK?; (2) What are their experiences in trying to access support?; (3) In these regards, do the experiences of parents of children with duplication converge or vary from those of parents of children with 16p11.2 deletion?, Methods: 33 parents with children (aged 7-17 years) with 16p11.2 deletion or duplication participated in structured interviews, including the Autism Diagnostic Interview- Revised (ADI-R). Their answers to the ADI-R question 'what are your current concerns' were transcribed and subsequently analysed using Braun and Clarke's six step reflexive thematic analysis framework., Results: Three themes were identified: (1) Child is Behind Peers (subthemes: developmentally; academically; socially; emotionally); (2) Metabolism and Eating Patterns and; (3) Support (subthemes: insufficient support available; parent has to fight to access support; COVID-19 was a barrier to accessing support; 16p11.2 diagnosis can be a barrier to support, child is well-supported)., Conclusions: Parents of children with either 16p11.2 deletion or duplication shared similar experiences. However, metabolism concerns were specific to parents of children with 16p11.2 deletion. The theme Child is Behind Peers echoed concerns raised in previous Neurodevelopmental Copy Number Variant research. However, there were some key subthemes relating to research question (2) which were specific to this study. This included parents' descriptions of diagnostic overshadowing and the impact of a lack of eponymous name and scant awareness of 16p11.2., (© 2024. The Author(s).)

This study investigated the influence of yoga breathing techniques (YBT) on physiological and perceptual responses during sub-maximal treadmill running. Runners (n = 21) of various fitness (VO2max 48.4 ± 9.5 ml/kg/min) were assigned to Yoga (YG) or control (CT) group before completing pre/post treadmill trials where velocity was self-selected to produce an RPE 4 and RPE 7 (10 min each). YG (n =11) practiced three styles of YBT (30 min/day, 6 days/wk) for 3 consecutive wks. Self-selected running velocity for YG improved significantly at both prescribed RPE 4 (pre 157.63 ± 26.20 M/min, post 181.02 ± 24.22 M/min, p = 0.01) and prescribed RPE 7 (pre 201.97 ± 31.28 M/min, post 222.68± 35.32 M/min, p = 0.01). VO2 at RPE 7 increased significantly (pre 42.6 ± 6.9 ml/kg/min, post 47.3 ± 6.2 ml/kg/min, p = 0.02), TV at RPE 7 (pre 1.81 ± 0.30, post 2.04 ± 0.41, p = 0.01), and MV at RPE 7 (pre 77.25 ± 12.42, post 91.23 ± 20.05, p = 0.01). The CT group showed no significant changes except for TV at RPE 7 (pre 1.9 ± 0.3, post 2.0 ± 0.3, p = 0.04). Current results suggest YBT positively influences running velocity regulation during self-selected running.

Importance: Unhoused status is a substantial problem in the US. Pregnancy characteristics and maternal outcomes of individuals experiencing homelessness are currently under active investigation to optimize health outcomes for this population., Objective: To assess the trends, characteristics, and maternal outcomes associated with unhoused status in pregnancy., Design, Setting, and Participants: This cross-sectional study analyzed data from the Healthcare Cost and Utilization Project National (Nationwide) Inpatient Sample. The study population included hospitalizations for vaginal and cesarean deliveries from January 1, 2016, to December 31, 2020. Unhoused status of these patients was identified from use of International Statistical Classification of Diseases, Tenth Revision, Clinical Modification code Z59.0. Statistical analysis was conducted from December 2022 to June 2023., Main Outcomes and Measures: Primary outcomes were (1) temporal trends; (2) patient and pregnancy characteristics associated with unhoused status, which were assessed with a multivariable logistic regression model; (3) delivery outcomes, including severe maternal morbidity (SMM) and mortality at delivery, which used the Centers for Disease Control and Prevention definition for SMM indicators and were assessed with a propensity score-adjusted model; and (4) choice of long-acting reversible contraception method and surgical sterilization at delivery., Results: A total of 18 076 440 hospital deliveries were included, of which 18 970 involved pregnant patients who were experiencing homelessness at the time of delivery, for a prevalence rate of 104.9 per 100 000 hospital deliveries. These patients had a median (IQR) age of 29 (25-33) years. The prevalence of unhoused patients increased by 72.1% over a 5-year period from 76.1 in 2016 to 131.0 in 2020 per 100 000 deliveries (P for trend < .001). This association remained independent in multivariable analysis. In addition, (1) substance use disorder (tobacco, illicit drugs, and alcohol use disorder), (2) mental health conditions (schizophrenia, bipolar, depressive, and anxiety disorders, including suicidal ideation and past suicide attempt), (3) infectious diseases (hepatitis, gonorrhea, syphilis, herpes, and COVID-19), (4) patient characteristics (Black and Native American race and ethnicity, younger and older age, low or unknown household income, obesity, pregestational hypertension, pregestational diabetes, and asthma), and (5) pregnancy characteristics (prior uterine scar, excess weight gain during pregnancy, and preeclampsia) were associated with unhoused status in pregnancy. Unhoused status was associated with extreme preterm delivery (<28-week gestation: 34.3 vs 10.8 per 1000 deliveries; adjusted odds ratio [AOR], 2.76 [95% CI, 2.55-2.99]); SMM at in-hospital delivery (any morbidity: 53.8 vs 17.7 per 1000 deliveries; AOR, 2.30 [95% CI, 2.15-2.45]); and in-hospital mortality (0.8 vs <0.1 per 1000 deliveries; AOR, 10.17 [95% CI, 6.10-16.94]), including case fatality risk after SMM (1.5% vs 0.3%; AOR, 4.46 [95% CI, 2.67-7.45]). Individual morbidity indicators associated with unhoused status included cardiac arrest (AOR, 12.43; 95% CI, 8.66-17.85), cardiac rhythm conversion (AOR, 6.62; 95% CI, 3.98-11.01), ventilation (AOR, 6.24; 95% CI, 5.03-7.74), and sepsis (AOR, 5.37; 95% CI, 4.53-6.36)., Conclusions and Relevance: Results of this national cross-sectional study suggest that unhoused status in pregnancy gradually increased in the US during the 5-year study period and that pregnant patients with unhoused status were a high-risk pregnancy group.

Revisions to the Common Rule and NIH policy require the use of a single Institutional Review Board (sIRB) for the review of most federally funded, multisite research, with the intent of streamlining the review process. However, since initial implementation in 2018, many IRBs and institutions continue to struggle with the logistics of implementing this requirement. In this paper, we report the findings of a workshop held in 2022 to examine why sIRB review remains problematic and propose possible solutions. Workshop participants identified several issues as major barriers, including new responsibilities for study teams, persistent duplicative review processes, the lack of harmonization of policies and practices across institutions, the absence of additional guidance from federal agencies, and the need for greater flexibility in policy requirements. Addressing these problems will require providing additional resources and training to research teams, the commitment of institutional leaders to harmonize practice, and policymakers to critically evaluate the requirement and provide flexibility in applicability., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

Self-collection of dried blood samples (DBS) in the participant's home provides an alternative to university/hospital visits for research and has the potential to improve the representation of population heterogeneity in research. This study aimed to assess the feasibility of guardian and/or self-DBS collection in healthy youth in the lab and home. Guardians/youth [ N  = 140; females = 63; M age  = 8.73, SD age  = 3.56] who enrolled in a longitudinal study of typical development were asked during a lab visit to provide a DBS. Upon providing a sample, the participants were asked if they would be willing to self-collect in the home and return the sample via the post office. Of those asked to provide a sample in the lab, 82% consented and 18% declined, with a significant difference in age but no significant difference in sex, ethnicity, race, or family income. Of those who provided a sample in the lab, 75% were willing to self-collect DBS in the home, with no significant difference in demographic variables between them. We report a quality assessment and DNA extraction results from a subset of samples. The results demonstrate a high feasibility of DBS collection from healthy youth for research purposes both in the laboratory and in the home across different demographic variables. Developmental researchers should consider including this approach in their studies to increase population heterogeneity representation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Green, Barry, Burton, Beauchemin, Huentelman, Deoni and Lewis.)

Background: Previous research has demonstrated that epigenetic changes in specific hypothalamic-pituitary-adrenal (HPA) genes may predict successful psychotherapy in post-traumatic stress disorder (PTSD). A recent Phase 3 clinical trial reported high efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for treating patients with severe PTSD compared to a therapy with placebo group (NCT03537014). This raises important questions regarding potential mechanisms of MDMA-assisted therapy. In the present study, we examined epigenetic changes in three key HPA axis genes before and after MDMA and placebo with therapy. As a pilot sub-study to the parent clinical trial, we assessed potential HPA epigenetic predictors for treatment response with genomic DNA derived from saliva (MDMA, n = 16; placebo, n = 7). Methylation levels at all 259 CpG sites annotated to three HPA genes ( CRHR1 , FKBP5 , and NR3C1 ) were assessed in relation to treatment response as measured by the Clinician-Administered PTSD Scale (CAPS-5; Total Severity Score). Second, group (MDMA vs. placebo) differences in methylation change were assessed for sites that predicted treatment response., Results: Methylation change across groups significantly predicted symptom reduction on 37 of 259 CpG sites tested, with two sites surviving false discovery rate (FDR) correction. Further, the MDMA-treatment group showed more methylation change compared to placebo on one site of the NR3C1 gene., Conclusion: The findings of this study suggest that therapy-related PTSD symptom improvements may be related to DNA methylation changes in HPA genes and such changes may be greater in those receiving MDMA-assisted therapy. These findings can be used to generate hypothesis driven analyses for future studies with larger cohorts., Competing Interests: BY-K and CH received payment for full-time employment from the MAPS or the MAPS Public Benefit Corporation throughout their work on the parent trial. JT is the Executive Director of Modern Spirit, the non-profit organization that funded this study. BC is on the Board of Directors for Modern Spirit. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lewis, Tafur, Spencer, Green, Harrison, Kelmendi, Rabin, Yehuda, Yazar-Klosinski and Cahn.)

Astaxanthin (AX) is an antioxidant which may spare endogenous carbohydrates and improve fat oxidation rates, thus improving metabolic flexibility. To date, no studies have attempted to examine the impact of AX in an overweight cohort, whom often suffer from metabolic inflexibility. Nineteen subjects (mean ± SD: age: 27.5 ± 6.3 years; height: 169.7 ± 9.0 cm; body mass: 96.4 ± 17.9 kg; BF%: 37.9 ± 7.0%; BMI: 33.4 ± 5.6 kg/m 2 ; VO 2peak : 25.9 ± 6.7 ml·kg -1 ·min -1 ) were recruited and supplemented with either 12 mg of AX or placebo (PLA) for 4 weeks. Subjects completed a graded exercise test on a cycling ergometer to examine changes in substrate oxidation rates. A total of 5 stages, each lasting 5 min and resistance increased 15 W each stage, were completed to examine changes in levels of glucose and lactate, fat and carbohydrate (CHO) oxidation rates, heart rate, and rating of perceived exertion (RPE). Although there were no changes found in rates of fat oxidation, blood lactate or glucose, or RPE (all p > 0.05), a significant decrease was observed in CHO oxidation from pre to post supplementation in the AX group only. Further, the AX group demonstrated a 7% decrease in heart rate across the graded exercise test. These findings suggest that 4 weeks of AX supplementation may offer some cardiometabolic benefits to overweight individuals, and be a favorable supplement for these individuals beginning an exercise program.

Risk factors for liver cancer include tobacco use, alcohol consumption, obesity, and male sex. Administration of 4-nitroquinonline-1-oxide (4NQO) in drinking water mimics the effects of tobacco and leads to oral carcinoma in mice. This study compared the effects of diets high and low in saturated fat (HF and LF, respectively), and sex, on liver histopathology in 4NQO-treated mice and controls. We hypothesized that 4NQO would cause histopathological changes in liver, and that a HF diet would increase hepatic pathology when compared to the LF diet. Mice (C57Bl/6, 36/sex), were divided into a low fat (10 kcal% fat; LF) or high fat (60 kcal% fat, HF) diet. Mice were further subdivided into one of 3 water treatment groups for 17 weeks: water (control), vehicle (1.25% propylene glycol in water [PG]), or 4NQO in (50 μg/ml; 4NQO). All mice were subsequently given water alone for 6 more weeks. Upon euthanasia, livers were harvested, fixed, sectioned, and stained with hematoxylin and eosin (H&E). H&E slides were graded for histopathology; frozen liver samples were analyzed for triglyceride content. Trichrome stained sections were graded for fibrosis. CD3+ T cells, CD68+ macrophages, and Ly6+ neutrophils were detected by immunohistochemistry. Compared to water controls, 4NQO-treatment caused mouse liver histopathological changes such as fibrosis, and increases in hepatic neutrophils, T cells, and macrophages. HF diet exacerbated pathological changes compared to LF diet. Male controls, but not females, demonstrated severe steatosis and increased triglyceride content. 4NQO treatment decreased hepatic fat accumulation, even in animals on a HF diet. In conclusion, this murine model of oral cancer may serve as a model to study the effects of tobacco and diet on liver., Competing Interests: The authors have declared that no competing interests exist.

Estrogens are well-known to regulate development of sexual dimorphism of the brain; however, their role in embryonic brain development prior to sex-differentiation is unclear. Using estrogen biosensor zebrafish models, we found that estrogen activity in the embryonic brain occurs from early neurogenesis specifically in a type of glia in the olfactory bulb (OB), which we name estrogen-responsive olfactory bulb (EROB) cells. In response to estrogen, EROB cells overlay the outermost layer of the OB and interact tightly with olfactory sensory neurons at the olfactory glomeruli. Inhibiting estrogen activity using an estrogen receptor antagonist, ICI182,780 (ICI), and/or EROB cell ablation impedes olfactory glomerular development, including the topological organisation of olfactory glomeruli and inhibitory synaptogenesis in the OB. Furthermore, activation of estrogen signalling inhibits both intrinsic and olfaction-dependent neuronal activity in the OB, whereas ICI or EROB cell ablation results in the opposite effect on neuronal excitability. Altering the estrogen signalling disrupts olfaction-mediated behaviour in later larval stage. We propose that estrogens act on glia to regulate development of OB circuits, thereby modulating the local excitability in the OB and olfaction-mediated behaviour., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Caffeine (CAF) has been extensively studied for its ergogenic and analgesic effects during exercise. However, the majority of these studies have been conducted in male populations. This study investigated the effects of acute CAF chewing gum on self-selected exercise intensity during a rating of perceived exertion (RPE) production trial in active females ( n = 16, 21.0 ± 2.8 y). Data were also analyzed based on habitual CAF consumption level. Participants completed a V̇O 2peak trial, followed by a familiarization and two randomized, triple-blinded experimental RPE production trials on an arm ergometer [clamped resistance, blinded to self-selected cadence (CAD)] with either CAF gum (300 mg; 4.8 ± 0.7 mg/kg -1 body mass) or placebo (PLA), at a prescribed RPE of 4 and 7 (10 min each). Self-selected CAD did not statistically differ ( p > 0.05) between CAF or PLA for an RPE4 (37.7 ± 1.6 vs. 37.6 ± 1.6 rev·min -1 ) or RPE7 (42.9 ± 1.6 vs. 41.2 ± 1.7 rev·min -1 ), respectively. There were no statistical differences between treatment groups for any other variables, except restlessness rating which was significantly higher (3.5 vs. 2.2; p = 0.03, d = 0.64) for the CAF group compared to PLA. Secondary analysis revealed no statistical differences for any variables between habitual consumers of low (23 ± 20 mg/day) or mod/high (195 ± 93 mg/day) CAF. Our data support previous studies examining CAF in women across different testing modalities and suggest that regardless of habitual CAF consumption, females might require higher doses of CAF to replicate subjective and physiological responses commonly observed using similar RPE production protocols in male participants. These findings support the need for additional investigations into female physiological and perceptual responses following CAF ingestion.

Objective. To evaluate the short-term effectiveness of an online bridging course to increase the knowledge of struggling incoming students' in crucial content areas within the Doctor of Pharmacy (PharmD) curriculum. Methods. An assessment was administered to all incoming first-year pharmacy students (N=180) during orientation to determine their foundational knowledge in key areas. Students who scored <70% on the assessment (N=137) were instructed to complete a 10-module, online, self-directed bridging course focusing on physiology, biochemistry, math, and medical terminology during the first two weeks of the quarter to prepare them for first-quarter coursework. After completing the bridging course, participants completed the same assessment to determine content knowledge acquisition and retention. At the end of the quarter, the assessment was again administered to all first-year students, regardless of whether they had completed the bridging course. Results. The average assessment score of students who completed the bridging course modules improved significantly (53% vs 76%). All students demonstrated significant improvement in assessment scores between orientation and the end of the quarter; however, bridging course participants achieved a greater increase in assessment scores (53% vs 73%) than nonparticipants (76% vs 81%). Significant relationships were found between assessment scores following completion of the bridging course and pass rates in first-quarter courses. Conclusion. The online, self-directed bridging course offered at Midwestern University, Chicago College of Pharmacy proved successful as a method of knowledge acquisition and as a system for early identification (within the first two weeks of the quarter) of students in need of additional academic support., (© 2020 American Association of Colleges of Pharmacy.)

Background: Infants with severe respiratory syncytial virus (RSV) bronchiolitis have an increased risk of recurrent wheezing and asthma. We aimed to evaluate the relationships between regulatory T cell (Treg) percentage and cytokine production of in vitro-stimulated CD4+ T cells during acute bronchiolitis and the development of recurrent wheezing in the first 3 years of life., Methods: We obtained peripheral blood from 166 infants hospitalized with their first episode of RSV-confirmed bronchiolitis. Granzyme B (GZB) expression, and interleukin-10, interferon-γ, tumor necrosis factor-α (TNF-α), IL-4, and IL-5 production by in vitro anti-CD3/CD28- and anti-CD3/CD46-activated CD4+ T cells, and percentage of peripheral Treg (CD4+CD25 hi Foxp3 hi ) cells were measured by flow cytometry. Wheezing was assessed every 6 months. Recurrent wheezing was defined as three or more episodes following the initial RSV bronchiolitis., Results: Sixty-seven percent (n = 111) of children had wheezing after their initial RSV infection, with 30% having recurrent wheezing. The percentage of peripheral Treg (CD4+CD25 hi Foxp3 hi ) cells was not significantly different between the wheezing groups. Decreased TNF-α production from anti-CD3/CD28- and anti-CD3/CD46- activated CD4+ T cells was observed in the recurrent wheezers, compared with nonwheezers (p = .048 and .03, respectively). There were no significant differences in the GZB+ CD4+ T cells and production of other inflammatory cytokines between these groups., Conclusions: We demonstrated lower TNF-α production by in vitro stimulated CD4+ T cells during severe RSV bronchiolitis in children that subsequently developed recurrent wheezing, compared with children with no subsequent wheeze. These findings support the role of CD4+ T cell immunity in the development of subsequent wheezing in these children., (© 2019 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Yogic breathing techniques (Pranayama) positively impact respiratory function (RF) in non-endurance trained individuals. The purpose of this study investigated effects of routine Pranayama practice on RF, running economy (RE) and perceptual responses. A between subject's case-control study design was incorporated. Eleven runners practiced three styles of Pranayama (30 min/day 6 days/week) for 3 consecutive weeks (YG) and completed a VO 2 max tests on a treadmill (trial 1), basic RF tests, and constant workload RE trials at 60, 70, and 80% VO 2 max (trial 2 and 3). A control group ( n = 10) (CT) completed the same pre - post testing without intervention. Pre vs. post values for resting forced vital capacity (FVC), peak expiratory flow rate (PEFR) and forced expiratory flow volume in one second (FEV1). Yoga improved FVC and FEV1, but did not significantly impact RE However, RPE-L for HIGH had an interaction ( p < 0.05) showing a decrease for YG and an increase for CT. The current study suggests 3 weeks of yogic Pranayama fails to significantly impact RE, however some evidence indicates YG may positively alter perceptual responses at individually prescribed workloads. More work is needed to definitively establish benefits of YG for runners.

This study examined the effects of caffeine on tennis serve accuracy. Division II tennis athletes ( n = 10) completed two serve trials (double-blind, counterbalanced) following ingestion of 6 mg/kg of caffeine or matched placebo an hour prior to data collection. During each tennis serve trial, participants completed 48 non-fault serves divided into 3 sets with 2 serves per 8 different targets. Following each 2 serves per target format, participants completed a shuttle run sprint. Separate 2 (trial) × 8 (targets) repeated measures analysis of variances (ANOVAs) were used for distances from the target center "delta", and necessary tries for each of the 3 sets. A 2 (treatment) × 3 (set) repeated measures ANOVA was used for shuttle run times. While results were not significant, the treatment main effect approached significance ( p = 0.07) in set 2 for the delta of distances when comparing caffeine (96.2 cm ± 19.8) versus placebo (107.1 cm ± 16.3). While there was no significance in sprint times, each sprint was consistently faster following caffeine consumption. Post-trial surveys revealed subjective responses approached significance with greater feelings of stomach distress ( p = 0.08) and nervousness ( p = 0.13) following caffeine and elevated feeling of fatigue ( p = 0.19) following placebo. Therefore, with no impairment in serve accuracy coupled with some evidence of reduced fatigue, results suggest caffeine may benefit tennis athletes. Extending the understanding of the effects of caffeine on tennis serve accuracy and performance could benefit overall match performance, with the potential of improving the match outcome in extended playtime.

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic lung transplants develop severe OB lesions and poorly regenerate club cells despite immunosuppression treatment. Lung allograft club cell ablation also triggers the recognition of alloantigens, and pulmonary restricted self-antigens reported associated with BOS development. However, CD8+ T cell depletion restores club cell reparative responses and prevents OB. In addition, ex-vivo analysis reveals a specific role for alloantigen-primed effector CD8+ T cells in preventing club cell proliferation and maintenance. Taken together, we demonstrate a vital role for club cells in maintaining lung transplant tolerance and propose a new model to identify the underlying mechanisms of OB.

Objective: Few studies have examined differences in ratings of perceived exertion (RPE) between overweight (OW) and non-OW (NW) youth. With lower voluntary participation in physical activity in OW children, it seems plausible that these youth may experience elevated RPE. Therefore, this study compared RPE during two separate steady-state cycling bouts OW (>95 th body mass index [BMI] percentile) and NW (<90 th BMI percentile) children., Methods: Participants completed one of two 20-min cycling trials; one performed at 70% age-predicted peak heart rate (HR) (70%) (OW n = 12 and NW n = 21) and a self-selected intensity (SS) (OW n = 6 and NW n = 13) with RPE overall, RPE legs (RPE-L), and RPE chest estimated at 5, 10, 15, and 20 min., Results: A repeated measures ANOVA revealed that OW individuals had significantly lower RPE-L values at 5, 15, and 20 min during the SS trial. No significant differences were identified during the 70% trial., Conclusions: OW youth do not perceive cycling at 70% age-predicted peak HR or at SS intensities more difficult than NW children. It may be that cycling could serve as an attractive mode to encourage physical activity in this population and perhaps increase self-efficacy of exercise in this population.

A patient with recent jaw reconstruction presented for treatment of postoperative oropharyngeal hemorrhage. Asleep nasal fiberoptic intubation was attempted, but a rare and unanticipated complication ensued: rupture of right facial artery pseudoaneurysm. The difficult airway algorithm was followed up to the point of surgical airway. While nasal or oral fiberoptic intubation is often perceived as the safest approach for management of a difficult airway, we discuss alternative treatment strategies for patients with a facial pseudoaneurysm. Such alternatives include preoperative angiographic endovascular embolization of the vessel(s) feeding the pseudoaneurysm, and/or elective tracheostomy.

Estrogen plays fundamental roles in a range of developmental processes and exposure to estrogen mimicking chemicals has been associated with various adverse health effects in both wildlife and human populations. Estrogenic chemicals are found commonly as mixtures in the environment and can have additive effects, however risk analysis is typically conducted for single-chemicals with little, or no, consideration given for an animal's exposure history. Here we developed a transgenic zebrafish with a photoconvertable fluorophore (Kaede, green to red on UV light exposure) in a skin pigment-free mutant element (ERE)-Kaede-Casper model and applied it to quantify tissue-specific fluorescence biosensor responses for combinations of estrogen exposures during early life using fluorescence microscopy and image analysis. We identify windows of tissue-specific sensitivity to ethinylestradiol (EE2) for exposure during early-life (0-5 dpf) and illustrate that exposure to estrogen (EE2) during 0-48 hpf enhances responsiveness (sensitivity) to different environmental estrogens (EE2, genistein and bisphenol A) for subsequent exposures during development. Our findings illustrate the importance of an organism's stage of development and estrogen exposure history for assessments on, and possible health risks associated with, estrogen exposure.

Objective: Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine whether macrophage-associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages., Approach and Results: We developed mice lacking lipin-1 in myeloid-derived cells and used adeno-associated viral vector 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (adeno-associated viral vector 8-proprotein convertase subtilisin/kexin type 9) to induce hypercholesterolemia and plaque formation. Mice lacking myeloid-associated lipin-1 had reduced atherosclerotic burden compared with control mice despite similar plasma lipid levels. Stimulation of bone marrow-derived macrophages with modLDL activated a persistent protein kinase Cα/βII-extracellular receptor kinase1/2-jun proto-oncogene signaling cascade that contributed to macrophage proinflammatory responses that was dependent on lipin-1 enzymatic activity., Conclusions: Our data demonstrate that macrophage-associated lipin-1 is atherogenic, likely through persistent activation of a protein kinase Cα/βII-extracellular receptor kinase1/2-jun proto-oncogene signaling cascade that contributes to foam cell proinflammatory responses. Taken together, these results suggest that modLDL-induced foam cell formation and modLDL-induced macrophage proinflammatory responses are not independent consequences of modLDL stimulation but rather are both directly influenced by enhanced lipid synthesis., (© 2017 American Heart Association, Inc.)

Background: Atherosclerotic plaque formation results from chronic inflammation and fibroproliferative remodeling in the vascular wall. We previously demonstrated that both human and mouse atherosclerotic plaques show elevated expression of EphA2, a guidance molecule involved in cell-cell interactions and tumorigenesis., Methods: Here, we assessed the role of EphA2 in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe - /- ) and by assessing EphA2 function in multiple vascular cell culture models. After 8 to 16 weeks on a Western diet, male and female mice were assessed for atherosclerotic burden in the large vessels, and plasma lipid levels were analyzed., Results: Despite enhanced weight gain and plasma lipid levels compared with Apoe -/- controls, EphA2 -/- Apoe -/- knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. Although plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest that hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2 -/- Apoe -/- mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression after smooth muscle transition to a synthetic phenotype, and EphA2 depletion reduces smooth muscle proliferation, mitogenic signaling, and extracellular matrix deposition both in atherosclerotic plaques and in vascular smooth muscle cells in culture., Conclusions: Together, these data identify a novel role for EphA2 in atherosclerosis, regulating both plaque inflammation and progression to advanced atherosclerotic lesions. Cell culture studies suggest that endothelial EphA2 contributes to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas smooth muscle EphA2 expression may regulate the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition., (© 2017 American Heart Association, Inc.)

Objective: Quality improvement interventions for depression care have been shown to be effective for improving quality of care and depression outcomes in settings with primarily insured patients. The aim of this study was to determine the impact of a collaborative care intervention for depression that was tailored for low-income Latino patients seen in public-sector clinics., Methods: A total of 400 depressed patients from three public-sector primary care clinics were enrolled in a randomized controlled trial of a tailored collaborative care intervention versus enhanced usual care. Social workers without previous mental health experience served as depression care specialists for the intervention patients (N=196). Depending on patient preference, they delivered a cognitive-behavioral therapy (CBT) intervention or facilitated antidepressant medication given by primary care providers or both. In enhanced usual care, patients (N=204) received a pamphlet about depression, a letter for their primary care provider stating that they had a positive depression screen, and a list of local mental health resources. Intent-to-treat analyses examined clinical and process-of-care outcomes at 16 weeks., Results: Compared with patients in the enhanced usual care group, patients in the intervention group had significantly improved depression, quality of life, and satisfaction outcomes (p<.001 for all). Intervention patients also had significantly improved quality-of-care indicators, including the proportion of patients receiving either psychotherapy or antidepressant medication (77% versus 21%, p<.001)., Conclusions: Collaborative care for depression can greatly improve care and outcomes in public-sector clinics. Social workers without prior mental health experience can effectively provide CBT and manage depression care.

Patients with protracted sepsis develop impaired immunity, which predisposes them to acquiring secondary infections. One of the most common and lethal secondary infections is Pseudomonas aeruginosa pneumonia. Immunoadjuvant therapy is a promising approach to reverse sepsis-induced immunosuppression and improve morbidity and mortality from secondary infections. Interleukin-7 is an immunoadjuvant that improves survival in clinically relevant animal models of polymicrobial peritonitis and in fungal sepsis. This study investigated the effect of recombinant human interleukin-7 (rhIL-7) on survival in a 2-hit model of sublethal cecal ligation and puncture followed by P. aeruginosa pneumonia. Potential immunologic mechanisms responsible for the rhIL-7 putative beneficial effect were also examined, focusing on IL-17, IL-22, IFN-γ, and TNF-α, cytokines that are critical in the control of sepsis and pulmonary Pseudomonas infections. Results showed that rhIL-7 was highly effective in preventing P. aeruginosa-induced death, i.e., 92% survival in rhIL-7-treated mice versus 56% survival in control mice. rhIL-7 increased absolute numbers of immune effector cells in lung and spleen and ameliorated the sepsis-induced loss of lung innate lymphoid cells (ILCs). rhIL-7 also significantly increased IL-17-, IFN-γ-, and TNF-α-producing lung ILCs and CD8 T cells as well as IFN-γ- and TNF-α-producing splenic T cell subsets and ILCs. Furthermore, rhIL-7 enhanced NF-κB and STAT3 signaling in lungs during sepsis and pneumonia. Given the high mortality associated with secondary P. aeruginosa pneumonia, the ability of rhIL-7 to improve immunity and increase survival in multiple animal models of sepsis, and the remarkable safety profile of rhIL-7, clinical trials with rhIL-7 should be considered., (© Society for Leukocyte Biology.)

Erythropoiesis-stimulating agents (ESAs) that exert long-acting antianemia effects have been developed recently, but their mechanisms are poorly understood. Analyses reveal unique erythropoietin receptor (EPOR)-binding properties for one such ESA, the synthetic EPOR agonist peginesatide. Compared with recombinant human EPO and darbepoietin, peginesatide exhibited a slow on rate, but sustained EPOR residency and resistant displacement. In EPO-dependent human erythroid progenitor UT7epo cells, culture in peginesatide unexpectedly upmodulated endogenous cell surface EPOR levels with parallel increases in full-length EPOR-68K levels. These unique properties are suggested to contribute to the durable activity of this (and perhaps additional) dimeric peptide hematopoietic growth factor receptor agonist., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)