6-Year Follow-Up of a World Record Breaking Master Marathon Runner.

Endurance performance declines with advancing age. Of the three main physiological factors that determine endurance running performance (maximal oxygen consumption [V̇O2max], lactate threshold, and running economy [RE]), V̇O2max appears to be most affected by age. While endurance performance declines with age, recently, endurance performance has rapidly improved in master athletes as the number of master athletes competing in endurance events has increased. Master athletes represent an intriguing model to study healthy aging. In this case study, we reassessed the physiological profile of a 76-year-old distance runner who broke the marathon world record for men over 70 years of age in 2018. This runner was tested a few months before breaking the world record and retested in 2024. Between 2018 and 2024, his marathon running velocity decreased significantly. Therefore, the purpose of this case study was to determine the physiological changes that explain his performance decline. RE remained similar to 2018, and while there was not a clear breakpoint in blood lactate, he still likely runs marathons at a high percentage (~90%) of his V̇O2max. However, V̇O2max declined by 15.1%. HRmax declined by 3.2% and maximal O2 pulse declined by 12.4%, suggesting that maximal stroke volume and/or arteriovenous O2 difference decreased. Altogether, although this marathoner continues to compete at an elite level, his performance has declined since his record-breaking marathon due to a reduction in V̇O2max. This is likely caused by reductions in maximal stroke volume and/or arteriovenous O2 difference. We speculate that these changes reflect primarily age-related processes.

Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47.

Spastic paraplegia 47 (SPG47) is a neurological disorder caused by mutations in the adaptor protein complex 4 ß1 subunit (AP4B1) gene leading to AP-4 complex deficiency. SPG47 is characterised by progressive spastic paraplegia, global developmental delay, intellectual disability and epilepsy. Gene therapy aimed at restoring functional AP4B1 protein levels is a rational therapeutic strategy to ameliorate the disease phenotype. Here we report that a single delivery of adeno-associated virus serotype 9 expressing hAP4B1 (AAV9/hAP4B1) into the cisterna magna leads to widespread gene transfer and restoration of various hallmarks of disease, including AP-4 cargo (ATG9A) mislocalisation, calbindin-positive spheroids in the deep cerebellar nuclei, anatomical brain defects and motor dysfunction, in an SPG47 mouse model. Furthermore, AAV9/hAP4B1-based gene therapy demonstrated a restoration of plasma neurofilament light (NfL) levels of treated mice. Encouraged by these preclinical proof-of-concept data, we conducted IND-enabling studies, including immunogenicity and GLP non-human primate (NHP) toxicology studies. Importantly, NHP safety and biodistribution study revealed no significant adverse events associated with the therapeutic intervention. These findings provide evidence of both therapeutic efficacy and safety, establishing a robust basis for the pursuit of an IND application for clinical trials targeting SPG47 patients.

Direct measurement of forces in air-based acoustic levitation systems.

Acoustic levitation is frequently used for non-contact manipulation of objects and to study the impact of microgravity on physical and biological processes. While the force field produced by sound pressure lifts particles against gravity (primary acoustic force), multiple levitating objects in the same acoustic cavity interact via forces that arise from scattered sound (secondary acoustic forces). Current experimental techniques for obtaining these force fields are not well-suited for mapping the primary force field at high spatial resolution and cannot directly measure the secondary scattering force. Here, we introduce a method that can measure both acoustic forces in situ, including secondary forces in the near-field limit between arbitrarily shaped, closely spaced objects. Operating similarly to an atomic force microscope, the method inserts into the acoustic cavity a suitably shaped probe tip at the end of a long, flexible cantilever and optically detects its deflection. This makes it possible to measure forces with a resolution better than 50 nN and also to apply stress or strain in a controlled manner to manipulate levitated objects. We demonstrate this by extracting the acoustic potential present in a levitation cavity, directly measuring the acoustic scattering force between two objects, and applying tension to a levitated granular raft of acoustically bound particles in order to obtain the force-displacement curve for its deformation.

Artery Grafting for Arterial Anastomoses in Head and Neck Free Tissue Transfer Reconstruction.

BACKGROUND: Vessel grafting is an important technique in head and neck free tissue transfer (FTT) reconstruction when a tension-free anastomosis is not otherwise feasible. To our knowledge, there are limited data regarding interposition artery grafts for arterial anastomoses in head and neck reconstruction. Here, we present a multi-institutional cohort of arterial interposition grafts for FTT reconstruction for head and neck defects. METHODS: A retrospective review was conducted at four tertiary care institutions for patients who underwent FTT reconstruction for head and neck defects which utilized an interposition artery graft for the arterial anastomosis. Charts were reviewed for type and length of artery grafts harvested, surgical indication, indication for artery graft, types of flaps harvested, and various preoperative characteristics (including history of radiation or previous FTT reconstruction surgery). Postoperative complications within postoperative day 30 were measured and reported. RESULTS: Nine patients met inclusion criteria. The lateral circumflex femoral artery (either transverse or descending branches) (n = 3) and facial artery (n = 3) were the most commonly harvested arteries. The scalp (n = 5) was the most common primary defect site. Seven grafts were harvested initially and in a planned fashion, while two were harvested as salvage techniques (either for flap salvage or vein graft failure). In planned grafts, arteries were the preferred interposition grafting method due to either size match preferences (n = 4) or similarities in wall thickness (n = 3) between graft and recipient artery. There were no reported cases of unplanned readmission, postoperative hematoma, fistula formation, wound infection, or donor site morbidities. Two patients required unplanned return to the operating room for flap compromise, both of which ultimately resulted in flap failure secondary to clot formation at both arterial and venous anastomoses. CONCLUSIONS: When arterial pedicle length is insufficient, interposition artery grafting is both a feasible and viable technique to achieve tension-free arterial anastomoses for select cases of highly complex head and neck free tissue reconstruction.

Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.

Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an "eat-me" signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial "don't eat-me" signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance. Whole-genome CRISPR-Cas9 screening showed that Toll-like receptor 3 (Tlr3) signaling regulated b2m expression. Targeting b2m or tlr3 reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive element (RE) transcripts. Overall, our data suggest that RE-associated double-stranded RNA could interact with TLR3 to stimulate surface expression of B2m on hematopoietic stem and progenitor cells. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.

Semaglutide for the management of diabesity: The real-world experience.

BACKGROUND: Diabesity (diabetes as a consequence of obesity) has emerged as a huge healthcare challenge across the globe due to the obesity pandemic. Judicious use of antidiabetic medications including semaglutide is important for optimal management of diabesity as proven by multiple randomized controlled trials. However, more real-world data is needed to further improve the clinical practice. AIM: To study the real-world benefits and side effects of using semaglutide to manage patients with diabesity. METHODS: We evaluated the efficacy and safety of semaglutide use in managing patients with diabesity in a large academic hospital in the United States. Several parameters were analyzed including demographic information, the data on improvement of glycated hemoglobin (HbA1c), body weight reduction and insulin dose adjustments at 6 and 12 months, as well as at the latest follow up period. The data was obtained from the electronic patient records between January 2019 to May 2023. RESULTS: 106 patients (56 males) with type 2 diabetes mellitus (T2DM), mean age 60.8 ± 11.2 years, mean durations of T2DM 12.4 ± 7.2 years and mean semaglutide treatment for 2.6 ± 1.1 years were included. Semaglutide treatment was associated with significant improvement in diabesity outcomes such as mean weight reductions from baseline 110.4 ± 24.6 kg to 99.9 ± 24.9 kg at 12 months and 96.8 ± 22.9 kg at latest follow up and HbA1c improvement from baseline of 82 ± 21 mmol/mol to 67 ± 20 at 12 months and 71 ± 23 mmol/mol at the latest follow up. An insulin dose reduction from mean baseline of 95 ± 74 units to 76.5 ± 56.2 units was also observed at the latest follow up. Side effects were mild and mainly gastrointestinal like bloating and nausea improving with prolonged use of semaglutide. CONCLUSION: Semaglutide treatment is associated with significant improvement in diabesity outcomes such as reduction in body weight, HbA1c and insulin doses without major adverse effects. Reviews of largescale real-world data are expected to inform better clinical practice decision making to improve the care of patients with diabesity.

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.

A high-throughput, microplate reader-based method to monitor in vitro HIV latency reversal in the absence of flow cytometry.

J-Lat cells are derivatives of the Jurkat CD4+ T cell line that contain a non-infectious, inducible HIV provirus with a GFP tag. While these cells have substantially advanced our understanding of HIV latency, their use by many laboratories in low and middle-income countries is restricted by limited access to flow cytometry. To overcome this barrier, we describe a modified J-Lat assay using a standard microplate reader that detects HIV-GFP expression following treatment with latency-reversing agents (LRAs). We show that HIV reactivation by control LRAs like prostratin and romidepsin is readily detected with dose dependence and with significant correlation and sensitivity to standard flow cytometry. For example, 10 µM prostratin induced a 20.1 ± 3.3-fold increase in GFP fluorescence in the microplate reader assay, which corresponded to 64.2 ± 5.0% GFP-positive cells detected by flow cytometery. Similarly, 0.3 µM prostratin induced a 1.7 ± 1.2-fold increase compared to 8.7 ± 5.7% GFP-positive cells detected. Using this method, we screen 79 epigenetic modifiers and identify molibresib, quisinostat, and CUDC-101 as novel LRAs. This microplate reader-based method offers accessibility to researchers in resource-limited regions to work with J-Lat cells and more actively participate in global HIV cure research efforts. Highlights: J-Lat T-cell lines are important to HIV cure research but require flow cytometryWe describe a method to work with J-Lat cells using a standard microplate readerThis assay can detect control LRAs similar to flow cytometry and discover new LRAsThis assay allows low-resourced laboratories to contribute to HIV cure research.

Validation of a computerized model for a new biomechanical concept- the fossa-foveolar mismatch- the answer to lesions of the ligamentous fossa-foveolar complex in the hip?

BACKGROUND: Hip-preserving surgery in young patients frequently reveals lesions of the ligamentum teres (LT). Histological and clinical evidence supports that those lesions could be source of intraarticular hip pain. It has been hypothesized that LT degeneration could be linked to the abnormal positioning of the fovea outside the lunate surface during various daily motions. We introduce the "fossa-foveolar mismatch" (FFM) by determining the trajectory of the fovea in the fossa during hip motions, enabling a comparison across diverse hip-pathomorphologies. AIMS: to determine (1) intraobserver reliability and (2) interobserver reproducibility of our computer-assisted 3-dimensional (3D) model of the FFM. MATERIALS AND METHODS: All patients with joint preserving surgery for femoroacetabular impingement syndrome (FAIS) or developmental dysplasia of the hip (DDH) at our institution (11. 2015-08.2019)were initially eligible. We employed a simple random sampling technique to select 15 patients for analysis. Three-dimensional surface models based on preoperative computed tomography (CT) scans were built, the fossa virtually excised, the fovea capitis marked. Models were subjected to physiological range of motion with validated 3D collision detection software. Using a standardized medial view on the resected fossa and the transparent lunate surface, the FFM-index was calculated for 17 motions. It was obtained by dividing the surface occupied by the fovea outside of the fossa by the total foveolar tracking surface. Three observers independently performed all analyses twice. (1) Intraobserver reliability and (2) interobserver reproducibility were calculated using intraclass correlation coefficients (ICCs). RESULTS: (1) We obtained excellent intraobserver ICCs for the FFM-index averaging 0.92 with 95% CI 0.77-0.9 among the three raters for all motions. (2) Interobserver reproducibility between raters was good to excellent, ranging from 0.76 to 0.98. CONCLUSIONS: The FFM-index showed excellent intraobserver reliability and interobserver reproducibility for all motions. This innovative approach deepens our understanding of biomechanical implications, providing valuable insights for identifying patient populations at risk.

Enhancing training in spiritual and religious competencies in mental health graduate education: Evaluation of an integrated curricular approach.

Despite practice guidelines for multiculturally competent care, including spiritual/religious diversity, most mental health graduate training programs do not formally address spiritual/religious competencies. Thus, we enhanced the Spiritual Competency Training in Mental Health (SCT-MH) course curriculum to train graduate students in foundational attitudes, knowledge, and skills for addressing clients' spirituality and/or religion (S/R). The hybrid (online and in-person) SCT-MH course curriculum was integrated into existing required graduate clinical courses (replacing 15% of a course's curriculum) and taught to 309 students by 20 instructors in 20 different graduate training programs across counseling, psychology, and social work disciplines. Using a multiple baseline waitlist control design in which students served as their own controls, students completed validated assessments at three timepoints evaluating their spiritual/religious competencies for understanding the intersection between S/R and mental health. We also collected qualitative data from the students to evaluate acceptability of the content and format of the training program. Students' scores on all seven measures of spiritual/religious competencies had a statistically significant positive increase after engaging with the SCT-MH curriculum compared to the control period. At the end of the course, 97% of the students envisioned using spiritually integrated therapy techniques with their clients at least some of the time, 92% or more rated the materials as helpful and relevant, and 96% were satisfied with the training modules. Results demonstrate that dedicating a small (i.e., 6 hours of class time; 10 hours outside class time) but intentional amount of course time to teaching spiritual/religious competencies increases students' attitudes, knowledge, and skills for attending to clients' S/R in clinical practice. The SCT-MH hybrid course content is freely available to all graduate programs on our website. https://www.spiritualandreligiouscompetenciesproject.com/resources/sct-mh.

A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier to SARS-CoV-2 entry that recent virus variants have evolved to resist.

Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently.

Protein profiling of zebrafish embryos unmasks regulatory layers during early embryogenesis.

The maternal-to-zygotic transition is crucial in embryonic development, marked by the degradation of maternally provided mRNAs and initiation of zygotic gene expression. However, the changes occurring at the protein level during this transition remain unclear. Here, we conducted protein profiling throughout zebrafish embryogenesis using quantitative mass spectrometry, integrating transcriptomics and translatomics datasets. Our data show that, unlike RNA changes, protein changes are less dynamic. Further, increases in protein levels correlate with mRNA translation, whereas declines in protein levels do not, suggesting active protein degradation processes. Interestingly, proteins from pure zygotic genes are present at fertilization, challenging existing mRNA-based gene classifications. As a proof of concept, we utilized CRISPR-Cas13d to target znf281b mRNA, a gene whose protein significantly accumulates within the first 2 h post-fertilization, demonstrating its crucial role in development. Consequently, our protein profiling, coupled with CRISPR-Cas13d, offers a complementary approach to unraveling maternal factor function during embryonic development.

COMPOSITE SCORES FOR TRANSPLANT CENTER EVALUATION: A NEW INDIVIDUALIZED EMPIRICAL NULL METHOD.

Risk-adjusted quality measures are used to evaluate healthcare providers with respect to national norms while controlling for factors beyond their control. Existing healthcare provider profiling approaches typically assume that the between-provider variation in these measures is entirely due to meaningful differences in quality of care. However, in practice, much of the between-provider variation will be due to trivial fluctuations in healthcare quality, or unobservable confounding risk factors. If these additional sources of variation are not accounted for, conventional methods will disproportionately identify larger providers as outliers, even though their departures from the national norms may not be "extreme" or clinically meaningful. Motivated by efforts to evaluate the quality of care provided by transplant centers, we develop a composite evaluation score based on a novel individualized empirical null method, which robustly accounts for overdispersion due to unobserved risk factors, models the marginal variance of standardized scores as a function of the effective sample size, and only requires the use of publicly-available center-level statistics. The evaluations of United States kidney transplant centers based on the proposed composite score are substantially different from those based on conventional methods. Simulations show that the proposed empirical null approach more accurately classifies centers in terms of quality of care, compared to existing methods.

Localized and Long-Lasting Adaptation in Dragonfly Target-Detecting Neurons.

Some visual neurons in the dragonfly (Hemicordulia tau) optic lobe respond to small, moving targets, likely underlying their fast pursuit of prey and conspecifics. In response to repetitive targets presented at short intervals, the spiking activity of these "small target motion detector" (STMD) neurons diminishes over time. Previous experiments limited this adaptation by including intertrial rest periods of varying durations. However, the characteristics of this effect have never been quantified. Here, using extracellular recording techniques lasting for several hours, we quantified both the spatial and temporal properties of STMD adaptation. We found that the time course of adaptation was variable across STMD units. In any one STMD, a repeated series led to more rapid adaptation, a minor accumulative effect more akin to habituation. Following an adapting stimulus, responses recovered quickly, though the rate of recovery decreased nonlinearly over time. We found that the region of adaptation is highly localized, with targets displaced by ∼2.5° eliciting a naive response. Higher frequencies of target stimulation converged to lower levels of sustained response activity. We determined that adaptation itself is a target-tuned property, not elicited by moving bars or luminance flicker. As STMD adaptation is a localized phenomenon, dependent on recent history, it is likely to play an important role in closed-loop behavior where a target is foveated in a localized region for extended periods of the pursuit duration.

Do small effects matter more in vulnerable populations? an investigation using Environmental influences on Child Health Outcomes (ECHO) cohorts.

BACKGROUND: A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. METHODS: Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight < 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach. RESULTS: When the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1-5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated. CONCLUSIONS: Vulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals.

Reevaluation of Recipient Vessel Selection in Breast Free Flap Reconstruction.

BACKGROUND: Current consensus has established the internal mammary vessels (IMV) over the thoracodorsal vessels (TDV) as the preferred recipients for microvascular breast reconstruction due to their superior flow rates and long-established outcomes. Yet, there are occurrences where the IMVs are not reliable and may subsequently prompt intraoperative decision-making. Several options exist, including the contralateral IMVs, thoracoacromial vessels, and TDVs. The appropriate sequence for vessel choice is not universally agreed upon. This study reevaluates the TDVs to highlight their viability as a second-line intraoperative alternative to the IMV and provide reference to the straightforward dissection required for harvest. METHODS: A retrospective, single-institution, breast-level analysis examining 4754 breast free flaps from 2978 patients undergoing bilateral free flap reconstruction was conducted. Postoperative complications within 180 days were evaluated, and cohorts based on anatomic anastomosis (IMV vs. TDV) were created to compare outcomes. Subanalysis was conducted based on flap laterality as well as whether a flap was planned or converted intraoperatively. RESULTS: Of 4754 breast free flaps, 4269 (89.8%) used the IMV while 485 (10.2%) used the TDV. Most complication rates between the TVD and IMV were not significantly different. Rates of flap loss were 1.0% and 1.2% for the IMV and TDV anastomosis (p = 0.59). IMV and TDV anastomosed flaps experienced similar rates of fat necrosis (6.3% vs. 6.2%, p = 0.915). However, multivariable analysis of all breasts regardless of laterality showed that skin necrosis was significantly less likely in TDV breasts (OR 0.45, 95% CI 0.29-0.71, p < 0.001). CONCLUSIONS: Given the relative similarity in cohort outcomes, TDV anastomosis can be considered a viable alternative to the IMV when the IMV is unavailable or technically disadvantageous. The TDV artery remains a robust and reliable option in the present-day plastic surgeon's repertoire for breast reconstruction.

Positive allosteric modulation of glutamate transporter reduces cocaine-induced locomotion and expression of cocaine conditioned place preference in rats.

The glutamatergic system, located throughout the brain including the prefrontal cortex and nucleus accumbens, plays a critical role in reward and reinforcement processing, and mediates the psychotropic effects of addictive drugs such as cocaine. Glutamate transporters, including EAAT2/GLT-1, are responsible for removing glutamate from the synaptic cleft. Reduced expression of GLT-1 following chronic cocaine use and abstinence has been reported. Here, we demonstrate that targeting GLT-1 with a novel positive allosteric modulator (PAM), NA-014, results in reduction of cocaine-associated behaviors in rats. Pharmacokinetic analysis demonstrated that NA-014 is brain-penetrant and suitable for in vivo studies.We found that 15 and 30 mg/kg NA-014 significantly reduced cocaine-induced locomotion in males. Only the 15 mg/kg dose was effective in females and 60 mg/kg was ineffective in both sexes. Furthermore, 30 and 60 mg/kg NA-014 reduced expression of cocaine conditioned place preference (CPP) in males. 30 mg/kg NA-014 reduced expression of cocaine CPP in females and 15 mg/kg did not affect cocaine CPP in either sex, suggesting GLT-1 influences cocaine-associated behaviors in a sex-dependent manner. NA-014 did not elicit rewarding behavior, nor alter baseline locomotion. Twice daily/7-day administration of 100 mg/kg of NA-014 did not alter GLT-1 or GLAST expression in either sex in the prefrontal cortex (PFC). Collectively, these studies demonstrated that NA-014 reduced the locomotor stimulant and rewarding effects of cocaine in male and female rats. In the context of psychostimulant use disorders, our study suggests studying GLT-1 PAMs as alternatives to ß-lactam compounds that increase GLT-1 protein levels.

Smoking prevalence and association with sociodemographic variables in cancer clinical trial participants.

BACKGROUND: Tobacco use (smoking) causes adverse clinical outcomes among patients with cancer, including increased cancer-related mortality. In participants in cancer clinical trials, the prevalence of tobacco use and the factors associated with tobacco use are not well described. METHODS: Data were examined from participants enrolled in SWOG cancer clinical treatment trials between 2016 and 2022 who reported their smoking status at trial enrollment. Baseline variables (smoking status, insurance type, zip code, and demographic factors) were obtained from patient registration forms. Bivariate and multivariable associations were examined via logistic regression. RESULTS: Among 4326 patients enrolled in 29 trials, 48.1% reported currently/previously smoking, including 12.4% currently, 4.9% recently, and 30.7% formerly. Ever smoking was more commonly reported in males, patients aged ≥65 years, patients with Medicaid or no insurance, patients from areas of high socioeconomic deprivation, and rural patients. Patients of Hispanic ethnicity and Asian and Pacific Islander patients were less likely to have ever smoked. In multivariable regression, patients with lung cancer were most likely to report ever smoking compared to patients with breast cancer (odds ratio, 4.98; p < .001). CONCLUSIONS: In the first comprehensive evaluation of smoking status among trial participants enrolled in National Cancer Institute network group treatment trials, nearly half reported ever smoking and one in six reported current or recent smoking. Smoking was more common among vulnerable population patients defined by demographic and socioeconomic factors. Tobacco use should be routinely assessed and reported in clinical trials to help reduce the negative cancer and overall health effects of persistent tobacco use and to address disparities among patients with cancer.

Robot-Assisted Spine Surgery: The Pearls and Pitfalls.

Robot-assisted spine surgery has gained notable popularity among surgeons because of recent advancements in technology. These innovations provide several key benefits, including high screw accuracy rates, reduced radiation exposure, customized preoperative and intraoperative planning options, and improved ergonomics for surgeons. Despite the promising outcomes reported in literature, potential technical challenges remain across various robotic platforms. It is crucial for surgeons to remember that robotic platforms are shared-control systems, requiring the surgeon to maintain primary control throughout the procedure. To ensure patient safety, surgeons should be well versed in common technical pitfalls and strategies to mitigate these limitations.