A phase II trial of sitravatinib + nivolumab after progression on immune checkpoint inhibitor in patients with metastatic clear cell RCC

Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to immune checkpoint inhibitors (ICI) by reducing immune-suppressive myeloid cells in metastatic clear cell RCC (ccRCC). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve clinical outcomes. Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into 3 cohorts: (1) 1L nivolumab + ipilimumab, (2) 1L pembrolizumab + axitinib, (3) prior cabozantinib or lenvatinib and ICI. Starting dose of sitravatinib was 100 mg PO daily and nivolumab was 480 mg IV every 4 weeks. The co-primary endpoints were objective response rate (ORR) and disease control rate (DCR) at 24 weeks. The study was designed to enroll 88 patients with an interim analysis for futility in each cohort using a BOP2 design, but it was terminated early due to discontinuation of sitravatinib development. Results: Fourteen patients were enrolled with 2 in cohort A, 6 in cohort B, and 6 in cohort C. Across all cohorts, the ORR was 15.4% (2/13, 1 not evaluable) and DCR at 24 weeks was 35.7% (5/14). DCR at 24 months was 63% for Cohort A + B and 0% for Cohort C. Median progression free survival was 5.5 mo [95% CI 3.8-not reached (NR)], and median overall survival was 13.3 mo (95% CI 8.77-NR). Six patients (42.9%) experienced a grade 3-4 adverse event (AE) and 2 patients (14.3%) experienced an immune-mediated AE. Conclusion: In this small phase 2 trial with limited sample size due to early termination, sitravatinib plus nivolumab demonstrated a manageable safety profile and produced modest clinical benefit. The observed responses occurred in patients who did not receive prior treatment with cabozantinib or lenvatinib

Factors associated with early sexual onset and delaying sex in rural middle school youth

Purpose: Early sexual onset contributes to poor health outcomes through the life course. We use the social behavioral model to examine the behaviors and attitudes associated with early sexual onset and the intention to delay sex in middle school youth. Methods: Youth in rural communities with high rates of hepatitis C and HIV filled out a survey prior to implementation of an evidence-based sex education program. Participants were asked if they had ever had sex and whether they planned to abstain from sex until the end of high school. We collected demographics, attitudes about abstinence, agency for sexual refusal, parent communication, sexual health knowledge, and history of system involvement. Logistic regression was utilized to examine factors associated with each outcome. Findings: Our sample included 6,799 students, 12.7 years old ± 0.9 and 50.3% female. 5.1% had ever had sex and 73.9% planned to abstain until the end of high school. Early sexual onset was associated with older age, negative attitudes toward abstinence, lower agency for sexual refusal, more frequent parent communication about sex, history of child welfare, and history of juvenile involvement. Planning to abstain until the end of high school was associated with being younger, female, positive attitudes toward abstinence, higher agency for sexual refusal, less communication with parents about sex, more communication with parents about relationships, not having a history of foster involvement, and not having a history of juvenile involvement. Conclusions: Age, agency, and parent communication were all associated with both outcomes. Our findings highlight the importance of early comprehensive, trauma-informed sex education

Neurostimulation devices to treat Alzheimer’s disease

The use of neurostimulation devices for the treatment of Alzheimer's disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD

Steps toward clinical validation of exhaled volatile organic compound biomarkers for hypoglycemia in persons with type 1 diabetes

Persons with type 1 diabetes (T1D) must track/control their blood glucose (BG) levels to avoid hypoglycemic events (BG < 70 mg/dL), which in the most severe cases can lead to seizures or even death. Canines may lead the way toward innovative testing solutions, as they can be trained to identify hypoglycemia simply and noninvasively by smelling exhaled volatile organic compounds (VOCs). To identify breath-based biomarkers of hypoglycemia, samples were collected during two consecutive summers at a diabetes camp (Cohort 1 and Cohort 2), and VOCs were analyzed by gas chromatography-mass spectrometry. Conserved VOCs between the two cohorts were identified, but individual VOCs alone had low accuracies for detection. Therefore, supervised multivariate statistical analysis was undertaken to identify a biosignature in the training data set (Cohort 1) that could detect hypoglycemia with higher accuracy (sensitivity = 94.8%/specificity = 95.0%). When this model was blindly tested on Cohort 2, hypoglycemia was classified with sensitivity = 90.0%/specificity = 89.9%. Ultimately, this study makes strides toward clinical validation through verifying biomarkers of hypoglycemia in hundreds of breath samples. These results may be translated to design a sensor array that could be integrated into a portable breathalyzer to increase glycemic control in persons with T1D

Species differences in comorbid alcohol use disorder and major depressive disorder: A narrative review

Alcohol use disorder (AUD) and major depressive disorder (MDD) are often comorbid, and it is estimated that between 15 % to 33% of people dependent on alcohol have an MDD diagnosis. Mood‐related symptoms are also common in humans during acute withdrawal, but by most accounts, symptoms abate after 2–4 weeks of alcohol abstinence. Preclinical studies, important for understanding the etiology and finding treatments for this comorbidity, also find depression‐like and anxiety‐like phenotypes in early abstinence along with protracted negative affect detectable past 2 weeks postcessation. In this narrative review, we focus on the translational divergence of AUD and MDD comorbidity with a focus on the time line mismatch between species in concurrent AUD + MDD and MDD following AUD. We also highlight the preclinical success and clinical failure of classic antidepressants for AUD and the relative absence of withdrawal and negative affect in high‐drinking selected lines of mice and rats. We suggest sources of these discrepancies, including discussion of relief/reward‐driven drinking subpopulations and future directions for the field

Considerations and recommendations from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 3-Ex vivo imaging: Data processing, comparisons with microscopy, and tractography

Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages that facilitate high spatial resolution and high SNR images, cutting-edge diffusion contrasts, and direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work concludes a three-part series of recommendations and considerations for preclinical dMRI. Herein, we describe best practices for dMRI of ex vivo tissue, with a focus on image pre-processing, data processing, and comparisons with microscopy. In each section, we attempt to provide guidelines and recommendations but also highlight areas for which no guidelines exist (and why), and where future work should lie. We end by providing guidelines on code sharing and data sharing and point toward open-source software and databases specific to small animal and ex vivo imaging

I'm Not Fine, Thanks for Asking: The Communication Work of Birth Trauma

IUIResearch on traumatic birth asserts that up to 68% of birth persons describe their birth experience as traumatic. Despite this significant statistic, societal expectations regarding communication practices following the traumatic birth of a child remain rooted in stigmatized perceptions, often decentering the trauma from communication. This study investigates birth trauma through the lens of Donovan’s communication work and Tracy’s reflexive approach to qualitative research to explore how communication work surrounding birth trauma, while inherently individual in its nuances, impacts broader communication processes and relational dynamics. Twenty-three interviews were conducted with birth persons who experienced trauma during and after the delivery of a living child. Reflexivity played a central role in both the design and execution of the study, allowing for an evolving interview guide informed by participants' experiences and the researcher’s own lived experience of birth trauma. Findings from a phronetic iterative analysis revealed that communication work related to birth trauma is multifaceted, involving the navigation of interpersonal relationships, medical interactions, and self-advocacy. The study highlights how birth persons engage in legitimizing their trauma, managing multiple communication goals, and handling the emotional labor of managing relationships with others regarding their trauma. Furthermore, participants frequently noted the significant impact of external validation or invalidation, from healthcare professionals and social supports in processing their trauma. Ultimately, this research contributes to a deeper understanding of how communication functions as both a barrier and conduit in addressing the lived experiences of birth persons, and how these insights can inform future clinical and social approaches to trauma and the way it is discussed