Midpoint of sleep is associated with sleep quality in older adults with and without symptomatic Alzheimer's disease.

Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep affects sleep-wake activity and is also associated with AD, but little is known about links between sleep architecture and the midpoint of sleep in older adults. In this study, we tested if the midpoint of sleep is associated with different measures of sleep architecture, AD biomarkers, and cognitive status among older adults with and without symptomatic AD. Methods: Participants (N = 243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, a home sleep apnea test, and self-reported sleep logs. The midpoint of sleep was defined by actigraphy. Results: A later midpoint of sleep was associated with African-American race and greater night-to-night variability in the sleep midpoint. After adjusting for multiple potential confounding factors, a later sleep midpoint was associated with longer rapid-eye movement (REM) onset latency, decreased REM sleep time, more actigraphic awakenings at night, and higher < 2 Hz non-REM slow-wave activity. Conclusions: Noninvasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions in older adults at risk for AD. Sleep timing is associated with multiple other sleep measures and may affect their utility as markers of AD. The midpoint of sleep may be changed through behavioral intervention and should be taken into account when using sleep as a marker for AD risk.

CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL.

ABSTRACT: CD19-negative relapse is a leading cause of treatment failure after chimeric antigen receptor (CAR) T-cell therapy for acute lymphoblastic leukemia. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral cotransduction with vectors encoding our previously described fast-off rate CD19 CAR (AUTO1) combined with a novel CD22 CAR capable of effective signaling at low antigen density. Twelve patients with advanced B-cell acute lymphoblastic leukemia were treated (CARPALL [Immunotherapy with CD19/22 CAR Redirected T Cells for High Risk/Relapsed Paediatric CD19+ and/or CD22+ Acute Lymphoblastic Leukaemia] study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Of 12 patients, 10 (83%) achieved a measurable residual disease (MRD)-negative complete remission at 2 months after infusion. Of 10 responding patients, 5 had emergence of MRD (n = 2) or relapse (n = 3) with CD19- and CD22-expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months, there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95% confidence interval [CI], 41%-91%) at 6 and 12 months. The 6- and 12-month event-free survival rates were 75% (95% CI, 41%-91%) and 60% (95% CI, 23%-84%), respectively. These data suggest dual targeting with cotransduction may prevent antigen-negative relapse after CAR T-cell therapy.

Obesity intervention evidence synthesis: Where are the gaps and which should we address first?

Health professionals and policymakers rely on evidence synthesized from high quality research studies. Yet, there remain unanswered questions about how to prevent and treat obesity. In this research project, international practice guidelines and Cochrane systematic reviews were examined in order to identify gaps in the synthesized obesity intervention evidence base. One hundred and forty-two partial or complete gaps were found. Systematic review questions to address these gaps were formulated and subjected to a prioritization consultation process with 36 international obesity expert stakeholders. Forty-three review questions were priority-assessed. The top 10 ranked review questions received support from at least 75.0% of stakeholders. The leading questions focused on preventive and community-based approaches, including those delivered through primary-care. Children within the context of their families were a highly-prioritized target group, as were persons with diabetes or disabilities. Experts also prioritized reviews to determine which elements of programs are the most effective, and by which mode they are best delivered. Experts recommended that negative, psycho-social, and longer-term outcomes be captured in reviews. We request reviewers and funders to strongly consider addressing the top 10 leading prioritized review questions presented here.

eNOS plays essential roles in the developing heart and aorta linked to disruption of Notch signalling.

eNOS (NOS3) is the enzyme that generates nitric oxide, a signalling molecule and regulator of vascular tone. Loss of eNOS function is associated with increased susceptibility to atherosclerosis, hypertension, thrombosis and stroke. Aortopathy and cardiac hypertrophy have also been found in eNOS null mice, but their aetiology is unclear. We evaluated eNOS nulls before and around birth for cardiac defects, revealing severe abnormalities in the ventricular myocardium and pharyngeal arch arteries. Moreover, in the aortic arch, there were fewer baroreceptors, which sense changes in blood pressure. Adult eNOS null survivors showed evidence of cardiac hypertrophy, aortopathy and cartilaginous metaplasia in the periductal region of the aortic arch. Notch1 and neuregulin were dysregulated in the forming pharyngeal arch arteries and ventricles, suggesting that these pathways may be relevant to the defects observed. Dysregulation of eNOS leads to embryonic and perinatal death, suggesting mutations in eNOS are candidates for causing congenital heart defects in humans. Surviving eNOS mutants have a deficiency of baroreceptors that likely contributes to high blood pressure and may have relevance to human patients who suffer from hypertension associated with aortic arch abnormalities.

PMart Web Application: Marketplace for Interactive Analysis of Panomics Data.

PMart is a web-based tool for reproducible quality control, exploratory data analysis, statistical analysis, and interactive visualization of 'omics data, based on the functionality of the pmartR R package. The newly improved user interface supports more 'omics data types, additional statistical capabilities, and enhanced options for creating downloadable graphics. PMart supports the analysis of label-free and isobaric-labeled (e.g., TMT, iTRAQ) proteomics, nuclear magnetic resonance (NMR) and mass-spectrometry (MS)-based metabolomics, MS-based lipidomics, and ribonucleic acid sequencing (RNA-seq) transcriptomics data. At the end of a PMart session, a report is available that summarizes the processing steps performed and includes the pmartR R package functions used to execute the data processing. In addition, built-in safeguards in the backend code prevent users from utilizing methods that are inappropriate based on omics data type. PMart is a user-friendly interface for conducting exploratory data analysis and statistical comparisons of omics data without programming.

Comparison of thoracolumbar spine kinematics and injuries in reclined frontal impact sled tests between mid-size adult female and male PMHS.

Disparities in injury tolerance and kinematic response remain understudied despite field data highlighting sex-based differences in injury risk. Furthermore, the automotive industry anticipates occupants will prefer reclined seating in highly automated vehicles. This study aimed to compare thoracolumbar spine kinematics and injuries between mid-size female and male post-mortem human subjects (PMHS) in reclined frontal impacts. Seven adult PMHS (three female, four male) were tested in reclined (50°) 50 km/h frontal impacts. The PMHS were seated on a semi-rigid seat and restrained by a prototype three-point seat belt system designed to mitigate submarining. The 3-D motions of five vertebrae and the pelvis were measured by an optical motion tracking system. Pressure transducers were inserted into intervertebral discs at three locations along the lumbar spine to track timing of lumbar vertebra fractures. Due to variations in the geometry of the pelvis and soft tissue surrounding the pelvis compared to the male subjects, the female subjects could not be positioned in the seat the same as the males, and, as a result, the females and their belt anchors needed to be translated forward in the seat to maintain similar belt geometry relative to the males. The females exhibited similar pre-test spinal curvatures and kinematics to the males. An L1 fracture was observed in one of three female subjects and two of four male subjects, and timing of these fractures were both similar (61 âˆ¼ 65 ms) and close to the time of peak downward seat force. Generally, the female and male subjects exhibited similar kinematic and injury responses in this reclined frontal impact sled test condition.

Chronotype is Associated with Sleep Quality in Older Adults.

Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep or chronotype affects sleep-wake activity and is also associated with AD, but little is known about links between sleep and chronotype in older adults. In this study, we tested if different measures of sleep and chronotype are associated among older adults even after adjusting for multiple potentially confounding variables. Methods: Participants (N=243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, and self-reported sleep logs. Chronotype was defined as the midpoint of sleep measured by actigraphy. Results: Later mid-point of sleep (i.e., late chronotype) was associated with African American race and greater night-to-night variability in the sleep mid-point. After controlling for age, race, sex, cognitive status, AD biomarkers, and sleep disorders, a later mid-point of sleep was associated with longer rapid eye movement (REM) onset latency, decreased REM sleep time, lower sleep efficiency, increased sleep onset latency, and more awakenings at night. Late chronotype was also associated with increased <2 Hz non-REM slow-wave activity. Conclusions: To identify individuals at risk for cognitive impairment before symptoms onset, non-invasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions. Chronotype is a potential modifiable AD risk factor and should also be taken into account when using sleep as a marker for AD risk.

Mental Health First Aid as a tool for improving mental health and well-being.

BACKGROUND: The prevalence of mental health problems is high, and they have a wide-ranging and deleterious effect on many sectors in society. As well as the impact on individuals and families, mental health problems in the workplace negatively affect productivity. One of the factors that may exacerbate the impact of mental health problems is a lack of 'mental health literacy' in the general population. This has been defined as 'knowledge and beliefs about mental disorders, which aid their recognition, management, or prevention'. Mental Health First Aid (MHFA) is a brief training programme developed in Australia in 2000; its aim is to improve mental health literacy and teach mental health first aid strategies. The course has been adapted for various contexts, but essentially covers the symptoms of various mental health disorders, along with associated mental health crisis situations. The programmes also teach trainees how to provide immediate help to people experiencing mental health difficulties, as well as how to signpost to professional services. It is theorised that improved knowledge will encourage the trainees to provide support, and encourage people to actively seek help, thereby leading to improvements in mental health. This review focuses on the effects of MHFA on the mental health and mental well-being of individuals and communities in which MHFA training has been provided. We also examine the impact on mental health literacy. This information is essential for decision-makers considering the role of MHFA training in their organisations. OBJECTIVES: To examine mental health and well-being, mental health service usage, and adverse effects of MHFA training on individuals in the communities in which MHFA training is delivered. SEARCH METHODS: We developed a sensitive search strategy to identify randomised controlled trials (RCTs) of MHFA training. This approach used bibliographic databases searching, using a search strategy developed for Ovid MEDLINE (1946 -), and translated across to Ovid Embase (1974 -), Ovid PsycINFO (1967 -), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Common Mental Disorders Group's Specialised Register (CCMDCTR). We also searched online clinical trial registries (ClinicalTrials.gov and WHO ICTRP), grey literature and reference lists of included studies, and contacted researchers in the field to identify additional and ongoing studies. Searches are current to 13th June 2023. SELECTION CRITERIA: We included RCTs and cluster-RCTs comparing any type of MHFA-trademarked course to no intervention, active or attention control (such as first aid courses), waiting list control, or alternative mental health literacy interventions. Participants were individuals in the communities in which MHFA training is delivered and MHFA trainees. Primary outcomes included mental health and well-being of individuals, mental health service usage and adverse effects of MHFA training. Secondary outcomes related to individuals, MHFA trainees, and communities or organisations in which MHFA training has been delivered DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We analysed categorical outcomes as risk ratios (RRs) and odds ratios (ORs), and continuous outcomes as mean differences (MDs) or standardised mean differences (SMDs), with 95% confidence intervals (CIs). We pooled data using a random-effects model. Two review authors independently assessed the key results using the Risk of Bias 2 tool and applied the GRADE criteria to assess the certainty of evidence MAIN RESULTS: Twenty-one studies involving a total of 22,604 participants were included in the review. Fifteen studies compared MHFA training with no intervention/waiting list, two studies compared MHFA training with an alternative mental health literacy intervention, and four studies compared MHFA training with an active or an attention control intervention. Our primary time point was between six and 12 months. When MHFA training was compared with no intervention, it may have little to no effect on the mental health of individuals at six to 12 months, but the evidence is very uncertain (OR 0.88, 95% CI 0.61 to 1.28; 3 studies; 3939 participants). We judged all the results that contributed to this outcome as being at high risk of bias. No study measured mental health service usage at six to 12 months. We did not find published data on adverse effects. Only one study with usable data compared MHFA training with an alternative mental health literacy intervention. The study did not measure outcomes in individuals in the community. It also did not measure outcomes at our primary time point of six to 12 months. Four studies with usable data compared MHFA training to an active or attention control. None of the studies measured outcomes at our primary time point of six to 12 months. AUTHORS' CONCLUSIONS: We cannot draw conclusions about the effects of MHFA training on our primary outcomes due to the lack of good quality evidence. This is the case whether it is compared to no intervention, to an alternative mental health literacy intervention, or to an active control. Studies are at high risk of bias and often not sufficiently large to be able to detect differences.

malbacR: A Package for Standardized Implementation of Batch Correction Methods for Omics Data.

Mass spectrometry is a powerful tool for identifying and analyzing biomolecules such as metabolites and lipids in complex biological samples. Liquid chromatography and gas chromatography mass spectrometry studies quite commonly involve large numbers of samples, which can require significant time for sample preparation and analyses. To accommodate such studies, the samples are commonly split into batches. Inevitably, variations in sample handling, temperature fluctuation, imprecise timing, column degradation, and other factors result in systematic errors or biases of the measured abundances between the batches. Numerous methods are available via R packages to assist with batch correction for omics data; however, since these methods were developed by different research teams, the algorithms are available in separate R packages, each with different data input and output formats. We introduce the malbacR package, which consolidates 11 common batch effect correction methods for omics data into one place so users can easily implement and compare the following: pareto scaling, power scaling, range scaling, ComBat, EigenMS, NOMIS, RUV-random, QC-RLSC, WaveICA2.0, TIGER, and SERRF. The malbacR package standardizes data input and output formats across these batch correction methods. The package works in conjunction with the pmartR package, allowing users to seamlessly include the batch effect correction in a pmartR workflow without needing any additional data manipulation.

Transcriptional signatures associated with persisting CD19 CAR-T cells in children with leukemia.

In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukemia (R/R B-ALL), CD19-targeting chimeric antigen receptor (CAR)-T cells often induce durable remissions, which requires the persistence of CAR-T cells. In this study, we systematically analyzed CD19 CAR-T cells of 10 children with R/R B-ALL enrolled in the CARPALL trial via high-throughput single-cell gene expression and T cell receptor sequencing of infusion products and serial blood and bone marrow samples up to 5 years after infusion. We show that long-lived CAR-T cells developed a CD4/CD8 double-negative phenotype with an exhausted-like memory state and distinct transcriptional signature. This persistence signature was dominant among circulating CAR-T cells in all children with a long-lived treatment response for which sequencing data were sufficient (4/4, 100%). The signature was also present across T cell subsets and clonotypes, indicating that persisting CAR-T cells converge transcriptionally. This persistence signature was also detected in two adult patients with chronic lymphocytic leukemia with decade-long remissions who received a different CD19 CAR-T cell product. Examination of single T cell transcriptomes from a wide range of healthy and diseased tissues across children and adults indicated that the persistence signature may be specific to long-lived CAR-T cells. These findings raise the possibility that a universal transcriptional signature of clinically effective, persistent CD19 CAR-T cells exists.

The Effects of Recline Angle and Restraint Geometry on Lap Belt-Pelvis Interaction for Above-Normal BMI Motor Vehicle Occupants.

The interaction of the three-point seat belt with the occupant, particularly the lap belt with the pelvis, is affected by a multitude of intrinsic and extrinsic factors, including the torso recline angle, lap belt angle, and occupant body mass index (BMI). While field data analyses have shown the strong safety benefit for seat belt use regardless of occupant size or crash direction, the term "submarining" historically has been used to describe a scenario in which the lap belt loads the abdominal soft tissue and organs, superior and posterior to the pelvic bone. While contemporary restraint systems work to effectively address the risk of submarining in occupants properly seated and properly belted, scenarios in which the lap belt may not properly engage the load-bearing pelvis remain. These scenarios, including a reclined torso angle or shallow lap belt angle, require further study. In this research study, eight non-injurious seated belt pull tests were conducted on two constrained whole-body cadavers of above-normal BMI (≥ 25 kg/m2) with controlled variation of torso and lap belt-pelvis angles. Test factors affecting belt engagement with the pelvis were identified for each subject. Belt engagement was largely affected by the initial placement of the lap belt. The initial belt placement was affected by the torso angle which influenced the distribution of the abdominal soft tissue. The belt disengagement thresholds differed between subjects due to the inter-subject differences in soft tissue distribution, which affected the lap belt kinematics relative to the pelvis. In addition to improving the understanding of this particular submarining mechanism, this study provides a dataset for future validation of human body model soft tissue deformation response from lap belt loading.

Graphene oxide exposure alters gut microbial community composition and metabolism in an in vitro human model.

Graphene oxide (GO) nanomaterials have unique physicochemical properties that make them highly promising for biomedical, environmental, and agricultural applications. There is growing interest in the use of GO and extensive in vitro and in vivo studies have been conducted to assess its nanotoxicity. Although it is known that GO can alter the composition of the gut microbiota in mice and zebrafish, studies on the potential impacts of GO on the human gut microbiome are largely lacking. This study addresses an important knowledge gap by investigating the impact of GO exposure- at low (25 mg/L) and high (250 mg/L) doses under both fed (nutrient rich) and fasted (nutrient deplete) conditions- on the gut microbial communitys' structure and function, using an in vitro model. This model includes simulated oral, gastric, small intestinal phase digestion of GO followed by incubation in a colon bioreactor. 16S rRNA amplicon sequencing revealed that GO exposure resulted in a restructuring of community composition. 25 mg/L GO induced a marked decrease in the Bacteroidota phylum and increased the ratio of Firmicutes to Bacteroidota (F/B). Untargeted metabolomics on the supernatants indicated that 25 mg/L GO impaired microbial utilization and metabolism of substrates (amino acids, carbohydrate metabolites) and reduced production of beneficial microbial metabolites such as 5-hydroxyindole-3-acetic acid and GABA. Exposure to 250 mg/L GO resulted in community composition and metabolome profiles that were very similar to the controls that lacked both GO and digestive enzymes. Differential abundance analyses revealed that 3 genera from the phylum Bacteroidota (Bacteroides, Dysgonomonas, and Parabacteroides) were more abundant after 250 mg/L GO exposure, irrespective of feed state. Integrative correlation network analysis indicated that the phylum Bacteroidota showed strong positive correlations to multiple microbial metabolites including GABA and 3-indoleacetic acid, are much larger number of correlations compared to other phyla. These results show that GO exposure has a significant impact on gut microbial community composition and metabolism at both low and high GO concentrations.

Rapid remodeling of the soil lipidome in response to a drying-rewetting event.

BACKGROUND: Microbiomes contribute to multiple ecosystem services by transforming organic matter in the soil. Extreme shifts in the environment, such as drying-rewetting cycles during drought, can impact the microbial metabolism of organic matter by altering microbial physiology and function. These physiological responses are mediated in part by lipids that are responsible for regulating interactions between cells and the environment. Despite this critical role in regulating the microbial response to stress, little is known about microbial lipids and metabolites in the soil or how they influence phenotypes that are expressed under drying-rewetting cycles. To address this knowledge gap, we conducted a soil incubation experiment to simulate soil drying during a summer drought of an arid grassland, then measured the response of the soil lipidome and metabolome during the first 3 h after wet-up. RESULTS: Reduced nutrient access during soil drying incurred a replacement of membrane phospholipids, resulting in a diminished abundance of multiple phosphorus-rich membrane lipids. The hot and dry conditions increased the prevalence of sphingolipids and lipids containing long-chain polyunsaturated fatty acids, both of which are associated with heat and osmotic stress-mitigating properties in fungi. This novel finding suggests that lipids commonly present in eukaryotes such as fungi may play a significant role in supporting community resilience displayed by arid land soil microbiomes during drought. As early as 10 min after rewetting dry soil, distinct changes were observed in several lipids that had bacterial signatures including a rapid increase in the abundance of glycerophospholipids with saturated and short fatty acid chains, prototypical of bacterial membrane lipids. Polar metabolites including disaccharides, nucleic acids, organic acids, inositols, and amino acids also increased in abundance upon rewetting. This rapid metabolic reactivation and growth after rewetting coincided with an increase in the relative abundance of firmicutes, suggesting that members of this phylum were positively impacted by rewetting. CONCLUSIONS: Our study revealed specific changes in lipids and metabolites that are indicative of stress adaptation, substrate use, and cellular recovery during soil drying and subsequent rewetting. The drought-induced nutrient limitation was reflected in the lipidome and polar metabolome, both of which rapidly shifted (within hours) upon rewet. Reduced nutrient access in dry soil caused the replacement of glycerophospholipids with phosphorus-free lipids and impeded resource-expensive osmolyte accumulation. Elevated levels of ceramides and lipids with long-chain polyunsaturated fatty acids in dry soil suggest that lipids likely play an important role in the drought tolerance of microbial taxa capable of synthesizing these lipids. An increasing abundance of bacterial glycerophospholipids and triacylglycerols with fatty acids typical of bacteria and polar metabolites suggest a metabolic recovery in representative bacteria once the environmental conditions are conducive for growth. These results underscore the importance of the soil lipidome as a robust indicator of microbial community responses, especially at the short time scales of cell-environment reactions. Video Abstract.

pmartR 2.0: A Quality Control, Visualization, and Statistics Pipeline for Multiple Omics Datatypes.

The pmartR (https://github.com/pmartR/pmartR) package was designed for the quality control (QC) and analysis of mass spectrometry data, tailored to specific characteristics of proteomic (isobaric or labeled), metabolomic, and lipidomic data sets. Since its initial release, the tool has been expanded to address the needs of its growing userbase and now includes QC and statistics for nuclear magnetic resonance metabolomic data, and leverages the DESeq2, edgeR, and limma-voom R packages for transcriptomic data analyses. These improvements have made progress toward a unified omics processing pipeline for ease of reporting and streamlined statistical purposes. The package's statistics and visualization capabilities have also been expanded by adding support for paired data and by integrating pmartR with the trelliscopejs R package for the quick creation of trellis displays (https://github.com/hafen/trelliscopejs). Here, we present relevant examples of each of these enhancements to pmartR and highlight how each new feature benefits the omics community.

Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial.

BACKGROUND AIMS: Delayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies. METHODS: Patients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm. RESULTS: The authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively. CONCLUSIONS: These data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion.

A multidimensional examination of psychological distress among Latina mothers with and without HIV.

The Latino population is disproportionally affected by HIV in the United States. Latina women, in particular, have significantly higher rates of HIV diagnosis than their White counterparts. Latinas with HIV who are primary family caregivers face multidimensional challenges from caregiving demands to stressors related to chronic illness, acculturation, family functioning, and socioeconomic disparities, which may contribute to higher psychological distress than Latina mothers without HIV. However, to date, scant research has focused on the mental health needs of Latina mothers living with HIV (MLHs) and how these needs are similar or different to Latina mothers without HIV. Thus, using a multidimensional approach we: (a) examined the associations between HIV status, acculturation, family functioning, socioeconomic status, and psychological distress among Latina mothers and (b) identified how these associations differed between Latina mothers with and without HIV. Cross-sectional, self-reported data were obtained via face-to-face interviews from 221 Latina MLHs and 116 Latina neighborhood control mothers (NCMs) living without HIV in Los Angeles, California. Results from multivariate ordinary least square regressions showed that higher acculturation was associated with psychological distress among MLHs, whereas higher levels of family conflict and education were associated with psychological distress among NCMs. Findings highlight the differential mental health needs of Latina mothers based on HIV status. Our study findings provide social work implications for culturally responsive interventions that can address multidimensional stressors experienced by marginalized Latinas MLHs.

Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.

Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells.

Pharmacological Programming of Endosomal Signaling Activated by Small Molecule Ligands of the Follicle Stimulating Hormone Receptor.

Follicle-stimulating hormone receptor (FSHR) is a G protein-coupled receptor (GPCR) with pivotal roles in reproduction. One key mechanism dictating the signal activity of GPCRs is membrane trafficking. After binding its hormone FSH, FSHR undergoes internalization to very early endosomes (VEEs) for its acute signaling and sorting to a rapid recycling pathway. The VEE is a heterogeneous compartment containing the Adaptor Protein Phosphotyrosine Interacting with Pleckstrin homology Domain and Leucine Zipper 1 (APPL1) with distinct functions in regulating endosomal Gαs/cAMP signaling and rapid recycling. Low molecular weight (LMW) allosteric FSHR ligands were developed for use in assisted reproductive technology yet could also provide novel pharmacological tools to study FSHR. Given the critical nature of receptor internalization and endosomal signaling for FSHR activity, we assessed whether these compounds exhibit differential abilities to alter receptor endosomal trafficking and signaling within the VEE. Two chemically distinct LMW agonists (benzamide, termed B3 and thiazolidinone, termed T1) were employed. T1 was able to induce a greater level of cAMP than FSH and B3. As cAMP signaling drives gonadotrophin hormone receptor recycling, rapid exocytic events were evaluated at single event resolution. Strikingly, T1 was able to induce a 3-fold increase in recycling events compared to FSH and two-fold more compared to B3. As T1-induced internalization was only marginally greater, the dramatic increase in recycling and cAMP signaling may be due to additional mechanisms. All compounds exhibited a similar requirement for receptor internalization to increase cAMP and proportion of FSHR endosomes with active Gαs, suggesting regulation of cAMP signaling induced by T1 may be altered. APPL1 plays a central role for GPCRs targeted to the VEE, and indeed, loss of APPL1 inhibited FSH-induced recycling and increased endosomal cAMP signaling. While T1-induced FSHR recycling was APPL1-dependent, its elevated cAMP signaling was only partially increased following APPL1 knockdown. Unexpectedly, B3 altered the dependence of FSHR to APPL1 in an opposing manner, whereby its endosomal signaling was negatively regulated by APPL1, while B3-induced FSHR recycling was APPL1-independent. Overall, FSHR allosteric compounds have the potential to re-program FSHR activity via altering engagement with VEE machinery and also suggests that these two distinct functions of APPL1 can potentially be selected pharmacologically.

Thoracolumbar spine kinematics and injuries in frontal impacts with reclined occupants.

OBJECTIVE: Highly automated vehicles may permit alternative seating postures, which could alter occupant kinematics and challenge current restraint designs. One predicted posture is a reclined seated position. While the spine of upright occupants is subjected to flexion during frontal crashes, the orientation of reclined occupants tends to subject the spine to high compressive loads followed by high flexion loads. This study aims to investigate kinematics and mechanisms of loading in the thoracolumbar spine for a reclined seated posture through the use of postmortem human subjects (PMHS). METHODS: Frontal impact sled tests (50 kph delta-v) were conducted on five adult midsize male PMHS seated with the torso reclined to 50 degrees with respect to the vertical. The PMHS were seated on a semi-rigid seat and restrained by a seat-integrated three-point belt with dual lap-belt pretensioners and a shoulder-belt pretensioner with a 3 kN load-limiter. 3-D kinematic trajectories of five chosen vertebrae, and the pelvis were measured relative to the vehicle buck. Intervertebral pressure transducers were installed at three locations in the lumbar column to detect load timing. RESULTS: Three PMHS suffered fractures at L1. Combined compression and flexion of the thoracolumbar spine occurred in all tests, but the magnitude of peak flexion varied across the PMHS. During the PMHS' forward excursion, the pelvis rotated anteriorly in two tests and posteriorly in two tests (lap-belt submarining occurred in one). In one test, the pelvis mount interacted with the seat, but did not affect kinematics. CONCLUSIONS: Anterior rotation of the pelvis caused increased extension of the lumbar spine, which exacerbated lumbar compression in two of the PMHS; the one subject whose pelvis kinematic tracking was lost exhibited similar compression kinematics. Posterior rotation of the pelvis enabled lumbar flexion, which decreased lumbar compression, but lead to lap-belt submarining in one case. Lumbar kinematics for these reclined frontal impacts were sensitive to changes in initial posture of the spine (magnitude of lordosis or kyphosis) and pelvis (pitch angle). To our knowledge, this study is the first to analyze thoracolumbar kinematics and resulting injuries of a reclined seating posture using PMHS.

Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.

BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.