Newly Diagnosed Mental Health Disorders in Patients With Breast Cancer Receiving Radiation Therapy.

PURPOSE: Patients with a mental health disorder (MHD) have higher age-adjusted mortality compared with the general population. Few reports investigate factors contributing to MHD among patients with breast cancer receiving radiation therapy. We report the incidence of acquired MHD after the diagnosis of breast cancer and treatment with radiation therapy. METHODS AND MATERIALS: Using a single institution, prospectively maintained database, we analyzed patients with breast cancer treated with radiation therapy between 2012 and 2017. We cross-referenced these patients with newly acquired International Classification of Diseases, Tenth Revision (ICD-10) MHD codes (F01-F99) within 3 years postbreast cancer diagnosis. The study included baseline National Comprehensive Cancer Network® (NCCN) distress tool scores and area deprivation index (ADI). Univariate and multivariable (MVA) Cox regression analyses were conducted to evaluate factors affecting new MHD onset. RESULTS: Of the 967 included patients, 318 (33%) developed an MHD after their breast cancer diagnosis, which was predominately anxiety (45.1%) and depression (20.1%) related, with a median (IQR) time to diagnosis of 30 (24-33) months. Univariate analysis showed lymph node-positive disease, receipt of chemotherapy, receipt of a mastectomy, high comorbidity index, divorced status, retired status, and fourth-quartile ADI as significant predictors. On MVA, only receipt of chemotherapy (hazard ratio [HR], 1.70; P = .014) and divorced status (HR, 2.04; P = .009) remained significant. Fourth-quartile ADI, retired status, and high comorbidity index showed trends toward significance (HR, 1.78, P = .065; HR, 1.46, P = .094; HR, 1.41, P = .059, respectively). On MVA examining the effects of the radiation therapy type on MHD, whole breast with regional nodal irradiation (HR, 2.31, P = .015) and postmastectomy radiation therapy (HR, 1.88, P = .024) were both strong predictors of MHD development. Additionally, an NCCN distress tool score of >3 was also predictive of MHD onset. CONCLUSIONS: In this cohort, 1 in 3 patients with localized breast cancer developed a new MHD, predominantly related to anxiety and depression. MHD risk was higher among divorced patients, those receiving chemotherapy, and patients receiving postmastectomy radiation therapy or whole breast with regional nodal irradiation. These findings highlight the importance of future studies and targeted interventions to support this vulnerable population.

Oncology's Silent Caregivers: A Mixed-Methods Exploration of the Experiences, Outcomes, and Unmet Needs of Caregiving Youth of a Parent With Cancer.

BACKGROUND: Cancer affects the whole family system causing reorganization of functioning and responsibilities where children may take on a caregiving role. In the United States, an estimated 204 000 to 475 000 caregiving youth provide multifaceted, extended care in oncology. This results in both positive and negative outcomes for youth-spanning multiple domains of health. OBJECTIVE: The aim of this study was to explore the caregiving experiences, outcomes, and unmet needs of caregiving youth (aged 12-24 years) in oncology. METHODS: An explanatory sequential mixed-methods study design was used. Fifty-two adults who lived with a parent with cancer as a child were recruited via social media and asked to complete an online survey. A subsample of 18 individuals reporting high to very high amounts of caregiving were subsequently interviewed. RESULTS: The mean reported caregiving youth age was 16.13 (±4.86) years. They provided care approximately 22.43 h/wk for approximately 3.04 years. Most (71.2%) reported high to very high amounts of caregiving activity. The highest reported categories of unmet needs were information, family, feelings, friends, and time out/recreation. Qualitative findings included 4 themes: stepping into the role, family communication, dealing with feelings, and a new separateness. CONCLUSIONS: Identified needs included a desire for more information to aid in uncertainty, better communication within the family, needing someone to help them process their feelings, and peer-to-peer support. IMPLICATIONS FOR PRACTICE: It is important for nurses and researchers to be aware of and acknowledge the needs of families dealing with cancer and aid in the development and implementation of tailored interventions to support caregiving youth.

Radiation Therapy in the Management of Extensive Giant Condyloma Acuminata With Rectal Involvement: A Case Report.

Giant condyloma acuminata (GCA) is a rare, locally aggressive manifestation of human papillomavirus (HPV) infection, typically affecting the anorectal area. Patients with GCA often have a poor prognosis due to the high risk of malignant transformation. In this case report, we present a 39-year-old man with HIV who developed progressive and refractory anorectal GCA. Despite initially non-cancerous pathology results, there were concerns regarding a malignant component to the mass. Multidisciplinary discussions led to the decision to pursue definitive radiation therapy. This case report and review of the literature highlight the role of radiation in the management of GCA and the importance of a multidisciplinary approach in the treatment of complex cases.

High Clinical Exome Sequencing Diagnostic Rates and Novel Phenotypic Expansions for Nonisolated Microphthalmia, Anophthalmia, and Coloboma.

Purpose: A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions. Methods: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC. Results: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes. Conclusions: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.

Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.

Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Importance: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma. Objective: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma. Design, Setting, and Participants: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023. Exposure: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs. Main Outcomes and Measures: Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene. Results: In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set. Conclusions and Relevance: This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

Deriving relations at multiple levels of complexity following minimal instruction: A demonstration.

Recommendations for achieving generalized instructional outcomes often overlook the capacity for generative learning for most verbally competent humans. Four children (ages 5-8) participated in this project. In Study 1, we provided decontextualized discrete trial teaching to establish arbitrary relations between colors, pictures of characters, and researcher motor actions. All participants engaged in derivative responding, providing evidence of relational framing. Subsequently, we demonstrated that, with no additional instruction, these derivatives contributed to effective action within a socially valid context (i.e., Candyland gameplay). Study 2 extended the demonstration by teaching frames of opposition. Following teaching, all participants engaged in novel and contextually appropriate responding that entailed the derivation of both coordination and opposition between untrained stimuli. This outcome demonstrates how teaching simple relations can result in learning that manifests at higher levels of complexity (i.e., relational networking), providing some evidence that there can be socially valid benefits to decontextualized discrete trial instruction.

Emerging methods for measuring physical activity using accelerometry in children and adolescents with neuromotor disorders: a narrative review.

BACKGROUND: Children and adolescents with neuromotor disorders need regular physical activity to maintain optimal health and functional independence throughout their development. To this end, reliable measures of physical activity are integral to both assessing habitual physical activity and testing the efficacy of the many interventions designed to increase physical activity in these children. Wearable accelerometers have been used for children with neuromotor disorders for decades; however, studies most often use disorder-specific cut points to categorize physical activity intensity, which lack generalizability to a free-living environment. No reviews of accelerometer data processing methods have discussed the novel use of machine learning techniques for monitoring physical activity in children with neuromotor disorders. METHODS: In this narrative review, we discuss traditional measures of physical activity (including questionnaires and objective accelerometry measures), the limitations of standard analysis for accelerometry in this unique population, and the potential benefits of applying machine learning approaches. We also provide recommendations for using machine learning approaches to monitor physical activity. CONCLUSIONS: While wearable accelerometers provided a much-needed method to quantify physical activity, standard cut point analyses have limitations in children with neuromotor disorders. Machine learning models are a more robust method of analyzing accelerometer data in pediatric neuromotor disorders and using these methods over disorder-specific cut points is likely to improve accuracy of classifying both type and intensity of physical activity. Notably, there remains a critical need for further development of classifiers for children with more severe motor impairments, preschool aged children, and children in hospital settings.

Lateral Extra-articular Tenodesis Augmentation of Anterior Cruciate Ligament Reconstruction Is Most Commonly Indicated for Pivot Shift of Grade 2 or Greater and for Revision Anterior Cruciate Ligament Reconstruction.

PURPOSE: To determine the most common indications for lateral extra-articular tenodesis (LET) augmentation of anterior cruciate ligament reconstruction (ACLR). METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Embase, Web of Science, and Cochrane Database of Systematic Reviews from 2000 to the present (June 2022). Studies that met the following criteria were included: patients of any age who underwent LET in addition to ACLR, studies reporting at least 1 indication for LET, and observational/randomized controlled trial study designs including prevalence of indications. Publications had to be reported in English and peer reviewed and to have originated in the United States or countries offering identical protocols and procedures. RESULTS: A total of 463 studies were identified from the initial search, 23 of which met inclusion criteria and were included in the review. Eight of the 23 studies (34.8%) used a modified Lemaire technique, seven (30.4%) used a MacIntosh modified by Arnold-Coker, and eight (34.8%) used other techniques to perform LET. A total of 2,125 patients (53% female, 47% male [3 studies did not report sex]) underwent ACLR augmented with LET. The indications along with prevalence were as follows: positive pivot shift test (grade ≥2) (19 of 23, 82.6%), revision ACLR (12 of 23, 52.2%), ligamentous laxity (11 of 23, 47.8%), general sports participation (11 of 23, 47.8%), age less than 25 years (8 of 23, 34.8%), high risk of graft failure (5 of 23, 21.7%), and positive Lachman test (4 of 23, 17.4%). CONCLUSIONS: Pivot shift grade ≥2 was the most common reason orthopaedic surgeons chose to add LET to ACLR, with revision ACLR, patient age <25, and general sports participation following closely behind. LEVEL OF EVIDENCE: Level I to IV, systematic review of studies.

Brain-Derived Neurotrophic Factor in Pediatric Acquired Brain Injury and Recovery.

We review emerging preclinical and clinical evidence regarding brain-derived neurotrophic factor (BDNF) protein, genotype, and DNA methylation (DNAm) as biomarkers of outcomes in three important etiologies of pediatric acquired brain injury (ABI), traumatic brain injury, global cerebral ischemia, and stroke. We also summarize evidence suggesting that BDNF is (1) involved in the biological embedding of the psychosocial environment, (2) responsive to rehabilitative therapies, and (3) potentially modifiable. BDNF's unique potential as a biomarker of neuroplasticity and neural repair that is reflective of and responsive to both pre- and post-injury environmental influences separates it from traditional protein biomarkers of structural brain injury with exciting potential to advance pediatric ABI management by increasing the accuracy of prognostic tools and informing clinical decision making through the monitoring of therapeutic effects.

Probing the impact of exposure to diversity on infants' social categorization.

Humans learn about the world through inductive reasoning, generalizing information about an individual to others in the category. Indeed, by infancy, monolingual children expect people who speak the same language (but not people who speak different languages) to be similar in their food preferences (Liberman et al., 2016). Here, we ask whether infants who are exposed to linguistic diversity are more willing to generalize information even across language-group lines. To test this, we ran an inductive inference task and collected data on exposure to linguistic diversity at the interpersonal and neighborhood levels. Infants with more linguistically diverse social networks were more likely to generalize a food preference across speakers of different languages. However, this relationship was not seen for neighborhood diversity. We discuss implications of this work on understanding the development of bias and its malleability based on early social experiences. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Magnetic resonance imaging shows spinal curvature in Chinook salmon (Oncorhynchus tshawytscha) is associated with chronic inflammation of peri-vertebral soft tissues.

Chinook salmon (Oncorhynchus tshawytscha) farmed in New Zealand are known to develop abnormal spinal curvature late in seawater production. Its cause is presently unknown, but there is evidence to suggest a neuromuscular pathology. Using magnetic resonance imaging (MRI), we evaluated the relationship between soft tissue pathology and spinal curvature in farmed Chinook salmon. Regions of interest (ROIs) presenting as pathologic MRI signal hyper-intensity were identified from scans of 24 harvest-sized individuals: 13 with radiographically-detectable spinal curvature and 11 without. ROIs were excised from individuals using anatomical landmarks as reference points and histologically analysed. Pathologic MRI signal was observed more frequently in individuals with radiographic curvature (92%, n = 12) than those without (18%, n = 2), was localized to the peri-vertebral connective tissues and musculature, and presented as three forms: inflammation, fibrosis, or both. These pathologies are consistent with a chronic inflammatory process, such as that observed during recovery from a soft tissue injury, and suggest spinal curvature in farmed Chinook salmon may be associated with damage to and/or compromised integrity of the peri-vertebral soft tissues. Future research to ascertain the contributing factors is required.

Resident Assessment of Clinician Educators According to Core ACGME Competencies.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires faculty to pursue annual development to enhance their teaching skills. Few studies exist on how to identify and improve the quality of teaching provided by faculty educators. Understanding the correlation between numeric scores assigned to faculty educators and their tangible, practical teaching skills would be beneficial. OBJECTIVE: This study aimed to identify and describe qualities that differentiate numerically highly rated and low-rated physician educators. DESIGN: This observational mixed-methods study evaluated attending physician educators between July 1, 2015, and June 30, 2021. Quantitative analysis involved descriptive statistics, normalization of scores, and stratification of faculty into tertiles based on a summary score. We compared the highest and lowest tertiles during qualitative analyses of residents' comments. PARTICIPANTS: Twenty-five attending physicians and 111 residents in an internal medicine residency program. MAIN MEASURES: Resident evaluations of faculty educators, including 724 individual assessments of faculty educators on 15 variables related to the ACGME core competencies. KEY RESULTS: Quantitative analyses revealed variation in attending physician educators' performance across the ACGME core competencies. The highest-rated teaching qualities were interpersonal and communication skills, medical knowledge, and professionalism, while the lowest-rated teaching quality was systems-based practice. Qualitative analyses identified themes distinguishing high-quality from low-quality attending physician educators, such as balancing autonomy and supervision, role modeling, engagement, availability, compassion, and excellent teaching. CONCLUSIONS: This study provides insights into areas where attending physicians' educational strategies can be improved, emphasizing the importance of role modeling and effective communication. Ongoing efforts are needed to enhance the quality of faculty educators and resident education in internal medicine residency programs.

Restoration of sensory feedback from the foot and reduction of phantom limb pain via closed-loop spinal cord stimulation.

Restoring somatosensory feedback in individuals with lower-limb amputations would reduce the risk of falls and alleviate phantom limb pain. Here we show, in three individuals with transtibial amputation (one traumatic and two owing to diabetic peripheral neuropathy), that sensations from the missing foot, with control over their location and intensity, can be evoked via lateral lumbosacral spinal cord stimulation with commercially available electrodes and by modulating the intensity of stimulation in real time on the basis of signals from a wireless pressure-sensitive shoe insole. The restored somatosensation via closed-loop stimulation improved balance control (with a 19-point improvement in the composite score of the Sensory Organization Test in one individual) and gait stability (with a 5-point improvement in the Functional Gait Assessment in one individual). And over the implantation period of the stimulation leads, the three individuals experienced a clinically meaningful decrease in phantom limb pain (with an average reduction of nearly 70% on a visual analogue scale). Our findings support the further clinical assessment of lower-limb neuroprostheses providing somatosensory feedback.

Availability of Family Caregiver Programs in US Cancer Centers.

Importance: Family caregivers provide the majority of health care to the 18 million patients with cancer in the US. Yet despite providing complex medical and nursing care, a large proportion of caregivers report no formal support or training. In recognition of this gap, many interventions to support cancer caregivers have been developed and tested over the past 2 decades. However, there are few system-level data on whether US cancer centers have adopted and implemented these interventions. Objective: To describe and characterize the availability of family caregiver support programs in US cancer centers. Design, Setting, and Participants: This cross-sectional national survey study was conducted between September 1, 2021, and April 30, 2023. Participants comprised clinical and administrative staff of Commission on Cancer-accredited US cancer centers. Data analysis was performed in May and June 2023. Main Outcomes and Measures: Survey questions about the availability of 11 types of family caregiver programs (eg, peer mentoring, education classes, and psychosocial programs) were developed after literature review, assessment of similar program evaluation surveys, and discussions among a 13-member national expert advisory committee. Family caregiver programs were defined as structured, planned, and coordinated groups of activities and procedures aimed at specifically supporting family caregivers as part of usual care. Survey responses were tabulated using standard descriptive statistics, including means, proportions, and frequencies. Results: Of the surveys sent to potential respondents at 971 adult cancer centers, 238 were completed (response rate, 24.5%). After nonresponse weight adjustment, most cancer centers (75.4%) had at least 1 family caregiver program; 24.6% had none. The most common program type was information and referral services (53.6%). Cancer centers with no programs were more likely to have smaller annual outpatient volumes (χ2 = 11.10; P = .011). Few centers had caregiver programs on training in medical and/or nursing tasks (21.7%), caregiver self-care (20.2%), caregiver-specific distress screening (19.3%), peer mentoring (18.9%), and children caregiving for parents (8.3%). Very few programs were developed from published evidence in a journal (8.1%). The top reason why cancer centers selected their programs was community members requesting the program (26.3%); only 12.3% of centers selected their programs based on scientific evidence. Most programs were funded by the cancer center or hospital (58.6%) or by philanthropy (42.4%). Conclusions and Relevance: In this survey study, most cancer centers had family caregiver programs; however, a quarter had none. Furthermore, the scope of programming was limited and rarely evidence based, with few centers offering caregiving education and training. These findings suggest that implementation strategies are critically needed to foster uptake of evidence-based caregiver interventions.

Polyamines and hypusination are important for Clostridioides difficile toxin B (TcdB)-mediated activation of group 3 innate lymphocytes (ILC3s).

Clostridioides difficile is the most common cause of nosocomial gastrointestinal tract bacterial infections. We lack fully effective reliable treatments for this pathogen, and there is a critical need to better understand how C. difficile interacts with our immune system. Group 3 innate lymphocytes (ILC3s) are rare immune cells localized within mucosal tissues that protect against bacterial infections. Upon activation, ILC3s secrete high levels of the cytokine interleukin-22 (IL-22), which is a critical regulator of tissue responses during infection. C. difficile toxin B (TcdB), the major virulence factor, directly activates ILC3s, resulting in high IL-22 levels. We previously reported that polyamines are important in the activation of ILC3s by the innate cytokine interleukin-23 (IL-23) but did not identify a specific mechanism. In this study, we examine how a pathogen impacts a metabolic pathway important for immune cell function and hypothesized that polyamines are important in TcdB-mediated ILC3 activation. We show that TcdB upregulates the polyamine biosynthesis pathway, and the inhibition of the pathway decreases TcdB-mediated ILC3 activation. Two polyamines, putrescine and spermidine, are involved. Spermidine is the key polyamine in the hypusination of eukaryotic initiation factor 5A (eIF5A), and the inhibition of eIF5A reduced ILC3 activation. Thus, there is potential to leverage polyamines in ILC3s to promote activation of ILC3s during C. difficile infection and other bacterial infections where ILC3s serve a protective role.

Treatment of a Non-syndromic Carotid Body Paraganglioma Using Fast Neutron Radiotherapy: A Case Report and Review of Literature.

Non-syndromic carotid body paragangliomas (CBPs) are the most common head and neck CBPs. Malignant transformation or symptomatic presentation is rare, but patients may occasionally endorse tinnitus, cranial nerve (CN) deficits, and ear pulsations. Historically, treatment of CBP was primarily through surgical intervention, which predisposed patients to CN deficits and significant blood loss due to the neurovascular structures in close proximity to these tumors. More recently, the utilization of pre-treatment embolization and radiotherapy has allowed for the reduction in treatment morbidity. Stereotactic radiosurgery (SRS) and external beam radiotherapy (EBRT) have been investigated as alternatives to traditional surgical intervention, with a documented reduction in the incidence of postoperative morbidity. While several retrospective studies and meta-analyses compare outcomes following surgical and traditional radiotherapeutic interventions, currently no literature exists regarding the potential utility of fast neutron therapy in treating this disease. In this case report, we highlight a patient with a non-syndromic CBP treated with pre-treatment embolization and fast neutron therapy, review the post-treatment course, and present a review of the extant literature on the subject.

Stress-mediated dysregulation of the Rap1 small GTPase impairs hippocampal structure and function.

The effects of repeated stress on cognitive impairment are thought to be mediated, at least in part, by reductions in the stability of dendritic spines in brain regions critical for proper learning and memory, including the hippocampus. Small GTPases are particularly potent regulators of dendritic spine formation, stability, and morphology in hippocampal neurons. Through the use of small GTPase protein profiling in mice, we identify increased levels of synaptic Rap1 in the hippocampal CA3 region in response to escalating, intermittent stress. We then demonstrate that increased Rap1 in the CA3 is sufficient in and of itself to produce stress-relevant dendritic spine and cognitive phenotypes. Further, using super-resolution imaging, we investigate how the pattern of Rap1 trafficking to synapses likely underlies its effects on the stability of select dendritic spine subtypes. These findings illuminate the involvement of aberrant Rap1 regulation in the hippocampus in contributing to the psychobiological effects of stress.

First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.