A Single-Dose Intranasal ChAd Vaccine Protects Upper and Lower Respiratory Tracts against SARS-CoV-2.

The coronavirus disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a prefusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal immunoglobulin A (IgA) and T cell responses, and almost entirely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission and curtailing pandemic spread.

Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor.

Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acute and chronic musculoskeletal disease in humans. Herein, we present a 2.2 Å resolution X-ray crystal structure of Mxra8 and 4 to 5 Å resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike. Two binding modes are observed with the fully mature VLP, with one Mxra8 binding with unique contacts. Only the high-affinity binding mode was observed in the complex with infectious CHIKV, as viral maturation and E3 occupancy appear to influence receptor binding-site usage. Our studies provide insight into how Mxra8 binds CHIKV and creates a path for developing alphavirus entry inhibitors.

A potently neutralizing SARS-CoV-2 antibody inhibits variants of concern by utilizing unique binding residues in a highly conserved epitope.

With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here, we developed a panel of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) that bound the receptor binding domain of the spike protein at distinct epitopes and blocked virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Although several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by ancestral SARS-CoV-2 strains, others induced escape variants in vivo or lost neutralizing activity against emerging strains. One mAb, SARS2-38, potently neutralized all tested SARS-CoV-2 variants of concern and protected mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engaged a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of neutralizing antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

Aerosol Jet Printing Conductive 3D Microstructures from Graphene Without Post-Processing.

Three-dimensional (3D) graphene microstructures have the potential to boost performance in high-capacity batteries and ultrasensitive sensors. Numerous techniques have been developed to create such structures; however, the methods typically rely on structural supports, and/or lengthy post-print processing, increasing cost and complexity. Additive manufacturing techniques, such as printing, show promise in overcoming these challenges. This study employs aerosol jet printing for creating 3D graphene microstructures using water as the only solvent and without any post-print processing required. The graphene pillars exhibit conductivity immediately after printing, requiring no high-temperature annealing. Furthermore, these pillars are successfully printed in freestanding configurations at angles below 45° relative to the substrate, showcasing their adaptability for tailored applications. When graphene pillars are added to humidity sensors, the additional surface area does not yield a corresponding increase in sensor performance. However, graphene trusses, which add a parallel conduction path to the sensing surface, are found to improve sensitivity nearly 2×, highlighting the advantages of a topologically suspended circuit construction when adding 3D microstructures to sensing electrodes. Overall, incorporating 3D graphene microstructures to sensor electrodes can provide added sensitivity, and aerosol jet printing is a viable path to realizing these conductive microstructures without any post-print processing.

Molecular neurobiology of loss: a role for basolateral amygdala extracellular matrix.

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an environmental enrichment removal (ER) paradigm in male rats. The basolateral amygdala (BLA) was identified as a region of interest, demonstrating differential Fos responsivity to ER and having an established role in stress processing and adaptation. A comprehensive multi-omics investigation of the BLA, spanning multiple cohorts, platforms, and analyses, revealed alterations in microglia and the extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition within the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, leading to a mismatch between stimulus and reaction intensity. These loss-like behaviors could be rescued by depleting BLA ECM during the removal period, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.

All-Carbon Thin-Film Transistors Using Water-Only Printing.

Printing thin-film transistors (TFTs) using nanomaterials is a promising approach for future electronics. Yet, most inks rely on environmentally harmful solvents for solubilizing and postprint processing the nanomaterials. In this work, we demonstrate water-only TFTs printed from all-carbon inks of semiconducting carbon nanotubes (CNTs), conducting graphene, and insulating crystalline nanocellulose (CNC). While suspending these nanomaterials into aqueous inks is readily achieved, printing the inks into thin films of sufficient surface coverage and in multilayer stacks to form TFTs has proven elusive without high temperatures, hazardous chemicals, and/or lengthy postprocessing. Using aerosol jet printing, our approach involves a maximum temperature of 70 °C and no hazardous chemicals─all inks are aqueous and only water is used for processing. An intermittent rinsing technique was utilized to address the surface adhesion challenges that limit film density of printed aqueous CNTs. These findings provide promising steps toward an environmentally friendly realization of thin-film electronics.

Early life cancer and chemotherapy lead to cognitive deficits related to alterations in microglial-associated gene expression in prefrontal cortex.

Children that survive leukemia are at an increased risk for cognitive difficulties. A better understanding of the neurobiological changes in response to early life chemotherapy will help develop therapeutic strategies to improve quality of life for leukemia survivors. To that end, we used a translationally-relevant mouse model consisting of leukemic cell line (L1210) injection into postnatal day (P)19 mice followed by methotrexate, vincristine, and leucovorin chemotherapy. Beginning one week after the end of chemotherapy, social behavior, recognition memory and executive function (using the 5 choice serial reaction time task (5CSRTT)) were tested in male and female mice. Prefrontal cortex (PFC) and hippocampus (HPC) were collected at the conclusion of behavioral assays for gene expression analysis. Mice exposed to early life cancer + chemotherapy were slower to progress through increasingly difficult stages of the 5CSRTT and showed an increase in premature errors, indicating impulsive action. A cluster of microglial-related genes in the PFC were found to be associated with performance in the 5CSRTT and acquisition of the operant response, and long-term changes in gene expression were evident in both PFC and HPC. This work identifies gene expression changes in PFC and HPC that may underlie cognitive deficits in survivors of early life exposure to cancer + chemotherapy.

Pediatric Chest Compression Improvement Via Augmented Reality Cardiopulmonary Resuscitation Feedback in Community General Emergency Departments: A Mixed-Methods Simulation-Based Pilot Study.

BACKGROUND: Yearly, more than 20,000 children experience a cardiac arrest. High-quality pediatric cardiopulmonary resuscitation (CPR) is generally challenging for community hospital teams, where pediatric cardiac arrest is infrequent. Current feedback systems are insufficient. Therefore, we developed an augmented reality (AR) CPR feedback system for use in many settings. OBJECTIVE: We aimed to evaluate whether AR-CPR improves chest compression (CC) performance in non-pediatric-specialized community emergency departments (EDs). METHODS: We performed an unblinded, randomized, crossover simulation-based study. A convenience sample of community ED nonpediatric nurses and technicians were included. Each participant performed three 2-min cycles of CC during a simulated pediatric cardiac arrest. Participants were randomized to use AR-CPR in one of three CC cycles. Afterward, participants participated in a qualitative interview to inquire about their experience with AR-CPR. RESULTS: Of 36 participants, 18 were randomized to AR-CPR in cycle 2 (group A) and 18 were randomized to AR-CPR in cycle 3 (group B). When using AR-CPR, 87-90% (SD 12-13%) of all CCs were in goal range, analyzed as 1-min intervals, compared with 18-21% (SD 30-33%) without feedback (p < 0.001). Analysis of qualitative themes revealed that AR-CPR may be usable without a device orientation, be effective at cognitive offloading, and reduce anxiety around and enhance confidence in the CC delivered. CONCLUSIONS: The novel CPR feedback system, AR-CPR, significantly changed the CC performance in community hospital non-pediatric-specialized general EDs from 18-21% to 87-90% of CC epochs at goal. This study offers preliminary evidence suggesting AR-CPR improves CC quality in community hospital settings.

Translationally relevant mouse model of early life cancer and chemotherapy exposure results in brain and small intestine cytokine responses: A potential link to cognitive deficits.

Survivors of acute lymphoblastic leukemia (ALL), the most common childhood cancer, are at increased risk for long-term cognitive problems, including executive function deficits. The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients and is closely associated with cognitive deficits. To address how early life cancer chemotherapy leads to cognitive deficits, we developed a translationally relevant mouse model of leukemia survival that exposed mice to leukemic cells and chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) in early life. Male and female mice were tested several weeks later using novel object recognition (recognition memory) and 5-choice serial reaction time task (executive function). Gene expression of proinflammatory, white matter and synapse-associated molecules was assessed in the prefrontal cortex and small intestine both acutely after chemotherapy and chronically after cognitive testing. Early life cancer-chemotherapy exposure resulted in recognition memory and executive function deficits in adult male mice. Prefrontal cortex expression of the chemokine Ccl2 was increased acutely, while small intestine expression of the proinflammatory cytokine tumor necrosis factor-alpha was elevated both acutely (both sexes) and chronically (males only). Inflammation in the small intestine was correlated with prefrontal cortical proinflammatory and synaptic gene expression changes, as well as to executive function deficits. Collectively, these data indicate that the current protocol results in a robust mouse model in which to study cognitive deficits in leukemia survivors, and suggest that small intestine inflammation may represent a novel contributor to adverse CNS consequences of early life chemotherapy.

Design and Validation of a Multimodal Wearable Device for Simultaneous Collection of Electrocardiogram, Electromyogram, and Electrodermal Activity.

Bio-signals are being increasingly used for the assessment of pathophysiological conditions including pain, stress, fatigue, and anxiety. For some approaches, a single signal is not sufficient to provide a comprehensive diagnosis; however, there is a growing consensus that multimodal approaches allow higher sensitivity and specificity. For instance, in visceral pain subjects, the autonomic activation can be inferred using electrodermal activity (EDA) and heart rate variability derived from the electrocardiogram (ECG), but including the muscle activation detected from the surface electromyogram (sEMG) can better differentiate the disease that causes the pain. There is no wearable device commercially capable of collecting these three signals simultaneously. This paper presents the validation of a novel multimodal low profile wearable data acquisition device for the simultaneous collection of EDA, ECG, and sEMG signals. The device was validated by comparing its performance to laboratory-scale reference devices. N = 20 healthy subjects were recruited to participate in a four-stage study that exposed them to an array of cognitive, orthostatic, and muscular stimuli, ensuring the device is sensitive to a range of stressors. Time and frequency domain analyses for all three signals showed significant similarities between our device and the reference devices. Correlation of sEMG metrics ranged from 0.81 to 0.95 and EDA/ECG metrics showed few instances of significant difference in trends between our device and the references. With only minor observed differences, we demonstrated the ability of our device to collect EDA, sEMG, and ECG signals. This device will enable future practical and impactful advances in the field of chronic pain and stress measurement and can confidently be implemented in related studies.

Feeding friend and foe: ample pollen mitigates the effects of pollen theft for a gynodioecious plant, Polemonium foliosissimum (Polemoniaceae).

BACKGROUND AND AIMS: Most angiosperms rely on pollinators to transport pollen and effect fertilization. While some floral visitors are effective pollinators, others act as thieves, consuming pollen but effecting little pollination in return. The importance of pollen theft in male and female reproductive success has received little attention. Here, we examined if pollen consumption by flies altered pollen receipt and exacerbated pollen limitation for a bumblebee-pollinated plant, Polemonium foliosissimum (Polemoniaceae). METHODS: To examine the effect of pollen-thieving flies, we took a three-pronged approach. First, we used single-visit observations to quantify pollen removal and pollen deposition by flies and bumblebees. Second, we manipulated pollen in the neighbourhood around focal plants in two years to test whether pollen reduction reduced pollen receipt. Third, we combined pollen reduction with hand-pollination to test whether pollen thieving exacerbated pollen limitation. Polemonium foliosissimum is gynodioecious in most populations in the Elk Mountains of central Colorado, USA. Thus, we also tested whether pollen theft affected hermaphrodites and females differently. RESULTS: Flies removed significantly more pollen and deposited less pollen per visit than did bumblebees. Reduction of pollen in the neighbourhood around focal plants reduced pollen receipt in both years but only nearly significantly so in 2015. In 2016, plants were significantly pollen-limited; hand-pollination significantly increased seeds per fruit for both hermaphrodites and females. However, the reduction of pollen around focal plants did not exacerbate pollen limitation for either hermaphrodites or females. CONCLUSIONS: Our results suggest that plants tolerate significant consumption of pollen by thieves and pollinators by producing ample pollen to feed both and fertilize available ovules. Our results demonstrate that pollen limitation in P. foliosissimum is driven by lack of effective pollinators rather than lack of pollen. Teasing out these effects elucidates the relative importance of drivers of reproductive success and thus the expected response to selection by different floral visitors.

Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial.

Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor. Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control. Design, Setting, and Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020. Interventions: Participants with PAD were randomized to low-intensity walking exercise (n = 116), high-intensity walking exercise (n = 124), or nonexercise control (n = 65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months. Main Outcomes and Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m). Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P = .34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P < .001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P < .001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P = .10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P = .44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation. Conclusions and Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.

Personalized Nutrition as a Key Contributor to Improving Radiation Response in Breast Cancer.

Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy.

The Impact of Environmental Conditions on Player Loads During Preseason Training Sessions in Women's Soccer Athletes.

ABSTRACT: Austin, AB, Collins, SM, Huggins, RA, Smith, BA, and Bowman, TG. The impact of environmental conditions on player loads during preseason training sessions in women's soccer athletes. J Strength Cond Res 35(10): 2775-2782, 2021-Our objective was to determine the impact of environmental conditions on player loads during preseason training sessions in women's soccer athletes. Eleven women's NCAA Division III soccer players (age = 20 ± 1 year, height = 167.28 ± 8.65 cm, body mass = 60.18 ± 5.42 kg, V̇o2max = 43.70 ± 3.95 ml·kg-1·min-1) volunteered to wear Global Positioning System (GPS) devices (Sports Performance Tracking, Melbourne, Australia) that provided measures of training session external intensity throughout all preseason practices (n = 15). We recorded wet-bulb globe temperature (WBGT), session Rating of Perceived Exertion-Training Load (sRPE-TL), and ΔBM during each preseason training session and set α ≤ 0.05. The combination of WBGT, sRPE-TL, and ΔBM explained 34% of the variance in GPS-based intensity score (proprietary measure) (F3,153 = 26.25, p < 0.001). Wet-bulb globe temperature (t156 = -2.58, p = 0.01), sRPE (t156 = 8.24, p < 0.001), and ΔBM (t156 = 2.39, p = 0.02) were significantly associated with intensity. The ΔBM from prepractice (60.00 ± 5.21 kg) to postpractice (59.61 ± 5.10 kg) was statistically significant (p < 0.001); however, ΔBM from the beginning of preseason (59.87 ± 5.31 kg) to the end of preseason (59.91 ± 5.58 kg) was not significant (p = 0.89). Despite relatively low to moderate environmental conditions, increases in WBGT were associated with reductions in GPS intensity and elevated internal load via sRPE-TL. Our findings support the association between exercise intensity and WBGT, internal load, and hydration status; thus, coaches and exercise scientists should take these factors into account when monitoring or interpreting intensity metrics. Furthermore, these findings support the continued use of environmental monitoring and hydration best-practice policies to limit exercise intensity in the heat so as to mitigate excessive heat stress.

Adolescent microglia play a role in executive function in male mice exposed to perinatal high fat diet.

In humans, excessive gestational weight gain during pregnancy is associated with an increased risk for executive function deficits in the offspring. Our previous work has confirmed this finding in mice, as offspring from dams fed a 60% high fat (HF) diet during breeding, gestation, and lactation demonstrate impulsive-like behavior in the 5 choice serial reaction time task (5CSRTT). Because the prefrontal cortex (PFC), which plays a key role in executive function, undergoes substantial postnatal adolescent pruning and microglia are actively involved in synaptic refinement, we hypothesized that microglia may play a role in mediating changes in brain development after maternal HF diet, with a specific focus on microglial activity during adolescence. Therefore, we treated male and female offspring from HF or control diet (CD) dams with PLX3397-formulated diet (PLX) to ablate microglia during postnatal days 23-45. After PLX removal and microglial repopulation, adult mice underwent testing to evaluate executive function. Adolescent PLX treatment did increase the control male dropout rate in learning the basic FR1 task, but otherwise had a minimal effect on behavior in control offspring. In males, HF offspring learned faster and performed better on a simple operant task (fixed ratio 1) without an effect of PLX. However, in HF offspring this increase in FR1 responding was associated with more impulsive errors in the 5CSRTT while PLX eliminated this association and decreased impulsive errors specifically in HF offspring. This suggests that adolescent PLX treatment improves executive function and particularly impulsive behavior in adult male HF offspring, without an overall effect of perinatal diet. In females, maternal HF diet impaired reversal learning but PLX had no effect on performance. We then measured gene expression in adult male PFC, nucleus accumbens (NAC), and amygdala (AMG), examining targets related to synaptic function, reward, and inflammation. Maternal HF diet increased PFC synaptophysin and AMG psd95 expression. PFC synaptophysin expression was correlated with more impulsive errors in the 5CSRTT in the HF offspring only and PLX treatment eliminated this correlation. These data suggest that adolescent microglia may play a critical role in mediating executive function after perinatal high fat diet in males.

The pathological features of hip abductor tendon tears - a cadaveric study.

BACKGROUND: The hip abductors are crucial in maintaining pelvic stability. Tears in these tendons are common and often debilitating. There is uncertainty regarding both the histological and macroscopic features of hip abductor tears. This study aims to clarify both the macroscopic and microscopic features of the tendon and enthesis in hip abductor tendon tears. METHODS: Thirty-six cadavers with an average age of 81 were dissected, and the hip abductor mechanisms removed en-bloc. The presence, location and size of the tears were recorded and analysed. The samples were processed into histological blocks and viewed using both transmitted and polarised light. Tendon histology was graded using the modified Movin's score in three sections (deep, middle and superficial layers) and the enthesis graded separately using 5-point criteria. Analysis of variance was used to confirm histological features associated with tears. RESULTS: Tears were found in 24 of 36 samples (67%). The most common finding was an isolated tear in the gluteus minimus (46%), followed by concurrent gluteus medius and gluteus minimus tears (33%). Histology revealed significantly more degeneration in both the tendon (p = 0.0005) and enthesis (p = 0.0011) when tears were present. Furthermore, these changes were concentrated in the deeper layers of the tendon (p = 0.0002) and enthesis (p = 0.003). CONCLUSION: This study demonstrated degeneration as the primary pathology underlying hip abductor tendon tears. Degenerative changes occur in both the tendon and enthesis, with the deeper layers predominantly affected. These findings are important for guiding surgical repair techniques and to aid the development of novel materials and biologics.

Adolescent environmental enrichment prevents behavioral and physiological sequelae of adolescent chronic stress in female (but not male) rats.

The late adolescent period is characterized by marked neurodevelopmental and endocrine fluctuations in the transition to early adulthood. Adolescents are highly responsive to the external environment, which enhances their ability to adapt and recover from challenges when given nurturing influences, but also makes them vulnerable to aberrant development when exposed to prolonged adverse situations. Female rats are particularly sensitive to the effects of chronic stress in adolescence, which manifests as passive coping strategies and blunted hypothalamo-pituitary adrenocortical (HPA) stress responses in adulthood. We sought to intervene by exposing adolescent rats to environmental enrichment (EE) immediately prior to and during chronic stress, hypothesizing that EE would minimize or prevent the long-term effects of stress that emerge in adult females. To test this, we exposed male and female rats to EE on postnatal days (PND) 33-60 and implemented chronic variable stress (CVS) on PND 40-60. CVS consisted of twice-daily unpredictable stressors. Experimental groups included: CVS/unenriched, unstressed/EE, CVS/EE and unstressed/unenriched (n = 10 of each sex/group). In adulthood, we measured behavior in the open field test and forced swim test (FST) and collected blood samples following the FST. We found that environmental enrichment given during the adolescent period prevented the chronic stress-induced transition to passive coping in the FST and reversed decreases in peak adrenocortical responsiveness observed in adult females. Adolescent enrichment had little to no effect on males or unstressed females tested in adulthood, indicating that beneficial effects are specific to females that were exposed to chronic stress.

Divergent effects of repeated restraint versus chronic variable stress on prefrontal cortical immune status after LPS injection.

Previous work from our group has shown that chronic homotypic stress (repeated restraint - RR) increases microglial morphological activation in the prefrontal cortex (PFC), while chronic heterotypic stress (chronic variable stress - CVS) produces no such effect. Therefore, we hypothesized that stressor modality would also determine the susceptibility of the PFC to a subsequent inflammatory stimulus (low dose lipopolysaccharide (LPS)). We found that RR, but not CVS, increased Iba-1 soma size in the PFC after LPS injection, consistent with microglial activation. In contrast, CVS decreased gene expression of proinflammatory cytokines and Iba-1 in the PFC under baseline conditions, which were not further affected by LPS. Thus, RR appears to promote microglial responses to LPS, whereas CVS is largely immunosuppressive. The results suggest that neuroimmune changes caused by CVS may to some extent protect the PFC from subsequent inflammatory stimuli. These data suggest that modality and/or intensity of stressful experiences will be a major determinant of central inflammation and its effect on prefrontal cortex-mediated functions.

Considerations for a Primary Care Physician Assistant in Treating Kidney Transplant Recipients.

The escalating amount of kidney transplant recipients (KTRs) represents a significant dilemma for primary care providers. As the number of physician assistants (PAs) has been steadily increasing in primary care in the United States, the utilization of these healthcare professionals presents a solution for the care of post-kidney transplant recipients. A physician assistant (PA) is a state licensed healthcare professional who practices medicine under physician supervision and can alleviate some of the increasing demands for primary patient care. Here we provide an outline of the crucial components and considerations for PAs caring for kidney transplant recipients. These include renal function and routine screenings, drug monitoring (both immunosuppressive and therapeutic), pre-existing and co-existing conditions, immunizations, nutrition, physical activity, infection, cancer, and the patient's emotional well-being. PAs should routinely monitor renal function and blood chemistry of KTRs. Drug monitoring of KTRs is a crucial responsibility of the PA because of the possible side-effects and potential drug-drug interactions. Therefore, PAs should obtain a careful and detailed patient history from KTRs. PAs should be aware of pre- and co-existing conditions of KTRs as this impacts treatment decisions. Regarding immunization, PAs should avoid administering vaccines containing live or attenuated viruses to KTRs. Because obesity following kidney transplantation is associated with decreased allograft survival, PAs should encourage KTRs to maintain a balanced diet with limited sugar. In addition, KTRs should be urged to gradually increase their levels of physical activity over subsequent years following surgery. PAs should be aware that immunosuppressive medications diminish immune defenses and make KTRs more susceptible to bacterial, viral, and fungal infections. Moreover, KTRs should be screened routinely for cancer due to the higher risk of development from immunosuppressive therapy. PAs must remain cognizant of the emotional well-being of the KTR, as many transplant patients struggle with fear, frustration, and acceptance.