Search

Summary: Both BRCA1 and CREBBP are tumor suppressor genes that are important for hematopoiesis. We have previously shown that mouse Brca1 is essential for hematopoietic stem cell (HSC) viability. In contrast to Brca1 deficiency, which results in pancytopenia, we report here that Crebbp deficiency results in myeloproliferation associated with an increase of splenic HSCs as well as a lethal systemic inflammatory disorder (LD50 = 86 days). To investigate the interaction of these two proteins in hematopoiesis, we generated double Crebbp/Brca1 knockout mice (DKOs). To our surprise, DKOs had accelerated bone marrow failure compared with Brca1-deficient mice and this was associated with an even shorter lifespan (LD50 = 88.5 versus 33 days). Furthermore, Crebbp or Brca1 heterozygosity influenced the hematopoietic phenotype associated with complete deficiency of Brca1 or Crebbp, respectively. We also observed lower BRCA1 protein levels in hematopoietic tissues when CREBBP is absent. Collectively, these data suggest Crebbp and Brca1 functionally interact to maintain normal hematopoiesis. : Biological Sciences; Physiology; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Physiology, Molecular Biology, Cell Biology

Abstract Background First-degree relatives (FDRs) of probands with colorectal cancer (CRC) may be at increased risk of CRC and require colonoscopy. Proband disclosure about this risk and need for colonoscopy is essential for FDRs to take appropriate action. Low colonoscopy rates are reported among FDRs and little is known about the proband disclosure process. A better understanding of the barriers surrounding colonoscopy and disclosure is needed. Methods CRC probands (n = 16) and FDRs (n = 9), recruited from a Canadian CRC Consortium, completed interviews to determine barriers to disclosure and colonoscopy, respectively. Interviews were analyzed using thematic analysis and participants’ motivation to disclose to FDRs or undertake colonoscopy was categorized into Stages of Change (i.e., Precontemplation, Contemplation, Preparation, Action, or Maintenance) using the transtheoretical model. Results 25% of probands had not disclosed to any first-degree kin and were categorized in the Precontemplation or Contemplation Stage of Change. Barriers to disclosure included lack of information, negative expectations about familial reaction, assuming FDRs were aware of risk or already being screened, dysfunctional family dynamics, and cultural barriers. 75% of FDRs were categorized in the Precontemplation or Contemplation Stage of Change. Barriers included negative perceptions about colonoscopy, health-care provider related factors, practical concerns, and lack of information about CRC, risk, and colonoscopy. Conclusions In the absence of barriers such as cost and accessibility, this Canadian sample still reported several challenges to disclosure and colonoscopy adherence. Future research should explore interventions such as motivational interviewing to improve proband disclosure and to increase FDR adherence to colonoscopy.

Chronic wounds are significant public health problems impacting the health-related quality of individuals’ lives (due to disability, decreased productivity, and loss of independence) and an immense economic burden to healthcare systems around the world. In this study, our main objective is to investigate how mechanotransduction can impact the healing process in chronic wounds. We have developed new three-dimensional models of wound tissue to study the distribution of forces within these tissues exerted by wound dressings with different characteristics. The roles of mechanical forces on wound healing have gained significant clinical attention; the application of mechanical forces is expected to influence the physiology of tissue surrounding a wound. We aim to investigate whether the force transmission within wound tissue is impacted by the dressing characteristics and whether this impact may differ with wound tissue’s properties. Our results show that wound dressings with lower stiffnesses promote force transmission within a wound tissue. This impact is even more significant on stiffer wound tissues. Furthermore, we show that size of wound dressing alters forces that transmit within the wound tissue where dressings with 9 cm length show higher stresses. The wound tissue stiffening has been associated with healing of a wound. Our results demonstrate that wounds with stiffer tissue experience higher stresses. Taken all together, our findings suggest that low stiffness of wound dressing and its size may be introduced as a criterion to explain parameters predisposing a chronic wound to heal. This study’s findings on the role of dressings and tissue characteristics demonstrate that precision dressings are required for wound management and understanding how a dressing impacts mechanotransduction in wound tissue will lead to design of novel dressings promoting healing in chronic wounds.

Objectives: Up to 70% of women service members in the United States report military sexual trauma (MST); many develop post-traumatic stress disorder (PTSD) and co-occurring disorders. Trauma-informed yoga (TIY) is suggested to improve psychiatric symptoms and shown feasible and acceptable in emerging research, yet no work has evaluated TIY in MST survivors. The current quality improvement project aimed to examine TIY’s feasibility, acceptability, and perceived effects in the context of MST. Design: Collective case series (N = 7). Setting: New England Vet Center. Interventions: Extant TIY program (Mindful Yoga Therapy) adapted for Veteran women with MST in concurrent psychotherapy. Main outcome measures: Attrition and attendance; qualitative exit interview; validated self-report measure of negative affect pre/post each yoga class, and symptom severity assessments and surveys before (T1; Time 1) and after the yoga program (T2; Time 2). Results: Feasibility was demonstrated and women reported TIY was acceptable. In qualitative interviews, women reported improved symptom severity, diet, exercise, alcohol use, sleep, and pain; reduced medication use; and themes related to stress reduction, mindfulness, and self-compassion. Regarding quantitative change, results suggest acute reductions in negative affect following yoga sessions across participants, as well as improved affect dysregulation, shame, and mindfulness T1 to T2. Conclusions: TIY is both feasible and acceptable to Veteran women MST survivors in one specific Vet Center, with perceived behavioral health benefits. Results suggest TIY may target psychosocial mechanisms implicated in health behavior change (stress reduction, mindfulness, affect regulation, shame). Formal research should be conducted to confirm these QI project results.

In March 2020, the University of Ottawa, like many other universities across Canada and the world, transitioned to online learning in response to the global COVID-19 pandemic. This shift resulted in confusion, anxiety, and uncertainty as students had to adjust their schedules, their study habits, and, for some, their living situation. Within the Faculty of Education, the 2019 PhD student cohort wondered how the shift to online learning would affect their work and their research. This paper outlines the experiences of 12 members of this cohort. By writing this paper, we hope to not only share our feelings with other scholars, but to validate the feelings of other students across Canada. Although this paper is intended for graduate students, we feel that the sentiments and experiences expressed here may also offer valuable insight for both University and College administration.

Objective To test if participation in the Health Start Programme, an Arizona statewide Community Health Worker (CHW) maternal and child health (MCH) home visiting programme, reduced rates of low birth weight (LBW), very LBW (VLBW), extremely LBW (ELBW) and preterm birth (PTB).Design Quasi-experimental retrospective study using propensity score matching of Health Start Programme enrolment data to state birth certificate records for years 2006–2016.Setting Arizona is uniquely racially and ethnically diverse with comparatively higher proportions of Latino and American Indian residents and a smaller proportion of African Americans.Participants 7212 Health Start Programme mothers matched to non-participants based on demographic, socioeconomic and geographic characteristics, health conditions and previous birth experiences.Intervention A statewide CHW MCH home visiting programme.Primary and secondary outcome measures LBW, VLBW, ELBW and PTB.Results Using Health Start Programme’s administrative data and birth certificate data from 2006 to 2016, we identified 7212 Health Start Programme participants and 53 948 matches. Programme participation is associated with decreases in adverse birth outcomes for most subgroups. Health Start participation is associated with statistically significant lower rates of LBW among American Indian women (38%; average treatment-on-the-treated effect (ATT): 2.30; 95% CI −4.07 to –0.53) and mothers with a pre-existing health risk (25%; ATT: -3.06; 95% CI −5.82 to –0.30). Among Latina mothers, Health Start Programme participation is associated with statistically significant lower rates of VLBW (36%; ATT: 0.35; 95% CI −0.69 to –0.01) and ELBW (62%; ATT: 0.31; 95% CI (−0.52 to –0.10)). Finally, Health Start Programme participation is associated with a statistically significant lower rate of PTB for teen mothers (30%; ATT: 2.81; 95% CI −4.71 to –0.91). Other results were not statistically significant.Conclusion A state health department-operated MCH home visiting intervention that employs CHWs as the primary interventionist may contribute to the reduction of LBW, VLBW, ELBW and PTB and could improve birth outcomes statewide, especially among women and children at increased risk for MCH inequity.

Infection with the SARS-CoV-2 virus affects a wide range of systems. Significant involvement of the central nervous system has been described, including ischemic and hemorrhagic strokes. Thus far, neuropathologic reports of patients who passed away from COVID-19 have generally described non-specific findings, such as variable reactive gliosis and meningeal chronic inflammatory infiltrates, as well as the consequences of the infection’s systemic complications on the brain, including ischemic infarcts and hypoxic/ischemic encephalopathy. The neuropathological changes in patients with COVID-19 and large hemorrhagic strokes have not been described in detail. We report the case of an elderly male who had a long course of COVID-19 and ultimately passed away from a large intracerebral hemorrhage. In addition to acute hemorrhage, neuropathologic examination demonstrated non-specific reactive changes and chronic periventricular lesions with macrophagic and perivascular lymphocytic infiltrates without evidence of demyelination or presence of SARS-CoV-2 by PCR test. This manuscript expands the spectrum of reported neuropathological changes in patients with COVID-19.

In May 2020, the Navajo Native American Research Center for Health Partnership (Navajo NARCH) was scheduled to launch two summer programs: a 10 weeks-long Summer Research Enhancement Program (SREP) for undergraduate students to learn and practice health research methods and participate in a practicum experience, and a week-long Indigenous Summer Enhancement Program (ISEP) for high school students that introduces a range of health professions and develops leadership qualities. Students accepted into the programs are predominantly Navajo and live within Navajo Nation (NN) during the summer. Due to NN restrictions and CDC guidelines for physically distancing in response to the coronavirus (COVID-19) pandemic, the Navajo NARCH team organized to offer both programs entirely online via Zoom™. This paper explores the instructional teams’ adaptation process to maintain a commitment to preserve the programs’ supportive environment for exploring and developing strong multicultural approaches in public health and health research. In preparation for online instruction, the team developed and offered workshops for staff and instructors to address anticipated challenges. The team identified the following challenges: technological difficulties, social disconnectedness, consistent student engagement, and facilitation of a practicum research experience. Results showed that program adaptations were successful as the team applied collaborative and holistic approaches, and established social connections remotely with students to offer meaningful research and practicum experiences.

ABSTRACT: Background: Aerosolized drug therapy administered to mechanically ventilated patients is a standard part of pulmonary critical care medicine. Aerosol particle size and distribution are important factors in the optimal delivery of aerosolized drugs to ventilated patients. Objective: The objective of this study was to characterize aerosol droplet size and distribution with laser diffraction for nebulized 3% sodium chloride, albuterol, and epoprostenol sodium (containing glycine) delivered via Aeroneb Solo Mesh Nebulizers (Aerogen, Mountain View, California). Methods: A series of functional flow tests were run on each of 8 Solo mesh nebulizers before the study to verify accuracy of flow rates in milliliters per minute. Aerosolized droplets exiting the nebulizer heads were then measured using a phase Doppler particle analyzer. Data collected during delivery of 3% sodium chloride, albuterol, and epoprostenol sodium included aerosol droplet size distribution, mass median aerodynamic diameter (MMAD), and geometric standard deviation. For each Solo nebulizer, droplet size measurements were taken 2 cm away from the nebulizer head and 2 cm away from the wye of a heated, humidified adult ventilator circuit. For measurements taken at the wye, 4 distinct, continuous flow rates (2, 10, 20, and 40 L/min) were generated by an air pump to simulate inspiratory flows delivered with mechanical ventilation. The expiratory limb was capped, and the nebulizer head was inserted into the breathing circuit upstream of the humidifier. Results: Each Solo nebulizer met Aerogen's recommended minimum flow rate of 0.2 mL/min, ranging from 0.23 to 0.31 mL/min. The MMAD of the 3 tested aerosols was several times smaller when measured at the wye outlet of the heated/humidified breathing circuit (0.82–2.73 µm) compared with droplets measured directly at the nebulizer outlet (MMAD, 4.6–7.3 µm). There was also significant variability across Solo heads with some ventilator flow rates. The mean MMAD at the wye for the 3% sodium chloride solution, albuterol, and epoprostenol test solutions was 1.62 µm, 1.09 µm, and 1.18 µm, respectively. The mean MMAD at the nebulizer for the 3% sodium chloride solution, albuterol, and epoprostenol test solutions was 5.37 µm, 5.73 µm, and 6.73 µm, respectively. Conclusions: Results from this study suggest that particle size of aerosolized drugs administered via a commonly used setup for delivery of in-line aerosols to mechanically ventilated patients may be several times smaller than expected and may result in less drug being delivered to the patient than previously realized.(Curr Ther Res Clin Exp. 2021; 82:XXX–XXX)© 2021 Elsevier HS Journals, Inc.

Preclinical studies of PD-L1 and CTLA-4 blockade have relied heavily on mouse syngeneic tumor models with intact immune systems, which facilitate dissection of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1, PD-1, and CTLA-4 may not demonstrate cross-reactive binding to their mouse orthologs, and surrogate anti-mouse antibodies are often used in their place to inhibit these immune checkpoints. In each case, multiple choices exist for surrogate antibodies, which differ with respect to species of origin, affinity, and effector function. To develop relevant murine surrogate antibodies for the anti-human PD-L1 mAb durvalumab and the anti-human CTLA-4 mAb tremelimumab, rat/mouse chimeric or fully murine mAbs engineered for reduced effector function were developed and compared with durvalumab and tremelimumab. Characterization included determination of target affinity, in vivo effector function, pharmacokinetic profile, and anti-tumor efficacy in mouse syngeneic tumor models. Results showed that anti–PD-L1 and anti–CTLA-4 murine surrogates with pharmacologic properties similar to those of durvalumab and tremelimumab demonstrated anti-tumor activity in a subset of commonly used mouse syngeneic tumor models. This activity was not entirely dependent on antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis effector function, or regulatory T-cell depletion, as antibodies engineered to lack these features showed activity in models historically sensitive to checkpoint inhibition, albeit at a significantly lower level than antibodies with intact effector function.

Introduction As oral factor Xa (oFXa) inhibitor use has increased, so has publication of case series describing related bleeding managed with four-factor prothrombin complex concentrate (4F-PCC).Objective This review aimed to identify case series describing 4F-PCC management of oFXa inhibitor-related bleeding and appraise their methodological and reporting quality.Design We searched Medline and EMBASE (1 January 2011 to 31 May 2020) to identify series of ≥10 patients with oFXa inhibitor-related major bleeding given off-label 4F-PCC. Case series were evaluated using a validated tool adapted for this topic. The tool addressed patient selection, bleed/outcome ascertainment, causal/temporal association and reporting.Results We identified 14 case series. None had ≥100 patients (range=13–84), three were prospective, two detailed appropriate inclusion criteria and four noted consecutive inclusion. While 12 series provided clear/appropriate methods for diagnosis of intracranial haemorrhage (ICH); none did so for extracranial bleeds and it was not clear whether bleeding was adjudicated in any. Haemostatic effectiveness, thrombosis and mortality were together evaluated in 12 series, but only seven used validated methods to evaluate/diagnosis haemostasis in ICH, six in gastrointestinal bleeds, five in other bleeds and three in thrombosis. Independent adjudication of haemostasis (n=1) and thrombosis (n=2) was infrequent. Thirty-day follow-up for mortality and thrombosis was noted in five and seven series. Anticoagulation measurement/levels in at least some patients were conveyed in three series. Few series provided data on anticoagulant agent/dose (n=4), time from anticoagulant (n=4), time-to-reversal (n=7), baseline (n=7) or change (n=0) in neurologic function.Conclusions Although many case series describe off-label use of 4F-PCC for oFXa inhibitor-related bleeding, methodological flaws and/or poor reporting necessitates caution in interpretation.

Introduction A paucity of contemporary data examining bleeding-related hospitalization outcomes in atrial fibrillation (AF) patients exists. Methods Adults in the Nationwide Readmissions Database (January 2016–November 2016) with AF and hospitalized for intracranial hemorrhage (ICH), gastrointestinal, genitourinary, or other bleeding were identified. Association between bleed types and outcomes were assessed using multivariable regression (gastrointestinal defined as referent) and reported as crude incidences and adjusted odds ratios (ORs) or mean differences with 95% confidence intervals (CIs). Results In total, 196,878 index bleeding-related hospitalizations were identified in this AF cohort (CHA2DS2VASc score ≥2 in 95.1%), with 70.8% classified as gastrointestinal. The overall incidences of in-hospital mortality, need for post-discharge out-of-home care, and 30-day readmission were 4.9, 50.8, and 18.2%, respectively. Multivariable regression suggested traumatic and nontraumatic ICHs were associated with higher odds of in-hospital mortality (OR = 3.99, 95% CI = 3.79, 4.19; OR = 13.09, 95% CI = 12.24, 13.99) and need for post-discharge out-of-home care (OR = 2.92, 95% CI = 2.83, 3.01; OR = 2.74, 95% CI = 2.59, 2.90), and increases in mean index hospitalization length-of-stay (8.31 days, 95% CI = 8.03, 8.60, 6.27 days, 95% CI = 5.97, 6.57) versus gastrointestinal bleeding. Genitourinary and other bleeds were associated with lower mortality (OR = 0.37, 95% CI = 0.25, 0.55; OR = 0.59, 95% CI = 0.53, 0.64) and reduced length-of-stays (−2.84 days, 95% CI = − 2.91, −2.76; −2.06 days, 95% CI = − 2.11, −2.01) versus gastrointestinal bleeding. Genitourinary bleeds were also associated with a reduced need for post-discharge out-of-home care (OR = 0.86, 95% CI = 0.77, 0.97). Conclusion The burden of bleeding-related hospitalizations was notably driven by relatively rare but severe and life-threatening ICH, and less morbid but more frequent gastrointestinal bleeding. There is need for continued research on bleeding risk factors and mitigation techniques to avoid bleeding-related patient hospitalizations.

Abstract Extracellular matrix (ECM) properties affect multiple cellular processes such as cell survival, proliferation, and protein synthesis. Thus, a polymeric‐cell delivery system with the ability to manipulate the extracellular environment can act as a fundamental regulator of cell function. Given the promise of stem cell therapeutics, a method to uniformly enhance stem cell function, in particular trophic factor release, can prove transformative in improving efficacy and increasing feasibility by reducing the total number of cells required. Herein, a click‐chemistry powered 3D, single‐cell encapsulation method aimed at synthesizing a polymeric coating with the optimal thickness around neural progenitor cells is introduced. Polymer encapsulation of neural stem cells significantly increases the release of neurotrophic factors such as VEGF and CNTF. Cell encapsulation with a soft extracellular polymer upregulates the ADCY8‐cAMP pathway, suggesting a mechanism for the increase in paracrine factors. Hence, the described single‐cell encapsulation technique can emerge as a translatable, nonviral cell modulation method and has the potential to improve stem cells' therapeutic effect.

Background: Clinical placements are essential for applied learning experiences in health professions education. Unfortunately, there is little consensus on how best to prepare learners for the transition between academic and clinical learning. We explored learners’ perceptions of hospital-based orientation and resulting preparedness for clinical placement. Methods: Sixty-three learners participated in a total of 18 semi-structured focus groups, during their clinical placements. Data were analyzed thematically. Results: We organized learners’ perceptions of hospital-based orientation that support their preparedness for placement into three themes: (1) adequate site orientation for learner acquisition of organization acumen and (2) clinical preceptor training to support unit/service and (3) individual components. Conclusion: Thoughtful attention to hospital-based orientation can support learners in transitioning from academic to clinical learning. Hospital organizations should attend to all three components during orientation to better support learners’ preparedness for clinical learning.

Abstract Background Clinical research investigating effective intervention strategies for adolescents to improve health behaviors has shifted to the application of motivational interviewing (MI). Evidence indicates that MI is an effective intervention for improving health behaviors as related to diet, exercise, and diabetes among adolescents. However, there is a lack of understanding about the mechanisms through which MI works and the contextual factors impacting MI effectiveness. The purpose of this review was to understand how, for whom, and under what circumstances MI works for adolescent health behavior change, which will inform future implementation of this intervention. To provide this in-depth understanding, a realist-informed systematic review was conducted in order to synthesize the evidence on the use of MI for health behaviors. Self-determination theory (SDT) was chosen as the candidate theory for testing in the present review. Methods Databases including PsycINFO, Healthstar, Cochrane, and PubMed were searched for articles published until March 2017. The search strategy included studies that examined or reviewed the effectiveness or efficacy of MI to change health behaviors among adolescent populations. The search identified 185 abstracts, of which 28 were included in the review. The literature was synthesized qualitatively (immersion/crystallization) and tested SDT as the candidate theory. Results Based on SDT, three mechanisms were found within reviewed studies, including competence, relatedness, and autonomy. The following contexts were found to impact mechanisms: school setting, clinician MI proficiency, parental involvement, and peer involvement. Conclusions This realist-informed systematic review provides advances in understanding the mechanisms involved in MI for adolescent health behavior change. Additionally, it provides important practical information as to which contexts create the conditions for these mechanisms to occur, leading to health behavior change. The results can inform future MI interventions for adolescent health behavior change. Future research should continue to test this realist theory and also examine mechanism variables not extensively documented in order to improve our understanding of MI in this population.

Abstract Background Psychosocial rehabilitation is a service that supports recovery from mental illness by providing opportunities for skill development, self-determination, and social interaction. One type of psychosocial rehabilitation is the Clubhouse model. The purpose of the current project was to create, test, and refine a realist theory of psychosocial rehabilitation at Progress Place, an accredited Clubhouse. Method Realist evaluation is a theory driven evaluation that uncovers contexts, mechanisms, and outcomes, in order to develop a theory as to how a program works. The current study involved two phases, encompassing four steps: Phase 1 included (1) initial theory development and (2) initial theory refinement; and Phase 2 included (3) theory testing and (4) refinement. Results The data from this two-phase approach identified three demi-regularities of recovery comprised of specific mechanisms and outcomes: the Restorative demi-regularity, the Reaffirming demi-regularity, and the Re-engaging demi-regularity. The theory derived from these demi-regularities suggests that there are various mechanisms that produce outcomes of recovery from the psychosocial rehabilitation perspective, and as such, it is necessary that programs promote a multifaceted, holistic perspective on recovery. Conclusions The realist evaluation identified that Progress Place promotes recovery for members. Additional research on the Clubhouse model should be conducted to further validate that the model initiates change and promotes recovery outcomes.

Drug formulation: Easing the toll of caregiving Switching from oral to long-acting injectable antipsychotic medication improves overall caregiver burden. The physical, emotional and financial toll of providing care for patients with schizophrenia is often underestimated. Poor adherence to conventional oral antipsychotics is a major cause of symptomatic relapse in patients and of stress for carers. Srihari Gopal and colleagues at Janssen Pharmaceuticals have pooled data from two large studies involving 1498 caregivers across 27 countries. They found that administration of either 1- or 3-monthly long-acting injectable antipsychotics not only eased the burden of daily dosing and patient compliance, but also had a positive impact on the stress conditions of caregivers. Using the Involvement Evaluation Questionnaire to measure caregiver burden, the authors showed that the switch in drug formulation decreased the need to urge patients to self-care and the hours spent caregiving.

Abstract Background The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations. Methods We explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC-1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations. Results In this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor–bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells. Conclusions When taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP.

Super-enhancers (SEs) are big DNA regions regulating the transcription of oncogenes. Here the authors identify two SE regions regulating the expression of CD47, a protein expressed by cancer cells to avoid phagocytosis by macrophages, thus suggesting a potential mechanism of immune surveillance escape.

Introduction: Traumatic intracranial hemorrhages (ICHs) are high priority injuries. Traumatic brain bleeds can be categorized as traumatic subarachnoid hemorrhage (SAH) versus non-SAH-ICH. Non-SAH-ICH includes subdural, epidural, and intraventricular hematomas and brain contusions. We hypothesize that awake patients with SAH will have lower mortality and needless interventions than awake patients with non-SAH-ICHs. Study Design and Methods: A review of data collected from our Level I trauma center was conducted. Awake was defined as an initial Glasgow coma score (GCS) 13–15. Patients were divided into two cohorts: awake SAH and awake non-SAH-ICH. Chi-square and t-test analyses were used with statistical significance defined as P < 0.05. Results: A total of 12,482 trauma patients were admitted during the study period, of which 225 had a SAH and GCS of 13–15 while 826 had a non-SAH-ICH with a GCS of 13–15. There was no significant difference in demographics between the two groups. Predicted survival between the two groups was similar (97.3 vs. 95.7%,P > 0.05). Mortality rates were, however, significantly lower in SAH patients compared to the non-SAH-ICH (4/225 [1.78%] vs. 22/826 [2.66%], P < 0.05). The need for neurosurgical intervention was significantly different comparing the SAH group versus non-SAH-ICH (2/225 [0.89%] vs. 100/826 [12.1%], P < 0.05). Conclusion: Despite similar predicted mortality rates, awake patients with a SAH are associated with a significantly lower risk of death and need for neurosurgical intervention when compared to other types of awake patients with a traumatic brain bleed.

Black/African-American girls are infected with sexually transmitted infections (STIs) at higher rates than their White counterparts. This study tested the efficacy of IMARA, a mother-daughter psychosocial STI/HIV prevention program, on adolescent Black/African-American girls' incident STIs at 12 months in a 2-arm group randomized controlled trial. Black/African-American girls 14-18 years old and their primary female caregiver were eligible for the study. Girls provided urine samples to test for N. gonorrhoeae, C. trachomatis, and T. vaginalis infection at baseline and 12-months. Mother-daughter dyads were randomly assigned to IMARA (n = 118) or a time-matched health promotion control program (n = 81). Retention at 12-months was 86% with no difference across arms. Both interventions were delivered over two consecutive Saturdays totaling 12 hours. Girls who received IMARA were 43% less likely to contract a new STI in the 12-month post-intervention period compared with those in the health promotion control program (p = .011). A secondary follow-up intent-to-treat analysis provided additional support for the protective effect of IMARA, albeit with a similar magnitude of 37% (p = .014). Findings provide early evidence for IMARA's efficacy, such that IMARA protected against STIs at 12-months among adolescent Black/African-American girls. Future research should examine the mechanisms associated with reduced STIs.

In recent years, immunotherapies have been clinically investigated in AML and other myeloid malignancies. While most of these are focused on stimulating the adaptive immune system (including T cell checkpoint inhibitors), several key approaches targeting the innate immune system have been identified. Macrophages are a key cell type in the innate immune response with CD47 being identified as a dominant macrophage checkpoint. CD47 is a “do not eat me” signal, overexpressed in myeloid malignancies that leads to tumor evasion of phagocytosis by macrophages. Blockade of CD47 leads to engulfment of leukemic cells and therapeutic elimination. Pre-clinical data has demonstrated robust anti-cancer activity in multiple hematologic malignancies including AML and myelodysplastic syndrome (MDS). In addition, clinical studies have been underway with CD47 targeting agents in both AML and MDS as monotherapy and in combination. This review will describe the role of CD47 in myeloid malignancies and pre-clinical data supporting CD47 targeting. In addition, initial clinical data of CD47 targeting in AML/MDS will be reviewed, and including the first-in-class anti-CD47 antibody magrolimab.

Introduction Emerging evidence suggests community health workers (CHWs) delivering preventive maternal and child health (MCH) interventions through home visiting improve several important health outcomes, including initiation of prenatal care, healthy birth weight and uptake of childhood immunisations.Methods and analysis The Arizona Health Start Program is a behavioral-based home visiting intervention, which uses CHWs to improve MCH outcomes through health education, referral support, and advocacy services for at-risk pregnant and postpartum women with children up to 2 years of age. We aim to test our central hypothesis that mothers and children exposed to this intervention will experience positive health outcomes in the areas of (1) newborn health; (2) maternal health and healthcare utilisation; and (3) child health and development. This paper outlines our protocol to retrospectively evaluate Health Start Program administrative data from 2006 to 2015, equaling 15 576 enrollees. We will use propensity score matching to generate a statistically similar control group. Our analytic sample size is sufficient to detect meaningful programme effects from low-frequency events, including preterm births, low and very low birth weights, maternal morbidity, and differences in immunisation and hospitalisation rates.Ethics and dissemination This work is supported through an inter-agency contract from the Arizona Department of Health Services and is approved by the University of Arizona Research Institutional Review Board (Protocol 1701128802, approved 25 January 2017). Evaluation of the three proposed outcome areas will be completed by June 2020.

Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.

Early home visiting intervention programmes have been associated with greater familial well-being, yet their success depends on attaining engagement from the outset. Implementation practices, central to positive programme outcomes, rely on a strong relationship between programme providers and families. The present study explored the role of this relationship in the implementation of an Irish early childhood intervention. A randomised controlled trial of the Preparing for Life (PFL) programme was conducted in disadvantaged Dublin communities involving 233 participants recruited during pregnancy and assigned to a high or low intervention group. High intervention involved regular home visits from a trained home visitor providing parenting support and information. This study presents qualitative findings from focus groups with high intervention parents (n=11) and interviews with home visitors (n=5) conducted when participating children were on average 5 months old. Though early engagement challenges were identified, in time parents noted the strengthening parent-home visitor relationship. Findings highlight the importance of programme flexibility and parent-home visitor rapport to programme engagement. Wellbeing did not arise as a salient theme, though it may emerge as a longer-term programme outcome. These findings reveal key aspects of early implementation which may contribute to the ultimate success of the programme.

Background: Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that Arg1 (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor.Methods: Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months.Results: C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADL's. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69).Conclusions: We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to juvenile AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.'s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage.Trial Registration: This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).

Background: Patients with psoriasis (PsO) suffer from a variety of symptoms. Tools are needed to assess PsO symptoms and signs from the patient’s perspective. Objective: To develop a patient-reported outcome (PRO) measure to assess symptoms and signs in individuals with moderate-to-severe PsO. Methods: Face-to-face concept elicitation interviews were conducted with 20 subjects with moderate-to-severe plaque PsO. Results from the interviews, a literature review, and clinical input informed the development of the draft Psoriasis Symptoms and Signs Diary (PSSD). Three waves of face-to-face cognitive interviews (n = 19) were conducted to evaluate the clarity and relevance of the PSSD. Additional interviews (n = 5) were conducted to confirm its content. Results: The PSSD assesses severity of 5 symptoms (itch, pain, stinging, burning, skin tightness) and 6 observable signs (skin dryness, cracking, scaling, shedding or flaking, redness, bleeding) using 0–10 numerical ratings. Two versions with different recall periods (24 h and past 7 days) were developed. PsO patients found the PSSD to be clear and relevant. Limitations: The sample had limited racial diversity. Conclusion: The PSSD, developed according to the Food and Drug Administration PRO Guidance, assesses severity of symptoms and signs commonly associated with plaque PsO. Its measurement properties are currently being evaluated.

Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase II trial compared safety and efficacy of three therapeutic strategies in patients 65 years or over with newly-diagnosed acute myeloid leukemia: 1) continuous high-dose lenalidomide (n=15); 2) sequential azacitidine and lenalidomide (n=39); and 3) azacitidine only (n=34). The efficacy end point was 1-year survival. Median age was 76 years (range 66–87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%) had adverse cytogenetics. One-year survival was 21% [95% confidence interval (CI): 0, 43%] with high-dose lenalidomide, 44% (95%CI: 28, 60%) with sequential azacitidine and lenalidomide, and 52% (95%CI: 35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early therapy discontinuations. Hazard of death in the first four months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential azacitidine and lenalidomide over the conventional dose and schedule of azacitidine only in patients aged 65 years or over with newly-diagnosed acute myeloid leukemia. (clinicaltrials.gov identifier: 01358734).

Federal school accountability policies like No Child Left Behind were based on a logic that measuring school performance and making the results public through tools like school report cards would incentivize educators to create strategies for improving school quality. Yet, most schools needed more than incentives to be able to design improvement strategies that would lead to all students becoming proficient in standard subjects like math and ELA. As a result, states and school districts implemented an infrastructure of supports. To date, there is little research that considers how support providers use accountability tools to diagnose problems and design targeted improvement strategies. Without better knowledge of how schools and providers commit to particular improvement strategies, it is difficult to determine whether we need better school report cards or strategies, or both to improve school quality. This study aims to address this gap by examining how four Children First Networks in New York City used accountability metrics to develop targeted improvement strategies, which led to distinctly different improvement strategies. The article closes with implications for policy.

Communicating service-specific practice patterns, guidelines, and provider information to a new team of learners that rotate frequently can be challenging. Leveraging individual and healthcare electronic resources, a mobile device platform was implemented into a newly revised resident onboarding process. We hypothesized that offering an easy-to-use mobile application would improve communication across multiple disciplines as well as improve provider experiences when transitioning to a new rotation. A mobile platform was created and deployed to assist with enhancing communication within a trauma service and its resident onboarding process. The platform had resource materials such as: divisional policies, Clinical Practice Guidelines (CMGs), and onboarding manuals along with allowing for the posting of divisional events, a divisional directory that linked to direct dialing, text or email messaging, as well as on-call schedules. A mixed-methods study, including an anonymous survey, aimed at providing information on team member's impressions and usage of the mobile application was performed. Usage statistics over a 3-month period were analyzed on those providers who completed the survey. After rotation on the trauma service, trainees were asked to complete an anonymous, online survey addressing both the experience with, as well as the utility of, the mobile app. Thirty of the 37 (81%) residents and medical students completed the survey. Twenty-five (83%) trainees stated that this was their first experience rotating on the trauma service and 6 (20%) were from outside of the health system. According to those surveyed, the most useful function of the app were access to the directory (15, 50%), the divisional calendar (4, 13.3%), and the on-call schedules (3, 10%). Overall, the app was felt to be easy to use (27, 90%) and was accessed an average of 7 times per day (1–50, SD 9.67). Over half the survey respondents felt that the mobile app was helpful in completing their everyday tasks (16, 53.3%). Fifteen (50%) of the respondents stated that the app made the transition to the trauma service easier. Twenty-five (83.3%) stated it was valuable knowing about departmental events and announcements, and 17 (56.7%) felt more connected to the division. The evolution of mobile technology is rapidly becoming fundamental in medical education and training. We found that integrating a service-specific mobile application improved the learner's experience when transitioning to a new service and was a valuable onboarding instrument.Level of evidence IV.

In Brief: Study abroad is a well-established method for transformative learning, recognized by the American Association of Colleges and Universities as a high-impact practice. Over the past decade, short-term faculty-led study abroad—immersive academic courses lasting eight weeks or less—has quickly become the most popular type of international experience in the United States, comprising more than 62% of all study abroad (Fast Facts Open Doors, 2015). Shorter and less expensive than traditional term or year-long experiences, these courses can potentially make study abroad more accessible to more students, in particular underrepresented populations. Librarians are highly qualified educators, yet they rarely lead these types of programs.

Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators, are therapeutically equivalent treatments for metastatic breast cancer. We hypothesized that toremifene as compared with tamoxifen given as adjuvant therapy for early stage breast cancer would result in equivalent survival with an improved side effect profile, therefore, providing superior therapeutic efficacy.Subjects and methods. The North American Fareston versus Tamoxifen Adjuvant trial assigned 1813 perimenopausal or postmenopausal women with hormone receptor (HR) – positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS) and overall survival (OS).Results. Median follow-up was 59 months. The baseline characteristics of the 2 treatment groups were well-balanced. On the basis of intenttotreat, 5-year actuarial DFS was not significantly different between tamoxifen and toremifene (91.2 % (standard error of the mean (SE) 1.2 %) vs 91.2 % (SE 1.1 %), respectively). Similarly, 5-year actuarial OS was not significantly different between tamoxifen and toremifene (92.7 % (SE 1.1 %) vs 93.7 % (SE 1.0 %), respectively). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene versus tamoxifen in terms of OS (OR 0.951; 95 % confidence interval (CI), 0.623–1.451, p = 0.951) or DFS (OR 1.037; 95 % CI, 0.721–1.491, p = 0.846). Adverse events were similar in the 2 groups.Conclusions. Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of HR-positive patients with either tamoxifen or toremifene is appropriate.

Bacteria in the genus Brucella are the cause of brucellosis in humans and many domestic and wild animals. A rapid and culture-free detection assay to detect Brucella in clinical samples would be highly valuable. Nanomaterial optical fiber biosensors (NOFS) are capable of recognizing DNA hybridization events or other analyte interactions with high specificity and sensitivity. Therefore, a NOFS assay was developed to detect Brucella DNA from cultures and in tissue samples from infected mice. An ionic self-assembled multilayer (ISAM) film was coupled to a long-period grating optical fiber, and a nucleotide probe complementary to the Brucella IS711 region and modified with biotin was bound to the ISAM by covalent conjugation. When the ISAM/probe duplex was exposed to lysate containing ≥100 killed cells of Brucella, or liver or spleen tissue extracts from Brucella-infected mice, substantial attenuation of light transmission occurred, whereas exposure of the complexed fiber to non-Brucella gram-negative bacteria or control tissue samples resulted in negligible attenuation of light transmission. Oligonucleotide probes specific for B. abortus, B. melitensis, and B. suis could also be used to detect and differentiate these three nomenspecies. In summary, the NOFS biosensor assay detected three nomenspecies of Brucella without the use of polymerase chain reaction within 30 min and could specifically detect low numbers of this bacterium in clinical samples.

Abstract Synovial fibroblast proliferation Is a hallmark of the Invasive pannus in the rheumatoid joint. Activated protein C (APC) is a natural anticoagulant that exerts antiinflammatory and cyto-protective effects in various diseases via endothelial protein C receptor (EPCR) and proteinase-activated receptor (PAR)-mediated pathways. In this study, we investigated the effect and the underlying cellular signaling mechanisms of APC on proliferation of human rheumatoid synovial fibroblasts (RSFs). We found that APC stimulated proliferation of mouse dermal fibroblasts (MDFs) and normal human dermal fibroblasts (HDFs) by up to 60%, but robustly downregulated proliferation of RSFs. APC induced the phosphorylation of extracellular signal-regulated protein kinase (ERK) and enhanced expression of p21 and p27 in a dose-dependent manner in RSFs. The latter effect was inhibited by pretreatment with the ERK inhibitors PD98059 and U0126 but not by p38 inhibitor SB203580. In addition, APC significantly downregulated tumor necrosis factor (TNF)α-stimulated cell proliferation and activation of p38, c-Jun NH2-terminal kinase (JNK) and Akt in RSFs. These results provide the first evidence that APC selectively inhibits proliferation and the inflammatory signaling pathways of RSFs. Thus, APC may reduce synovial hyperplasia and pannus invasion in rheumatoid arthritis.

How can dozens or even hundreds of organizations working on the Mississippi River be harnessed into a powerful body that has demonstrable influence in our nation’s capital, in capitals of states along the river, and in other places where the health of the river is decided?

In this article the $p$ -essential dimension of generic symbols over fields of characteristic $p$ is studied. In particular, the $p$ -essential dimension of the length $\ell$ generic $p$ -symbol of degree $n+1$ is bounded below by $n+\ell$ when the base field is algebraically closed of characteristic $p$ . The proof uses new techniques for working with residues in Milne–Kato $p$ -cohomology and builds on work of Babic and Chernousov in the Witt group in characteristic 2. Two corollaries on $p$ -symbol algebras (i.e, degree 2 symbols) result from this work. The generic $p$ -symbol algebra of length $\ell$ is shown to have $p$ -essential dimension equal to $\ell +1$ as a $p$ -torsion Brauer class. The second is a lower bound of $\ell +1$ on the $p$ -essential dimension of the functor $\operatorname{Alg}_{p^{\ell },p}$ . Roughly speaking this says that you will need at least $\ell +1$ independent parameters to be able to specify any given algebra of degree $p^{\ell }$ and exponent $p$ over a field of characteristic $p$ and improves on the previously established lower bound of 3.

Water column bulk Pseudo-nitzschia abundance and the dissolved and particulate domoic acid (DA) concentrations were measured in the Santa Barbara Basin (SBB), California from 2009⁻2013 and compared to bulk Pseudo-nitzschia cell abundance and DA concentrations and fluxes in sediment traps moored at 147 m and 509 m. Pseudo-nitzschia abundance throughout the study period was spatially and temporally heterogeneous (−1 to 3.8 × 106 cells L−1, avg. 2 × 105 ± 5 × 105 cells L−1) and did not correspond with upwelling conditions or the total DA (tDA) concentration, which was also spatially and temporally diverse (−1 to 2.2 × 105 ng L−1, avg. 7.8 × 103 ± 2.2 × 104 ng L−1). We hypothesize that the toxicity is likely driven in part by specific Pseudo-nitzschia species as well as bloom stage. Dissolved (dDA) and particulate (pDA) DA were significantly and positively correlated (p < 0.01) and both comprised major components of the total DA pool (pDA = 57 ± 35%, and dDA = 42 ± 35%) with substantial water column concentrations (>1000 cells L−1 and tDA = 200 ng L−1) measured as deep as 150 m. Our results highlight that dDA should not be ignored when examining bloom toxicity. Although water column abundance and pDA concentrations were poorly correlated with sediment trap Pseudo-nitzschia abundance and fluxes, DA toxicity is likely associated with senescent blooms that rapidly sink to the seafloor, adding another potential source of DA to benthic organisms.

Current fiscal cuts provide numerous challenges for community organizations in their mission to provide evidence-based services. Universities are focusing on career-related experiences, largely experiential learning opportunities, to support enhanced student outcomes. Community engagement is often touted as a goal for universities and community collaboration is increasingly viewed as favourable in research. Thus, a community-university partnership which focuses on evaluation would serve to meet the needs of both groups currently experiencing challenges in service delivery and training, respectively. This article presents a case study of a community-university partnership between Renascent and Ryerson University that has evolved over time to meet the needs of both partners. We discuss the applied learning ecosystem, which extends from the supervisory context to the history of the academic institutional partner. We also discuss the flexibility in collaboration, noting the change over time to meet the evolving needs of both the university and the community partner. We aspire to contribute to the literature documenting the range of community-engaged partnerships by providing experiences and reflections to support others in this area.

Background. The feasibility of digital health programs to prevent and manage diabetes in low-income patients has not been adequately explored. Methods. Researchers collaborated with a digital health company to adapt a diabetes prevention program for low-income prediabetes patients at a large safety net clinic. We conducted focus groups to assess patient perspectives, revised lessons for improved readability and cultural relevance to low-income and Hispanic patients, conducted a feasibility study of the adapted program in English and Spanish speaking cohorts, and implemented real-time adaptations to the program for commercial use and for a larger trial of in multiple safety net clinics. Results. The majority of focus group participants were receptive to the program. We modified the curriculum to a 5th-grade reading level and adapted content based on patient feedback. In the feasibility study, 54% of eligible contacted patients expressed interest in enrolling (n=23). Although some participants’ computer access and literacy made registration challenging, they were highly satisfied and engaged (80% logged in at least once/week). Conclusions. Underserved prediabetic patients displayed high engagement and satisfaction with a digital diabetes prevention program despite lower digital literacy skills. The collaboration between researchers and a digital health company enabled iterative improvements in technology implementation to address challenges in low-income populations.

This manuscript compares and contrasts the political obstacles faced by Bush and Obama when they sought to deepen U.S. involvement in the wars in Iraq and Afghanistan. I compare their efforts in three areas. First, I examine their attempts to rally public support for a surge by “going public” and making high-profile policy speeches. Second, I examine their attempts to silence congressional critics, by framing the choice as averting defeat. Finally, I examine each president’s attempt to quell a rebellion inside his administration. Although Bush failed to rally public support, he was able to implement the surge because he succeeded in unifying Republicans in support of his policy, and dividing and silencing congressional Democrats. Obama succeeded because he was able to successfully shape public opinion. This, in turn, allowed him to withstand criticism from hawkish Republicans in Congress and also rally the support of dovish Democratic elites.

In brief: The short research paper is ubiquitous in undergraduate liberal arts education. But is this assignment type an effective way to assess student learning or writing skills? We argue that it rarely is, and instead serves as an artifact maintained out of instructor familiarity with and unnecessary allegiance to timeworn conceptions of “academia.” As […]

Urban Indians in a Silver City: Zacatecas Mexico, 1546-1810, by Dana Velasco Murillo. Stanford University Press, pp. 328, June 2016, ISBN: 9780804796118.

Rat studies demonstrated that type II diabetes mellitus (T2DM) decreases both the production and bioavailability of nitric oxide (NO). L-arginine (LA) provides the precursor for the production of NO. We hypothesized that LA dietary supplementation will preserve NO production via endothelial nitric oxide synthase (eNOS) causing renal microvascular vasodilation and increased glomerular blood flow and thus increasing glomerular filtration rate (GFR). This would impede the formation of reactive oxygen species which contributes to cell damage and death. LA supplementation preserved GFR in the treated diabetic rats compared to untreated diabetic rats. We provide evidence that this effect may be due to increased levels of eNOS and urinary cyclic guanosine monophosphate, which leads to renal microvascular vasodilation. Plasma nitrotyrosine was decreased in the LA treated rats; however, plasma nitrite levels remained unaffected as expected. Marked improvements in glucose tolerance were also observed in the LA treated diabetic rats. These results demonstrate that LA supplementation preserves NO activity and may delay the onset of insulin resistance and renal dysfunction during hyperglycemic stress. These results suggest the importance of the NO pathway in consequent renal dysfunction and in the development of insulin resistance in diabetic rats.

To explore mechanisms underlying reduced fixation of eyes in autism, children with autistic spectrum disorders (ASD) and typically developing children were tested in five visual search experiments: simple color feature; color-shape conjunction; face in non-face objects; mouth region; and eye region. No group differences were found for reaction time profile shapes in any of the five experiments, suggesting intact basic search mechanics in children with ASD. Contrary to early reports in the literature, but consistent with other more recent findings, we observed no superiority for conjunction search in children with ASD. Importantly, children with ASD did show reduced accuracy for eye region search (p = .005), suggesting that eyes contribute less to high-level face representations in ASD or that there is an eye region-specific disruption to attentional processes engaged by search in ASD.

There are few published estimates of the cost of pediatric antiretroviral therapy (ART) in Africa. Our objective was to estimate the outpatient cost of providing ART to children remaining in care at six public sector clinics in Zambia during the first three years after ART initiation, stratified by service delivery site and time on treatment.Data on resource utilization (drugs, diagnostics, outpatient visits, fixed costs) and treatment outcomes (in care, died, lost to follow up) were extracted from medical records for 1,334 children at six sites who initiated ART at 50%) at four sites. At the two remaining sites, outpatient visits and fixed costs together accounted for >50% of outpatient costs. The distribution of costs is slightly skewed, with median costs 3% to 13% lower than average costs during the first year after ART initiation depending on site.Outpatient costs for children initiating ART in Zambia are low and comparable to reported outpatient costs for adults. Outpatient costs and retention in care vary widely by site, suggesting opportunities for efficiency gains. Taking advantage of such opportunities will help ensure that targets for pediatric treatment coverage can be met.

Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both (13)C-palmitate and (13)C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models.

The notions of strictly extreme and strictly exposed are introduced. Their properties are discussed, examples are given, and inter-relationships investigated. In particular it is proved that, for separable normed spaces, the strictly extreme points are just the strictly exposed points.