Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP impacts risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2 knockout (Tet2-/-) and floxed control mice (Tet2f/f) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2-/- mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2-/- mice. We delineated the transcriptional landscape of Tet2-/- neutrophils and found that while inflammation-related pathways were upregulated in Tet2-/- neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake and neutrophil extracellular trap (NET) formation by Tet2-/- neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

Youth, caregiver and healthcare professional perspectives on planning the implementation of a trauma-informed care programme: A qualitative study.

AIMS: To explore youth, caregiver and staff perspectives on their vision of trauma-informed care, and to identify and understand potential considerations for the implementation of a trauma-informed care programme in an inpatient mental health unit within a paediatric hospital. DESIGN AND METHODS: We applied the Interpretive Description approach, guided by complexity theory and the Implementation Roadmap, and used Applied Thematic Analysis methods. FINDINGS: Twenty-five individuals participated in individual or group interviews between March and June 2022, including 21 healthcare professionals, 3 youth and 1 caregiver. We identified two overarching themes. The first theme, 'Understanding and addressing the underlying reasons for distress', related to participants' understanding and vision of TIC in the current setting comprising: (a) 'Participants' understanding of TIC'; (b) 'Trauma screening and trauma processing within TIC'; (c) 'Taking "a more individualized approach"'; (d) 'Unit programming'; and (e) "Connecting to the community". The second theme, 'Factors that support or limit successful TIC implementation' comprises: (a) 'The need for a broad "cultural shift"'; (b) 'The physical environment on the unit'; and (c) 'Factors that may limit successful implementation'. CONCLUSION: We identified five key domains to consider within trauma-informed care implementation: (a) the centrality of engagement with youth, caregivers and staff in trauma-informed care delivery and implementation, (b) trauma-informed care core programme components, (c) factors that may support or limit success in implementing trauma-informed care within the mental health unit and (d) hospital-wide and (e) the importance of intersectoral collaboration (partnering with external organizations and sectors). IMPACT: When implementing TIC, there is an ongoing need to increase clarity regarding TIC interventions and implementation initiatives. Youth, caregiver and healthcare professional participants shared considerations important for planning the delivery and implementation of trauma-informed care in their setting. We identified five key domains to consider within trauma-informed care implementation: (a) the centrality of relational engagement, (b) trauma-informed care programme components, (c) factors that may support or limit successful implementation of trauma-informed care within the mental health unit and (d) hospital-wide and (e) the importance of intersectoral collaboration. Organizations wishing to implement trauma-informed care should consider ongoing engagement with all relevant knowledge user groups throughout the process. REPORTING METHOD: Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: The local hospital research institute's Patient and Family Advisory Committee reviewed the draft study methods and provided feedback.

Building Resilience and Attachment in Vulnerable Adolescents: The Feasibility of a Virtually Delivered Group Intervention for Adolescents with Suicidal Ideation and Their Caregivers.

Background: The COVID-19 pandemic required many interventions to be conducted virtually. Building Resilience and Attachment in Vulnerable Adolescents (BRAVA) is a group intervention designed for adolescents and their caregivers to reduce adolescent suicidal ideation (SI). Objective: We aimed to adapt BRAVA for virtual delivery and evaluate its acceptability and feasibility. Methods: We conducted an 8-week pre-post trial between October and December 2020. Six adolescents and six primary caregivers were recruited from a pediatric hospital in Ontario, Canada. Families completed a virtual intake and exit assessment together and 6 weekly BRAVA group sessions separately. Satisfaction feedback was collected after each group session and during their exit, and clinical outcomes were collected at intake and exit. Weekly team meetings were conducted to gather clinician feedback. Results: The study uptake rate was 42.9% of eligible participants. There were no dropouts. Adolescent and caregiver attendance rates for group sessions were high (median = 6). Most youth (83.4%) and caregivers (66.7%) reported that the virtual process worked well. All caregivers (100%) agreed they would participate in a virtual group session again, compared with youth (50%). Providers approved of the virtual adaptation but identified potential improvements (e.g., manual content, safety procedures). Adolescent SI decreased significantly post-treatment (Mpre = 50.7, Mpost = 29.7, p = 0.002). Conclusions: Virtual delivery of BRAVA is acceptable and feasible and may help reduce SI in adolescents. Uptake, retention, and satisfaction were high for adolescents and caregivers. Feedback collected will improve BRAVA for future evaluations, including a randomized controlled trial.

Development and evaluation of food preservation lessons for gardeners: application of the DESIGN process.

OBJECTIVE: This study presents the development and evaluation of food preservation lessons for gardeners. DESIGN: Lessons were developed using the DESIGN process, a nutrition education program planning framework. This study examines the effectiveness of this curriculum at increasing knowledge of proper food preservation practices and increasing participants' confidence in home food preservation, identifies challenges participants experienced with home food preservation and assesses the perceived influence of home food preservation on vegetable intake and aspects of food security. We used the DESIGN process developed by Contento and Koch to develop the curricula and used social cognitive theory to guide the lesson development. Lessons on three types of food preservation (freezing, water bath canning and pressure canning) were developed and presented to adult gardeners. The evaluation consisted of post-lesson surveys and a follow-up survey several months after the lessons. SETTING: Mid-Michigan, USA. PARTICIPANTS: Adult gardeners. RESULTS: Food preservation confidence increased following the lessons. At follow-up, 64 % of participants agreed or strongly agreed that they ate more fruit and vegetables because of preserving food, 57 % of respondents agreed or strongly agreed that they spend less money on food due to preserving, while 71 % reported being better able to provide food for themselves and their family. Lastly, 93 % reported feeling better about where their food comes from and wasting less food due to preserving. CONCLUSIONS: This study provides evidence that home food preservation may be beneficial in promoting fruit and vegetable intake and food security among gardeners.

Early humoral and cellular responses after bivalent SARS-CoV-2 mRNA-1273.214 vaccination in long-term care and retirement home residents in Ontario, Canada: An observational cohort study.

Immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) bivalent mRNA-1273.214 vaccine (Original/Omicron B.1.1.529 [BA.1]) is underreported in vulnerable older adults in congregate care settings. In residents of 26 long-term care and retirement homes in Ontario, Canada, humoral (i.e., serum anti-spike and anti-receptor binding domain [anti-RBD]) IgG and IgA antibodies and live SARS-CoV-2 neutralization) and cellular (i.e., CD4+ and CD8+ activation-induced marker spike-specific T cell memory) responses were assessed 7-120 days postvaccination with four monovalent mRNA vaccines (n = 494) or subsequent bivalent mRNA-1273.214 vaccination (fifth vaccine) (n = 557). Within 4 months, anti-spike and anti-RBD antibody levels were similar after monovalent and bivalent vaccination in infection-naïve individuals. Hybrid immunity (i.e., vaccination and natural infection) generally increased humoral responses. After bivalent vaccination, compared to monovalent vaccination, residents with hybrid immunity had elevated anti-spike and anti-RBD IgG and IgA antibodies. Omicron BA.1 antibody-mediated neutralization, and CD8+ T cell memory responses to the Omicron BA.1 spike protein, were also higher after bivalent vaccination. Humoral and cellular responses were, therefore, noninferior within 4 months of bivalent mRNA-1273.214 vaccination compared to monovalent mRNA vaccination. Waning of humoral but not cellular immunity was particularly evident in individuals without hybrid immunity. Continued monitoring of vaccine-associated and hybrid immunity against emerging Omicron variants of concern is necessary to assess longevity of protection.

Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities.

Background: Older adults are at increased risk of SARS-CoV-2 Omicron infection and severe disease, especially those in congregate living settings, despite high SARS-CoV-2 vaccine coverage. It is unclear whether hybrid immunity (combined vaccination and infection) after one Omicron infection provides increased protection against subsequent Omicron reinfection in older adults. Methods: Incidence of SARS-CoV-2 Omicron infection was examined in 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID in Long-Term Care Study in Ontario, Canada, within a 75-day period (July to September 2022). Risk of infection was assessed by Cox proportional hazards regression. Serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titres, and spike-specific T cell memory responses, were examined in a subset of 318 residents within the preceding three months. Findings: 133 of 750 participants (17.7%) had a PCR-confirmed Omicron infection during the observation period. Increased infection risk was associated with prior Omicron infection (at 9-29 days: 47.67 [23.73-95.76]), and this was not attributed to days since fourth vaccination (1.00 [1.00-1.01]) or residence outbreaks (>6 compared to ≤6: 0.95 [0.37-2.41]). Instead, reinfected participants had lower serum neutralizing antibodies to ancestral and Omicron BA.1 SARS-CoV-2, and lower anti-RBD IgG and IgA antibodies, after their initial Omicron infection. Interpretation: Counterintuitively, SARS-CoV-2 Omicron infection was associated with increased risk of Omicron reinfection in residents of long-term care and retirement homes. Less robust humoral hybrid immune responses in older adults may contribute to risk of Omicron reinfection. Funding: COVID-19 Immunity Task Force of the Public Health Agency of Canada.

Trauma-Informed Care Interventions Used in Pediatric Inpatient or Residential Treatment Mental Health Settings and Strategies to Implement Them: A Scoping Review.

Trauma-informed care (TIC) is an approach to care emerging in research and in practice that involves addressing the needs of individuals with histories of trauma. The aim of this scoping review was to examine the current literature relating to TIC interventions used in pediatric mental health inpatient and residential settings. We sought to answer the following two research questions: (a) What are the TIC interventions used in pediatric inpatient and residential treatment mental healthcare settings and what are their components? and (b) What are the implementation goals and strategies used with these TIC interventions? We conducted this scoping review according to JBI (formerly Joanna Briggs Institute) methodology for scoping reviews. We included any primary study describing a TIC intervention that was implemented at a specific site which identified and described implementation strategies used. Of 1,571 identified citations and 54 full-text articles located by handsearching, 49 met the eligibility criteria and were included, representing 21 distinct TIC interventions. We present the reported aim, ingredients, mechanism, and delivery (AIMD) of TIC interventions as well as the implementation goals and strategies used, which varied in detail, ranging from very little information to more detailed descriptions. In the context of these findings, we emphasize the complexity of TIC and of TIC interventions, and the importance of identifying and clearly reporting TIC intervention goals, intervention details, and implementation strategies. We suggest applying intervention frameworks or reporting guidelines to support clear and comprehensive reporting, which would better facilitate replication and synthesis of published TIC interventions.

Absence of Depressive and Anxious Behavior with Genetic Dysregulation in Adult C57Bl/6J Mice after Prenatal Exposure to Ionizing Radiation.

The exposure of ionizing radiation during early gestation often leads to deleterious and even lethal effects; however, few extensive studies have been conducted on late gestational exposures. This research examined the behavior al effects of C57Bl/6J mouse offspring exposed to low dose ionizing gamma irradiation during the equivalent third trimester. Pregnant dams were randomly assigned to sham or exposed groups to either low dose or sublethal dose radiation (50, 300, or 1000 mGy) at gestational day 15. Adult offspring underwent a behavioral and genetic analysis after being raised under normal murine housing conditions. Our results indicate very little change in the behavioral tasks measuring general anxiety, social anxiety, and stress-management in animals exposed prenatally across the low dose radiation conditions. Quantitative real-time polymerase chain reactions were conducted on the cerebral cortex, hippocampus, and cerebellum of each animal; results indicate some dysregulation in markers of DNA damage, synaptic activity, reactive oxygen species (ROS) regulation, and methylation pathways in the offspring. Together, our results provide evidence in the C57Bl/6J strain, that exposure to sublethal dose radiation (<1000 mGy) during the last period of gestation leads to no observable changes in behaviour when assessed as adults, although some changes in gene expression were observed for specific brain regions. These results indicate that the level of oxidative stress occurring during late gestation for this mouse strain is not sufficient for a change in the assessed behavioral phenotype, but results in some modest dysregulation of the genetic profile of the brain.

Low-Dose Hemibody Radiation, a Treatment Option for Recurrent Prostate Cancer: A Phase 2 Single-Arm Trial.

Purpose: Nontargeted low-dose ionizing radiation has been proposed as a cancer therapeutic for several decades; however, questions remain about the duration of hematological changes and optimal dosing regimen. Early studies delivering fractionated low doses of radiation to patients with cancer used varying doses and schedules, which make it difficult to standardize a successful dose and scheduling system for widespread use. The aim of this phase 2 two-stage trial was to determine whether low-dose radiation therapy (LD-RT) reduced prostate-specific antigen (PSA) in patients with recurrent prostate cancer in efforts to delay initiation of conventional therapies that are known to decrease quality of life. The primary study outcome was reduction in PSA levels by at least 50%. Methods and Materials: Sixteen patients with recurrent prostate cancer were recruited and received 2 doses of 150 mGy of nontargeted radiation per week, for 5 consecutive weeks, with 15 participants completing the study. Results: A maximal response of 40.5% decrease in PSA at 3 months was observed. A total of 8 participants remained off any additional interventions, of whom 3 had minor fluctuations in PSA for at least 1 year after treatment. The most common adverse event reported was mild fatigue during active treatment (n = 4), which did not persist in the follow-up period. No participants withdrew due to safety concerns or hematological abnormalities (ie, platelet ≤50 × 109/L, leukocyte ≤3 × 109/L, granulocyte ≤2 × 109/L). Conclusions: Our study did not meet the primary objective; however, LD-RT may be a potential therapy for some patients with recurrent prostate cancer by stalling rising PSA. This study also demonstrates that low-dose radiation is well tolerated by participants with minimal toxicities and no change in quality of life.

Building Resilience and Attachment in Vulnerable Adolescents (BRAVA): a brief group intervention for adolescents with mild-to-moderate suicidal ideation and their caregivers.

INTRODUCTION: Suicidal Ideation (SI) is common in adolescents and increases the risk of completed suicide. Few brief interventions have been shown to reduce SI in adolescents. The objective of this study was to evaluate the feasibility of a novel brief group intervention, building resilience and attachment in vulnerable adolescents (BRAVA), designed for adolescents and their caregivers to reduce adolescent SI. METHODS: The study was a pre-post, noncontrolled trial in which 46 adolescents were enrolled in the BRAVA intervention. Adolescents and caregivers completed an intake assessment, six BRAVA group sessions, and an exit assessment 1-week post-BRAVA. RESULTS: Adolescents' SI decreased significantly after completing the BRAVA treatment (pre-post difference = 18.1, 95% CI = 10.01-26.12). Significant improvements in associated symptoms of depression, anxiety, and perceived stress were also observed. Caregivers had reduced perceived stress (pre-post difference = 2.7, 95% CI = 0.30-5.16) and reduction in attachment avoidance (difference = 1.6, 95% CI = 0.29-2.91). Treatment satisfaction was high across the six modules. The rolling entry feature of the intervention allowed participants to begin treatment approximately 2 weeks sooner compared to waiting for the next group cycle. CONCLUSIONS: Study results demonstrate that the BRAVA intervention has the potential to reduce SI among adolescents who present to hospital services in crisis. Further studies are required to establish BRAVA's efficacy in a randomized controlled trial.

Lasting Changes to Circulating Leukocytes in People with Mild SARS-CoV-2 Infections.

Survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae. Whether survivors of mild or asymptomatic infections can expect any long-term health consequences is not yet known. Herein we investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n = 22), compared to those that had recovered from other mild respiratory infections (n = 11). Individuals who had experienced mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1-3 months after symptom onset, and changes in phenotype and function of circulating T-cells that were not apparent in individuals 6-9 months post-symptom onset. Markers of monocyte activation, and expression of adherence and chemokine receptors indicative of altered migratory capacity, were also higher at 1-3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6-9 months post-infection. Perhaps most surprisingly, significantly more T-cells could be activated by polyclonal stimulation in individuals who had recently experienced a mild SARS-CoV-2, infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for at least three months after mild or asymptomatic SARS-CoV-2 infections.

Hematological Changes Following Low Dose Radiation Therapy and Comparison to Current Standard of Care Cancer Treatments.

Cancer is the second leading cause of mortality worldwide accounting for almost 10 million deaths in 2020. Current standard of care treatment varies depending on the type and stage of disease, but commonly includes surgery, chemotherapy, and/or radiation therapy. There is evidence that whole- and half-body exposure to low dose ionizing radiation can also be an effective therapeutic due to its stimulation of anti-cancer immunity. One of the limiting factors for past clinical trials using low dose radiation therapy has been adverse hematological events. However, similar hematological changes are also frequently reported following standard of care treatments in oncology. This review summarizes the effects of various cancer therapies on hematologic toxicity through the evaluation of complete blood count reports. The reviewed literature elucidates hematological trends in patients undergoing chemotherapy, and both high and low dose radiation therapy. In general, high dose radiation and chemotherapy can result in widespread changes in blood counts, with the most severe effects related to leukopenia. Overall, compared to standard of care treatments, low dose radiation results in similar, yet more mild hematological changes. Taken together, hematological toxicities should not be a limiting factor in the applicability of low dose radiation as a cancer therapeutic.

The HEADS-ED: Evaluating the Clinical Use of a Brief, Action-Oriented, Pediatric Mental Health Screening Tool.

OBJECTIVES: This effectiveness study aimed to evaluate the clinical use of the HEADS-ED tool for patients presenting to a pediatric emergency department (PED) for mental health (MH) care. METHODS: In this pragmatic trial, PED physicians used the HEADS-ED to guide their assessment and identify areas of MH need in 639 patients (mean [SD], 15.16 [1.40] years; female, 72.6%) who presented to the emergency department with MH concerns between May 2013 and March 2014. RESULTS: The HEADS-ED guided consultation to psychiatry/crisis, with 86% receiving a recommended consult. Those with a HEADS-ED score of greater than or equal to 8 and suicidality of 2 (relative risk, 2.64; confidence interval, 2.28-3.06) had a 164% increased risk of physicians requesting a consult compared with those with a score of less than 8 or greater than or equal to 8 with no suicidality of 2. The HEADS-ED mean score was significantly higher for those who received a consult (M = 6.91) than those who did not (M = 4.70; P = 0.000). Similarly, the mean score for those admitted was significantly higher (M = 7.21) than those discharged (M = 5.28; P = 0.000). Agreement on needs requiring action between PED physicians and crisis intervention workers was obtained for a subset of 140 patients and ranged from 62% to 93%. CONCLUSIONS: Results support the HEADS-ED's use by PED physicians to help guide the assessment and referral process and for discussing the clinical needs of patients among health care providers using a common action-oriented language.

Evaluating mental health service use during and after emergency department visits in a multisite cohort of Canadian children and youth.

OBJECTIVES: The goal of this study was to examine the mental health needs of children and youth who present to the emergency department (ED) for mental health care and to describe the type of, and satisfaction with, follow-up mental health services accessed. METHODS: A 6-month to 1.5-year prospective cohort study was conducted in three Canadian pediatric EDs and one general ED, with a 1-month follow-up post-ED discharge. Measures included 1) clinician rating of mental health needs, 2) patient and caregiver self-reports of follow-up services, and 3) interviews regarding follow-up satisfaction. Data analysis included descriptive statistics and the Fisher's exact test to compare sites. RESULTS: The cohort consisted of 373 children and youth (61.1% female; mean age 15.1 years, 1.5 standard deviation). The main reason for ED presentations was a mental health crisis. The three most frequent areas of need requiring action were mood (43.8%), suicide risk (37.4%), and parent-child relational problems (34.6%). During the ED visit, 21.6% of patients received medical clearance, 40.9% received a psychiatric consult, and 19.4% were admitted to inpatient psychiatric care. At the 1-month post-ED visit, 84.3% of patients/caregivers received mental health follow-up. Ratings of service recommendations were generally positive, as 60.9% of patients obtained the recommended follow-up care and 13.9% were wait-listed. CONCLUSIONS: Children and youth and their families presenting to the ED with mental health needs had substantial clinical morbidity, were connected with services, were satisfied with their ED visit, and accessed follow-up care within 1-month with some variability.

An Emergency Department Clinical Pathway for Children and Youth with Mental Health Conditions.

Children and youth presenting to the emergency department with mental health concerns present a challenge for clinicians and system capacity. Addressing a significant system gap and sparse strategies in the literature, representative leaders from hospital and community agencies developed a novel pathway to guide efficient and doable risk assessment and ensure timely transition to appropriate community mental health services. This article describes and reflects on our innovative Emergency Department Clinical Pathway for Children and Youth with Mental Health Conditions that bridges traditional barriers between hospital and community settings to address mental health needs for this population.

Nerve growth factor inhibitor with novel-binding domain demonstrates nanomolar efficacy in both cell-based and cell-free assay systems.

Nerve growth factor (NGF), a member of the neurotrophin family, is known to regulate the development and survival of a select population of neurons through the binding and activation of the TrkA receptor. Elevated levels of NGF have been associated with painful pathologies such as diabetic neuropathy and fibromyalgia. However, completely inhibiting the NGF signal could hold significant side effects, such as those observed in a genetic condition called congenital insensitivity to pain and anhidrosis (CIPA). Previous methods of screening for NGF-inhibitors used labeling techniques which have the potential to alter molecular interactions. SPR spectroscopy and NGF-dependent cellular assays were utilized to identify a novel NGF-inhibitor, BVNP-0197 (IC50  = 90 nmol/L), the first NGF-inhibitor described with a high nanomolar NGF inhibition efficiency. The present study utilizes molecular modeling flexible docking to identify a novel binding domain in the loop II/IV cleft of NGF.

A Surface Plasmon Resonance Spectroscopy Method for Characterizing Small-Molecule Binding to Nerve Growth Factor.

Small-molecule inhibitors have been previously investigated to identify possible therapeutics for the treatment of chronic pain. In the present study, known nerve growth factor (NGF) inhibitors identified by (125)I-NGF binding were characterized using affinity and binding evaluations by surface plasmon resonance (SPR) spectroscopy. A novel strategy for characterizing NGF inhibitors was used to determine the binding affinity (KD) and saturation ability of each compound with immobilized NGF. Seventy-four percent of compounds screened demonstrated a positive binding event to NGF. A KD less than 10 µM and a percent saturation greater than 50% were used as thresholds to identify inhibitors that would warrant further investigation. This study details for the first time a methodology that can be used to directly characterize the binding event between small-molecule inhibitors and NGF.

Characterizing nerve growth factor-p75(NTR) interactions and small molecule inhibition using surface plasmon resonance spectroscopy.

Nerve growth factor (NGF) is critical for the proliferation, differentiation, and survival of neurons through its binding to the p75(NTR) and TrkA receptors. Dysregulation of NGF has been implicated in several pathologies, including neurodegeneration (i.e., Parkinson's and Alzheimer's diseases) and both inflammatory and neuropathic pain states. Therefore, small molecule inhibitors that block NGF-receptor interactions have significant therapeutic potential. Small molecule antagonists ALE-0540, PD90780, Ro 08-2750, and PQC 083 have all been reported to inhibit NGF from binding the TrkA receptor. Interestingly, the characterization of the ability of these molecules to block NGF-p75(NTR) interactions has not been performed. In addition, the inhibitory action of these molecules has never been evaluated using surface plasmon resonance (SPR) spectroscopy, which has been proven to be highly useful in drug discovery applications. In the current study, we used SPR biosensors to characterize the binding of NGF to the p75(NTR) receptor in addition to characterizing the inhibitory potential of the known NGF antagonists. The results of this study provide the first evaluation of the ability of these compounds to block NGF binding to p75(NTR) receptor. In addition, only PD90780 was effective at inhibiting the interaction of NGF with p75(NTR), suggesting receptor selectivity between known NGF inhibitors.

Physician response to parental requests to spread out the recommended vaccine schedule.

OBJECTIVES: To assess among US physicians (1) frequency of requests to spread out recommended vaccination schedule for children <2 years, (2) attitudes regarding such requests, and (3) strategies used and perceived effectiveness in response to such requests. METHODS: An e-mail and mail survey of a nationally representative sample of pediatricians and family physicians from June 2012 through October 2012. RESULTS: The response rate was 66% (534 of 815). In a typical month, 93% reported some parents of children <2 years requested to spread out vaccines; 21% reported ≥ 10% of parents made this request. Most respondents thought these parents were putting their children at risk for disease (87%) and that it was more painful for children (84%), but if they agreed to requests, it would build trust with families (82%); further, they believed that if they did not agree, families might leave their practice (80%). Forty percent reported this issue had decreased their job satisfaction. Most agreed to spread out vaccines when requested, either often/always (37%) or sometimes (37%); 2% would often/always, 4% would sometimes, and 12% would rarely dismiss families from their practice if they wanted to spread out the primary series. Physicians reported using a variety of strategies in response to requests but did not think they were effective. CONCLUSIONS: Virtually all providers encounter requests to spread out vaccines in a typical month and, despite concerns, most are agreeing to do so. Providers are using many strategies in response but think few are effective. Evidence-based interventions to increase timely immunization are needed to guide primary care and public health practice.

When tobacco targets direct democracy.

Tobacco control advocates began to use ballot initiatives to enact tobacco control measures in the late 1970s. In response, the tobacco industry worked for over two decades to change laws governing initiative and referendum processes to prevent passage of such measures. In 1981 the tobacco industry's political lobbying arm, the Tobacco Institute, created a front group that presented itself as a neutral initiative research clearinghouse to effect changes in state initiative and referenda laws. In 1990 the Tobacco Institute began creating an in-house team and worked with third-party groups to try to change state initiative laws. While the industry ultimately abandoned both efforts when neither achieved immediate success, over time the industry's goals have penetrated legitimate discourse on the initiative and referendum process in the United States, and many specific ideas it advocated have garnered mainstream support. Direct democracy advocates, as well as public health advocates and policy makers, need to understand the tobacco industry's goals (which other industries adopted) of limiting the direct democracy process to ensure that any changes do not inadvertently increase the power of the special interests that direct democracy was developed to counterbalance.