Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria.

BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. METHODS: We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. RESULTS: A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).

Novel Insights into Autism Knowledge and Stigmatizing Attitudes Toward Mental Illness in Dutch Youth and Family Center Physicians.

Professionals' limited knowledge on mental health and their stigmatizing attitudes toward mental illness can delay the diagnosis of autism. We evaluated the knowledge on Autism Spectrum Disorder (ASD) and stigmatizing attitudes in 93 physicians at Dutch Youth and Family Centers (YFC). These physicians screen for psychiatric symptoms in children. We show that their general ASD knowledge scored 7.1 (SD 1.2), but their specific ASD knowledge was only 5.7 (SD 1.7) (weighted means on 1-10 scale, 1 = least knowledge, 10 = most knowledge). Our physicians had positive attitudes toward mental illness (CAMI scores 2.18 (SD 0.33) to 2.22 (SD 0.40) on a 5-point Likert scale) but they had higher levels of stigmatizing attitudes than other Western healthcare professionals. Their levels were considerably lower than in non-Western professionals. We found no relations between ASD knowledge, stigmatizing attitudes and demographic variables. In conclusion, ASD knowledge and stigmatizing attitudes toward mental illness in Dutch YFC physicians require attention.

Perceptions on Support, Challenges and Needs among Parents of Children with Autism: the Serbian Experience.

BACKGROUND: Autism spectrum disorders (ASD) significantly impact lives of affected individuals and their families. They confront daunting challenges and multiple demands in their daily life, when compared to parents of children with other disabilities or parents of typically developing children. SUBJECTS AND METHODS: Participants completed The Caregiver Needs Survey, the survey intended for parents or primary caregivers of children with a diagnosis of ASD. During the study, 231 parents were interviewed; 167 mothers and 64 fathers. Parents were recruited from the patient database comprised of families from the two largest cities in Serbia. All of them were contacted before the study, either via phone or at the child's regular check-in visit. RESULTS: Over 90 percent of the parents reported that additional support at schools, home, and improved relationships with service providers are necessary and important. The most important challenges related to care were child's communication difficulties, social interaction difficulties, and problems with daily living skills. The significant predictors of lower overall satisfaction were parent's higher education, having a first concern related to problems of the child's interaction with others or playing alone, and parent frustration with accessing services in the past 12 months. Greater overall satisfaction, on the other hand, was related to having an in-school tutor training or assistance in managing child's needs or implementing treatments, and having primary care doctor or pediatrician as a source of information on autism. CONCLUSIONS: Future efforts to develop ASD-related policies and services should also take the following into consideration: the low level of awareness among caregivers and health care providers about the early signs of autism; disparities in access to services; educational problems and significant levels of dissatisfaction with the overall care and stigma.

Effectiveness of multimodal participant recruitment in SPARK, a large, online longitudinal research study of autism.

Background: SPARK launched in 2016 to build a US cohort of autistic individuals and their family members. Enrollment includes online consent to share data and optional consent to provide saliva for genomic analysis. SPARK's recruitment strategies include social media and support of a nation-wide network of clinical sites. This study evaluates SPARK's recruitment strategies to enroll a core study population. Methods: Individuals who joined between January 31, 2018, and May 29, 2019 were included in the analysis. Data include sociodemographic characteristics, clinical site referral, the website URL used to join, how the participant heard about SPARK, enrollment completion (online registration, study consents, and returning saliva sample), and completion of the baseline questionnaire. Logistic regressions were performed to evaluate the odds of core participant status (completing enrollment and baseline questionnaire) by recruitment strategy. Results: In total, 31,715 individuals joined during the study period, including 40% through a clinical site. Overall, 88% completed online registration, 46% returned saliva, and 38% were core participants. Those referred by a clinical site were almost twice as likely to be core participants. Those who directly visited the SPARK website or performed a Google search were more likely to be core participants than those who joined through social media. Discussion: Being a core participant may be associated with the "personal" connection and support provided by a clinical site and/or site staff, as well as greater motivation to seek research opportunities. Findings from this study underscore the value of adopting a multimodal recruitment approach that combines social media and a physical presence.

Evidence-based recruitment strategies for clinical research: Study personnel's and research participants' perceptions about successful methods of outreach for a U.S. Autism-Research Cohort.

Introduction: Under enrollment of participants in clinical research is costly and delays study completion to impact public health. Given that research personnel make decisions about which strategies to pursue and participants are the recipients of these efforts, we surveyed research staff (n = 52) and participants (n = 4,144) affiliated with SPARK (Simons Foundation Powering Autism for Knowledge) - the largest study of autism in the U.S. - to understand their perceptions of effective recruitment strategies. Methods: In Study 1, research personnel were asked to report recruitment strategies that they tried for SPARK and to indicate which ones they would and would not repeat/recommend. In Study 2, SPARK participants were asked to indicate all the ways they heard about the study prior to enrollment and which one was most influential in their decisions to enroll. Results: Staff rated speaking with a SPARK-study-team member (36.5%), speaking with a medical provider (19.2%), word of mouth (11.5%), and a live TV news story (11.5%) as the most successful strategies. Participants most often heard about SPARK via social media (47.0%), speaking with a medical provider (23.1%), and an online search (20.1%). Research personnel's and participants' views on effective recruitment strategies often differed, with the exception of speaking with a medical provider. Conclusion: Results suggest that a combination of strategies is likely to be most effective in reaching diverse audiences. Findings have implications for the selection of strategies that meet a study's specific needs, as well as recruitment-strategy "combinations" that may enhance the influence of outreach efforts.

Coupling remote sensing and eDNA to monitor environmental impact: A pilot to quantify the environmental benefits of sustainable agriculture in the Brazilian Amazon.

Monitoring is essential to ensure that environmental goals are being achieved, including those of sustainable agriculture. Growing interest in environmental monitoring provides an opportunity to improve monitoring practices. Approaches that directly monitor land cover change and biodiversity annually by coupling the wall-to-wall coverage from remote sensing and the site-specific community composition from environmental DNA (eDNA) can provide timely, relevant results for parties interested in the success of sustainable agricultural practices. To ensure that the measured impacts are due to the environmental projects and not exogenous factors, sites where projects have been implemented should be benchmarked against counterfactuals (no project) and control (natural habitat) sites. Results can then be used to calculate diverse sets of indicators customized to monitor different projects. Here, we report on our experience developing and applying one such approach to assess the impact of shaded cocoa projects implemented by the Instituto de Manejo e Certificação Florestal e Agrícola (IMAFLORA) near São Félix do Xingu, in Pará, Brazil. We used the Continuous Degradation Detection (CODED) and LandTrendr algorithms to create a remote sensing-based assessment of forest disturbance and regeneration, estimate carbon sequestration, and changes in essential habitats. We coupled these remote sensing methods with eDNA analyses using arthropod-targeted primers by collecting soil samples from intervention and counterfactual pasture field sites and a control secondary forest. We used a custom set of indicators from the pilot application of a coupled monitoring framework called TerraBio. Our results suggest that, due to IMAFLORA's shaded cocoa projects, over 400 acres were restored in the intervention area and the community composition of arthropods in shaded cocoa is closer to second-growth forests than that of pastures. In reviewing the coupled approach, we found multiple aspects worked well, and we conclude by presenting multiple lessons learned.

Nurse-to-nurse handoff with distractors and interruptions: An integrative review.

AIM: An integrative review of the literature was conducted to explore perceptions of distractors and interruptions during nurse-to-nurse handoff. BACKGROUND: Handoff distractors and interruptions are recognized as barriers to effective nurse handoff and may lead to preventable and costly medical errors. However, little is known about the perception of these barriers to nurses and strategies to mitigate distractors and interruptions during nurse-to-nurse handoff. METHODS: Using the framework of Whittemore and Knafl, four electronic databases were searched for articles written in English and published in the last five years. Inclusion criteria included: qualitative, quantitative, mixed-methods or quality improvement papers focused on distractors/interruptions during nurse handoff. A multi-author independent review of articles was completed with a rigorous process of data extraction and quality assessment. RESULTS: A total of 17 articles were reviewed with findings categorized into the following themes: perceptions of handoff, characteristics of handoff, or logistics of handoff. Nurses reported that interruptions and distractions were a limitation in handoff quality and handoff efficiency, occurring during inter-shift and unit-to-unit handoff. The two most common types of interruptions and distractions were people (patient, family) and environmental factors (equipment alarms). An organized and standardized approach to handoff was recommended, but few specific examples were reported. CONCLUSION: Despite recent research related to interruptions and distractions in nurse handoff, few evidence-based strategies have been identified that effectively mitigate these patient safety problems. More evidence is needed to determine best practice methods for handoff training for nurses and nursing students.

Correlates of schizophrenia spectrum disorders in children and adolescents cared for in community settings.

BACKGROUND: This study examined the prevalence and correlates of schizophrenia spectrum disorders (SSD) among a national sample of 9006 children. METHODS: Clinician-assigned diagnoses were used to divide the sample into two groups: children with SSD and children with other Axis I disorders. RESULTS: Three percent of the sample had a SSD diagnosis. African American (OR=1.71, 95% CI: 1.11, 2.65) and Hispanic race/ethnicity (OR=1.96, 95% CI: 1.31, 2.94), a greater number of comorbid psychiatric diagnoses (three diagnoses, OR=2.22, 95% CI: 1.49, 3.31), a history of attempting suicide (OR=1.45; 95% CI: 1.05, 2.02), and past residential treatment (OR=1.59; 95% CI: 1.11, 2.28) were all associated with increased odds of SSD diagnosis. CONCLUSIONS: Although schizophrenia spectrum disorders in youth are rare, children with these disorders present with a distinct risk profile that may inform service planning and delivery and assist in identifying individuals early in the course of their illness.

Re-Consenting Pediatric Research Participants as Legal Adulthood Approaches: Lessons from the SPARK Autism Study.

To explore issues surrounding re-consenting youth in longitudinal studies as they reach legal adulthood interviews were conducted with 46 parents plus 13 autistic teens enrolled in the Simons Foundation Powering Autism Research for Knowledge (SPARK) study. Qualitative analysis focused on family sensitivities regarding guardianship decisions, transition concerns, and the re-consenting process. Questions regarding guardianship were difficult for parents unsure of a teen's future status. Mothers were key facilitators of re-consenting for soon-to-be-independent teens. As legal adulthood approached, parents were willing to assist teens with re-consenting but needed support, asking for multiple contacts, transition resources, and explanatory materials from the research team. Most teens were not cognizant of SPARK but willing to continue participation once made aware.

Treated prevalence of and mental health services received by children and adolescents in 42 low-and-middle-income countries.

BACKGROUND: Little is known about the treated prevalence and services received by children and adolescents in low- and middle-income countries (LAMICs). The purpose of this study is to describe the characteristics and capacity of mental health services for children and adolescents in 42 LAMICs. METHODS: The World Health Organization Assessment Instrument for Mental Health Systems (WHO-AIMS), a 155-indicator instrument developed to assess key components of mental health service systems, was used to describe mental health services in 13 low, 24 lower-middle, and 5 upper-middle-income countries. Child and adolescent service indicators used in the analysis were drawn from Domains 2 (mental health services), 4 (human resources), and 5 (links with other sectors) of the WHO-AIMS instrument. RESULTS: The median one-year treated prevalence for children and adolescents is 159 per 100,000 population compared to a treated prevalence of 664 per 100,000 for the adult population. Children and adolescents make up 12% of the patient population in mental health outpatient facilities and less than 6% in all other types of mental health facilities. Less than 1% of beds in inpatient facilities are reserved for children and adolescents. Training provided for mental health professionals on child and adolescent mental health is minimal, with less than 1% receiving refresher training. Most countries (76%) organize educational campaigns on child and adolescent mental health. CONCLUSIONS: Mental health services for children and adolescents in low- and middle-income countries are extremely scarce and greatly limit access to appropriate care. Scaling up of services resources will be necessary in order to meet the objectives of the WHO Mental Health Gap Action (mhGAP) program which identifies increased services for the treatment of child mental disorders as a priority.

Psychological Safety in Simulation-Based Prelicensure Nursing Education: A Narrative Review.

BACKGROUND: Psychological safety, essential in high-quality simulation-based education, positively influences learning behaviors and outcomes in corporate organizations. Current assessment of psychological safety is grounded in Edmondson's work team learning model. To understand applicability of this model in nursing education, a literature review was conducted. We reviewed literature on psychological safety in nursing education to assess support for this learning model constructs. Adapting existing models and assessment instruments in different contexts is an important contribution to the profession. METHODS: A structured narrative review examined psychological safety in nursing education simulation literature to identify support for Edmondson's work team learning model constructs. RESULTS: Included articles (n = 13) supported the Edmondson model constructs. When faculty practiced specific leader behaviors, learners experienced psychological safety and demonstrated specific learning-oriented behaviors. CONCLUSION: Psychological safety literature in nursing education supports the work team learning model constructs. This link offers promise for transfer to an assessment instrument in nursing education.

Brief Report: Impact of COVID-19 on Individuals with ASD and Their Caregivers: A Perspective from the SPARK Cohort.

The impact of the 2019 coronavirus pandemic (COVID-19) in the United States is unprecedented, with unknown implications for the autism community. We surveyed 3502 parents/caregivers of individuals with an autism spectrum disorder (ASD) enrolled in Simons Powering Autism Research for Knowledge (SPARK) and found that most individuals with ASD experienced significant, ongoing disruptions to therapies. While some services were adapted to telehealth format, most participants were not receiving such services at follow-up, and those who were reported minimal benefit. Children under age five had the most severely disrupted services and lowest reported benefit of telehealth adaptation. Caregivers also reported worsening ASD symptoms and moderate family distress. Strategies to support the ASD community should be immediately developed and implemented.

Age at autism spectrum disorder diagnosis: A systematic review and meta-analysis from 2012 to 2019.

LAY ABSTRACT: We currently assume that the global mean age at diagnosis of autism spectrum disorder ranges from 38 to 120 months. However, this range is based on studies from 1991 to 2012 and measures have since been introduced to reduce the age at autism spectrum disorder diagnosis. We performed a systematic review and meta-analysis (statistical analysis that combines the results of multiple scientific studies) for studies published between 2012 and 2019 to evaluate the current age at autism spectrum disorder diagnosis. We included 56 studies that reported the age at diagnosis for 40 countries (containing 120,540 individuals with autism spectrum disorder). Results showed the current mean age at diagnosis to be 60.48 months (range: 30.90-234.57 months) and 43.18 months (range: 30.90-74.70 months) for studies that only included children aged ⩽10 years. Numerous factors that may influence age at diagnosis (e.g. type of autism spectrum disorder diagnosis, additional diagnoses and gender) were reported by 46 studies, often with conflicting or inconclusive results. Our study is the first to determine the global average age at autism spectrum disorder diagnosis from a meta-analysis. Although progress is being made in the earlier detection of autism spectrum disorder, it requires our constant attention.

Availability of Services and Caregiver Burden: Supporting Individuals With Neurogenetic Conditions During the COVID-19 Pandemic.

Because of the COVID-19 pandemic, in-person services for individuals with neurodevelopmental disabilities were disrupted globally, resulting in a transition to remote delivery of services and therapies. For individuals with neurogenetic conditions, reliance on nonclinical caregivers to facilitate all therapies and care was unprecedented. The study aimed to (1) describe caregivers' reported impact on their dependent's services, therapies, medical needs, and impact on themselves as a result of the COVID-19 pandemic and (2) assess the relationship between the extent of disruption of services and the degree of self-reported caregiver burden. Two online questionnaires were completed by caregivers participating in Simons Searchlight in April and May 2020. Surveys were completed by caregivers of children or dependent adults with neurodevelopmental genetic conditions in Simons Searchlight. Caregivers reported that the impact of the COVID-19 pandemic moderately or severely disrupted services, therapies, or medical supports. The majority of caregivers were responsible for providing some aspect of therapy. Caregivers reported "feeling stressed but able to deal with problems as they arise," and reported lower anxiety at follow-up. Caregivers reported that telehealth services were not meeting the needs of those with complex medical needs. Future surveys will assess if and how medical systems, educational programs, therapists, and caregivers adapt to the challenges arising during the COVID-19 pandemic.

Behavioral and Emotional Strengths among Youth in Systems-of-Care and the Effect of Race/Ethnicity.

Behavioral and emotional strengths are important to consider when understanding youth mental health and treatment. This study examined the association between youth strengths and functional impairment, and whether this association is modified by race/ethnicity. Multinomial logistic regression models were used to estimate the effects of strengths on impairment, and examine whether race and ethnicity modified this relationship in 8,129 Caucasian, African American, Hispanic, and American Indian/Alaska Native youth, between 5 and 18 years of age. Results suggest that youth with average and above average strengths were less likely to have impairment compared to youth with below average strengths. Race and ethnicity modified this relationship in both expected and unexpected ways. Among youth with average and above average strengths, racial and ethnic minority youth appear to have more impairment than Caucasian youth. However, among youth with below average strengths, racial and ethnic minority youth have less impairment than Caucasian youth. Findings highlight the importance of incorporating strengths-based approaches in youth mental health treatment and the need for further research to understand the specific nature of strengths as it effects impairment across racial/ethnic groups. Implications and recommendations are discussed.

Psychiatric and Medical Profiles of Autistic Adults in the SPARK Cohort.

This study examined lifetime medical and psychiatric morbidity reported by caregivers of 2917 autistic adults participating in the US research cohort SPARK. Participants were 78.4% male, 47.3% had intellectual disability, and 32.1% had persistent language impairments. Childhood language disorders (59.7%), speech/articulation problems (32.8%), sleep (39.4%) and eating problems (29.4%), motor delays (22.8%) and history of seizure (15.5%) were the most frequently reported clinical features. Over two thirds (67.2%) had been diagnosed with at least one psychiatric disorder (anxiety disorders: 41.1%; ADHD: 38.7%). Compared to verbally fluent participants, those with language impairments had lower frequencies of almost all psychiatric disorders. Female sex and older age were associated with higher medical and psychiatric morbidity.

A Statewide Curriculum Model for Teaching Simulation Education Leaders.

BACKGROUND: The Maryland Clinical Simulation Resource Consortium (MCSRC) was funded to increase the quality and quantity of simulation used in nursing education. PROBLEM: Schools of nursing are substituting simulation for clinical experience without requisite knowledge of simulation pedagogy. APPROACH: The MCSRC developed a statewide curriculum model for a 3-day train-the-trainer program framed in theory and grounded in evidence. The program teaches nurse educators across 3 levels: novice, competent, and expert. OUTCOMES: The evaluation plan was developed using Kirkpatrick's 4 levels to measure outcomes of the program. Self-confidence, satisfaction, knowledge, and behavioral changes have been realized. Nurse educators are now using theory, standards, and guidelines when conducting simulation-based experiences. CONCLUSIONS: The curriculum model has proved effective in increasing the quality and quantity of simulation used in educating Maryland's nurses. To date, 154 nurse educators have participated in the train-the-trainer program.

Impact of the 2007 Ica earthquake on health facilities and health service provision in southern Peru.

INTRODUCTION: Few studies have examined post-disaster coping abilities of health facilities and hospitals. On 15 August 2007, a 7.9 (Richter) earthquake struck off the western coast of Peru near the Department of Ica that devastated the healthcare infrastructure. The impact of the earthquake on the health facilities in the four most affected provinces (Cañete, Chincha, Ica, and Pisco), the risk factors associated with the damages incurred, ability to provide services, and humanitarian assistance received were assessed. METHODS: A stratified, systematic sampling design was used to interview a sample of 40 health facilities. The most senior healthcare provider at each facility was interviewed about the facility's experience with service provision following the earthquake. RESULTS: Sixty percent of the facilities reported some damage due to the earthquake; four (10%) were completely destroyed. A total of 78% of the facilities reported providing medical care within the first 48 hours after the earthquake and public facilities were more likely to remain open than were private facilities (p = 0.030). Facilities with an emergency response plan were more likely to provide services than were those without a plan (p = 0.043). Six months after the earthquake, similar numbers of HIV and tuberculosis (TB) patients were receiving treatment at the sampled facilities as prior to the earthquake, and no difficulties were reported in obtaining medications. Some form of assistance, most commonly medications, was received by 60% of the facilities; receipt of assistance was not associated with the facility type, location, damage incurred, or post-disaster service provision. CONCLUSIONS: Response plans were an important factor in the ability to provide services immediately following an earthquake. While a facility's ability to provide services can be determined by structural impacts of the precipitating event, response plans help the staff to continue to provide services and care for affected populations, and appropriately arrange referrals when care cannot be provided at the facility. The findings suggest that health facilities in disasterprone areas should invest in developing and implementing disaster response plans in order to improve health service provision capacity during disasters.

Conversion or conservation? Understanding wetland change in northwest Costa Rica.

Wetlands are more threatened than any other ecosystem type, with losses exceeding 50% of their original extent worldwide. Despite the small portion of the Earth's surface that they comprise, wetlands contribute significantly to global ecosystem services. In this study, we tested the hypothesis that the location and rate of change in wetland amount in the Tempisque Basin of northwest Costa Rica is predictable from landscape setting. Our results demonstrate that a strong potential exists for developing predictive models of wetland conversion based on an understanding of wetland location and surrounding trends of land use. We found that topography was the single most important predictor of wetland conversion in this area, entraining other conversion processes, and that spatial patterns of wetland loss could consistently be predicted from landscape-level variables. Areas with highest probabilities of conversion were found in the most accessible, non-protected regions of the landscape. While Palo Verde National Park made a substantial contribution to wetland conservation, our results highlight the dependence of lower-lying protected areas on upland processes, adding a little-addressed dimension of complexity to the dialogue about protected area management. Conservation strategies aimed at reducing wetland loss in tropical habitats will benefit from careful analysis of the dominant land use system(s) at a relatively broad scale, and the subsequent development of management and policy responses that take into account dynamic opportunities and constraints in the landscape.