Interprofessional education on autism and intellectual disabilities: Program description and initial evaluation.

Project INTERprofessional Autism Collaborative Training (INTERACT) is an interprofessional education program designed to prepare graduate students in psychology, special education, and speech-language pathology to work with autistic children with moderate to severe intellectual disabilities. The rising prevalence of autism, coupled with increased appreciation for interprofessional approaches to service delivery, indicates the need for university training programs to prepare graduate students to work interprofessionally with this population; yet descriptions of such programs and their effectiveness are not reported in the literature. In this article, we explain the process through which an interprofessional faculty team developed Project INTERACT, describe the sequence of coursework and team-based clinical experiences that comprise the program, and present preliminary data regarding its effectiveness. Twenty-four graduate students in psychology, special education, and speech-language pathology participated in this quantitative study. We report results from three rating scales that participants completed at program entry, midpoint, and program exit. Participants endorsed positive attitudes toward interprofessional practice and demonstrated high levels of knowledge about autism. Self-rated knowledge and abilities in interprofessional practice increased significantly by program exit. Project INTERACT scholars developed knowledge and skills related to understanding, assessing, and treating autistic children with intellectual disabilities, through the lens of team-based interprofessional collaboration. We discuss implications for practice with Project INTERACT. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients.

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.

Spatial and Temporal Characterization of Activity in Public Space, 2019-2020.

The data reported here characterize spatial and temporal variation in the ratio of short-to-long-duration visits in public places (i.e., points of interest) in the United States for each week between January 2019 and December 2020. The underlying data on anonymized and aggregated foot traffic to public places is curated by SafeGraph, a geospatial data provider. In this work, we report the estimated number and duration of "short" (i.e., <4 hours) and "long" (i.e., >4 hours) visits to public places at the US census block group level. Long visits are shown to be a good proxy for workers based on formal economic data. We propose that short visits are more likely to represent nonobligate activities: people visiting a public place for leisure, shopping, entertainment, or civic or cultural engagement. Our work constructs a ratio of short to long visits, which can be used to inform population estimates for nonworker use of public space. These data may be useful for understanding how people's use of public space has changed during the COVID-19 pandemic and, more generally, for understanding activity patterns in public.

Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1.

Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies.

Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma.

BACKGROUND: A first-in-human, randomized pilot phase II clinical trial combining vaccines targeting overexpressed, non-mutated tumor blood vessel antigens (TBVA) and tyrosine kinase inhibitor dasatinib was conducted in human leukocyte antigen (HLA)-A2+ patients with advanced melanoma. METHODS: Patient monocyte-derived type-1-polarized dendritic cells were loaded with HLA-A2-presented peptides derived from TBVA (DLK1, EphA2, HBB, NRP1, RGS5, TEM1) and injected intradermally as a vaccine into the upper extremities every other week. Patients were randomized into one of two treatment arms receiving oral dasatinib (70 mg two times per day) beginning in week 5 (Arm A) or in week 1 (Arm B). Trial endpoints included T cell response to vaccine peptides (interferon-γ enzyme-linked immunosorbent spot), objective clinical response (Response Evaluation Criteria in Solid Tumors V.1.1) and exploratory tumor, blood and serum profiling of immune-associated genes/proteins. RESULTS: Sixteen patients with advanced-stage cutaneous (n=10), mucosal (n=1) or uveal (n=5) melanoma were accrued, 15 of whom had previously progressed on programmed cell death protein 1 (PD-1) blockade. Of 13 evaluable patients, 6 patients developed specific peripheral blood T cell responses against ≥3 vaccine-associated peptides, with further evidence of epitope spreading. All six patients with specific CD8+ T cell response to vaccine-targeted antigens exhibited evidence of T cell receptor (TCR) convergence in association with preferred clinical outcomes (four partial response and two stabilization of disease (SD)). Seven patients failed to respond to vaccination (one SD and six progressive disease). Patients in Arm B (immediate dasatinib) outperformed those in Arm A (delayed dasatinib) for immune response rate (IRR; 66.7% vs 28.6%), objective response rate (ORR) (66.7% vs 0%), overall survival (median 15.45 vs 3.47 months; p=0.0086) and progression-free survival (median 7.87 vs 1.97 months; p=0.063). IRR (80% vs 25%) and ORR (60% vs 12.5%) was greater for females versus male patients. Tumors in patients exhibiting response to treatment displayed (1) evidence of innate and adaptive immune-mediated inflammation and TCR convergence at baseline, (2) on-treatment transcriptional changes associated with reduced hypoxia/acidosis/glycolysis, and (3) increased inflammatory immune cell infiltration and tertiary lymphoid structure neogenesis. CONCLUSIONS: Combined vaccination against TBVA plus dasatinib was safe and resulted in coordinating immunologic and/or objective clinical responses in 6/13 (46%) evaluable patients with melanoma, particularly those initiating treatment with both agents. TRIAL REGISTRATION NUMBER: NCT01876212.

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

PURPOSE: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma. PATIENTS AND METHODS: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m2/day i.v., 5 days per week for 4 weeks, then 10 MU/m2/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery. RESULTS: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (P = 0.002 and P = 0.008, respectively). CONCLUSIONS: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.See related commentary by Menzies et al., p. 4133.

Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.

Anti-programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti-PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti-PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti-PD-1 in patients with PD-1-refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti-PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8-expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma.

Effects of PEERS® Social Skills Training on Young Adults with Intellectual and Developmental Disabilities During College.

The Program for the Education and Enrichment of Relational Skills (PEERS®) was used to provide weekly social skills training to a group of 10 college students with intellectual and developmental disabilities (IDD) between ages 18 and 26 attending an inclusive residential postsecondary college program. Additionally, Circles curriculum was used to supplement the PEERS curriculum for teaching social relationship boundaries. An average of 12 sessions per semester of PEERS® training sessions were conducted over each academic year. The present study examines the impact of the program on social skills, friendship qualities, and conversational skills. Results showed increased social skill knowledge, friendship quality, and conversational skills from pretest to posttest intervention. In this paper, we discuss the training program, results, implications for practice, limitations, and future research needs.

IPEM Topical Report: An evidence and risk assessment based analysis of the efficacy of quality assurance tests on fluoroscopy units-part II; image quality.

This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of image quality tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen. Data was analysed from 469 testing sessions to 337 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0-10.6%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of image quality tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment. Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.

IPEM Topical Report: an evidence and risk assessment based analysis of the efficacy of quality assurance tests on fluoroscopy units-part I; dosimetry and safety.

This work aims to assess the efficacy of x-ray quality assurance tests undertaken on fluoroscopy units in the UK. Information was gathered on the results of dosimetry and safety tests recommended by the reports of the Institute of Physics and Engineering in Medicine, and those additionally undertaken by medical physics departments. The assessment of efficacy considers the frequency with which a test result breaches the remedial level or other relevant threshold where applicable. The third quartile of those results exceeding the remedial level or threshold is used to estimate the severity of such a breach in terms of potential impact on patient dose and image quality. A risk assessment approach is then used to recommend to what degree, if any, the test should be included in an on-going test regimen. Data was analysed from 468 testing sessions to 336 unique fluoroscopy units throughout the UK. Across all tests, the rate with which the remedial level was exceeded varied from 0%-29.5%, with severity ranging from little or none to major degradation to image quality or significant increase on population dose. Where possible, the data has also been used to produce representative ranges for the results of dosimetric tests. These could be useful as an up to date comparator for those sites considering the purchase of or commissioning new equipment. Overall the results indicate a wide range for the efficacy of those tests undertaken at present; this can be used to review local test protocols and to inform future changes to national guidance in the UK. The results also highlight some tests where measurement technique varies significantly throughout the UK, making any valid comparison difficult. This may indicate a need for further guidance on how best to undertake these tests.

IPEM Topical Report: an evidence and risk assessment based analysis of the efficacy of tube and generator quality assurance tests on general x-ray units.

This work aims to assess the efficacy of current x-ray quality assurance (QA) testing regimes on tube and generator systems for general radiographic usage in the UK. 1393 sets of QA results data from nine UK medical physics departments were collected and analysed. Test failure rates ranged from 0% to 39% and were used to assess the likelihood of the test finding a fault. The magnitude of the recorded faults were used to assess the severity of the failure with due consideration to its impact on image quality and patient dose. The severity and likelihood of the faults were used along with a risk matrix to assess the efficacy of each test. Eleven tests were graded 'orange' (indicating an effective test that should be continued), four tests were graded 'yellow' (indicating a less effective test that may be continued with a lower frequency considered) and four tests were graded green (indicating a low efficacy test that could be removed from test regimes).

Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma.

PURPOSE: Objective responses are reported in 34% to 37% of patients with programmed death-1 (PD-1)-naïve advanced melanoma treated with PD-1 inhibitors. Pre-existing CD8+ T-cell infiltrate and interferon (IFN) gene signature correlate with response to PD-1 blockade. Here, we report a phase Ib/II study of pembrolizumab/pegylated (PEG)-IFN combination in PD-1-naïve advanced melanoma. PATIENTS AND METHODS: PEG-IFN (1, 2, and 3 µg/kg per week) was dose escalated using a modified toxicity probability interval design in three cohorts of four patients each, whereas pembrolizumab was dosed at 2 mg/kg every 3 weeks in the phase Ib portion. Thirty-one patients were enrolled in the phase II portion. Primary objectives were safety and incidence of dose-limiting toxicities. Secondary objectives included objective response rate, progression-free survival (PFS), and overall survival. RESULTS: Forty-three patients with stage IV melanoma were enrolled in the phase Ib and II portions of the study and included in the analysis. At the data cutoff date (December 31, 2017), median follow-up duration was 25 months (range, 1 to 38 months). All 43 patients experienced at least one adverse event; grade 3/4 treatment-related adverse events occurred in 21 of 43 patients (48.8%). Objective responses were seen at all three dose levels among 43 evaluable patients. The objective response rate was 60.5%, with 46.5% of patients exhibiting ongoing response. Median PFS was 11.0 months in all patients and unreached in responders, whereas median overall survival remained unreached in all patients. The 2-year PFS rate was 46%. CONCLUSION: Pembrolizumab/PEG-IFN demonstrated an acceptable toxicity profile with promising evidence of clinical efficacy in PD-1-naïve metastatic melanoma. These results support the rationale to further investigate this pembrolizumab/PEG-IFN combination in this disease.

Contrast Sensitivity Is a Significant Predictor of Performance in Rifle Shooting for Athletes With Vision Impairment.

Purpose: In order to develop an evidence-based, sport-specific minimum impairment criteria (MIC) for the sport of vision-impaired (VI) shooting, this study aimed to determine the relative influence of losses in visual acuity (VA) and contrast sensitivity (CS) on shooting performance. Presently, VA but not CS is used to determine eligibility to compete in VI shooting. Methods: Elite able-sighted athletes (n = 27) shot under standard conditions with their habitual vision, and with their vision impaired by the use of simulation spectacles (filters which reduce both VA and CS) and refractive blur (lenses which reduce VA with less effect on CS). Habitual shooting scores were used to establish a cut-off in order to determine when shooting performance was 'below expected' in the presence of vision impairment. Logistic regression and decision tree analyses were then used to assess the relationship between visual function and shooting performance. Results: Mild reductions in VA and/or CS did not alter shooting performance, with greater reductions required for shooting performance to fall below habitual levels (below 87% of normalized performance). Stepwise logistic regression selected CS as the most significant predictor of shooting performance, with VA subsequently improving the validity of the model. In an unconstrained decision tree analysis, CS was selected as the sole criterion (80%) for predicting 'below expected' shooting score. Conclusion: Shooting performance is better predicted by losses in CS than by VA. Given that it is not presently tested during classification, the results suggest that CS is an important measure to include in testing for the classification of vision impairment for athletes competing in VI shooting.

Evaluation of Biodistribution of Sulforaphane after Administration of Oral Broccoli Sprout Extract in Melanoma Patients with Multiple Atypical Nevi.

Broccoli sprout extract containing sulforaphane (BSE-SFN) has been shown to inhibit ultraviolet radiation-induced damage and tumor progression in skin. This study evaluated the toxicity and potential effects of oral BSE-SFN at three dosages. Seventeen patients who each had at least 2 atypical nevi and a prior history of melanoma were randomly allocated to 50, 100, or 200 µmol oral BSE-SFN daily for 28 days. Atypical nevi were photographed on days 1 and 28, and plasma and nevus samples were taken on days 1, 2, and 28. Endpoints assessed were safety, plasma and skin sulforaphane levels, gross and histologic changes, IHC for phospho-STAT3(Y705), Ki-67, Bcl-2, HMOX1, and TUNEL, plasma cytokine levels, and tissue proteomics. All 17 patients completed 28 days with no dose-limiting toxicities. Plasma sulforaphane levels pooled for days 1, 2, and 28 showed median postadministration increases of 120 ng/mL for 50 µmol, 206 ng/mL for 100 µmol, and 655 ng/mL for 200 µmol. Median skin sulforaphane levels on day 28 were 0.0, 3.1, and 34.1 ng/g for 50, 100, and 200 µmol, respectively. Plasma levels of proinflammatory cytokines decreased from day 1 to 28. The tumor suppressor decorin was increased from day 1 to 28. Oral BSE-SFN is well tolerated at daily doses up to 200 µmol and achieves dose-dependent levels in plasma and skin. A larger efficacy evaluation of 200 µmol daily for longer intervals is now reasonable to better characterize clinical and biological effects of BSE-SFN as chemoprevention for melanoma. Cancer Prev Res; 11(7); 429-38. ©2018 AACR.

Locally adaptive, spatially explicit projection of US population for 2030 and 2050.

Localized adverse events, including natural hazards, epidemiological events, and human conflict, underscore the criticality of quantifying and mapping current population. Building on the spatial interpolation technique previously developed for high-resolution population distribution data (LandScan Global and LandScan USA), we have constructed an empirically informed spatial distribution of projected population of the contiguous United States for 2030 and 2050, depicting one of many possible population futures. Whereas most current large-scale, spatially explicit population projections typically rely on a population gravity model to determine areas of future growth, our projection model departs from these by accounting for multiple components that affect population distribution. Modeled variables, which included land cover, slope, distances to larger cities, and a moving average of current population, were locally adaptive and geographically varying. The resulting weighted surface was used to determine which areas had the greatest likelihood for future population change. Population projections of county level numbers were developed using a modified version of the US Census's projection methodology, with the US Census's official projection as the benchmark. Applications of our model include incorporating multiple various scenario-driven events to produce a range of spatially explicit population futures for suitability modeling, service area planning for governmental agencies, consequence assessment, mitigation planning and implementation, and assessment of spatially vulnerable populations.

Do the effects of adolescent employment differ by employment intensity and neighborhood context?

Research on the effects of adolescent employment on primarily middle-class youth suggests that intense employment, working more than 15 or 20 hours during the school year, is associated with increased participation in risky behavior. Despite these findings, scholars who focus on the development of youth living in low-income urban areas often hypothesize that adolescent employment will have beneficial effects on this population. There is some evidence that adolescent employment is associated with increased educational achievement and adult employment for low-income urban youth. The impact of adolescent employment on future engagement in risky behavior across levels of neighborhood deprivation and employment intensity was investigated on a sample of 1,057 adolescents from the Project on Human Development in Chicago Neighborhoods, a longitudinal study of neighborhood effects on development. After controlling for individual characteristics, intense employment during adolescence did predict increased use of cigarettes and alcohol and having a greater number of sexual partners 2 years after employment was measured. There were no significant interactions between neighborhood SES and adolescent employment status on involvement in risky behavior. These findings suggest that intense adolescent employment is associated with detrimental developmental outcomes for youth regardless neighborhood context.

Complex sleep apnea syndrome.

Complex sleep apnea is the term used to describe a form of sleep disordered breathing in which repeated central apneas (>5/hour) persist or emerge when obstructive events are extinguished with positive airway pressure (PAP) and for which there is not a clear cause for the central apneas such as narcotics or systolic heart failure. The driving forces in the pathophysiology are felt to be ventilator instability associated oscillation in PaCO2 arterial partial pressure of Carbon Dioxide, continuous cositive airway pressure (CPAP) related increased CO2 carbon dioxide elimination, and activation of airway and pulmonary stretch receptors triggering these central apneas. The prevalence ranges from 0.56% to 18% with no clear predictive characteristics as compared to simple obstructive sleep apnea. Prognosis is similar to obstructive sleep apnea. The central apnea component in most patients on followup using CPAP therap, has resolved. For those with continued central apneas on simple CPAP therapy, other treatment options include bilevel PAP, adaptive servoventilation, permissive flow limitation and/or drugs.