Development and validation of blood tumor mutational burden reference standards.

Tumor mutational burden (TMB), measured by exome or panel sequencing of tumor tissue or blood (bTMB), is a potential predictive biomarker for treatment benefit in patients with various cancer types receiving immunotherapy targeting checkpoint pathways. However, significant variability in TMB measurement has been observed. We developed contrived bTMB reference materials using DNA from tumor cell lines and donor-matched lymphoblastoid cell lines to support calibration and alignment across laboratories and platforms. Contrived bTMB reference materials were developed using genomic DNA from lung tumor cell lines blended into donor-matched lymphoblastoid cell lines at 0.5% and 2% tumor content, fragmented and size-selected to mirror the size profile of circulating cell-free tumor DNA with TMB scores of 7, 9, 20, and 26 mut/Mb. Variant allele frequency (VAF) and bTMB scores were assessed using PredicineATLAS and GuardantOMNI next-generation sequencing assays. DNA fragment sizes in the contrived reference samples were similar to those found within patient plasma-derived cell-free DNA, and mutational patterns aligned with those in the parental tumor lines. For the 7, 20, and 26 mut/Mb contrived reference samples with 2% tumor content, bTMB scores estimated using either assay aligned with expected scores from the parental tumor cell lines and showed good reproducibility. A bioinformatic filtration step was required to account for low-VAF artifact variants. We demonstrate the feasibility and challenges of producing and using bTMB reference standards across a range of bTMB levels, and how such standards could support the calibration and validation of bTMB platforms and help harmonization between panels and laboratories.

A blood-based immune marker for resistance to pembrolizumab in patients with metastatic urothelial cancer.

PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.

The Gut Microbiome in Hypertension: Recent Advances and Future Perspectives.

The pathogenesis of hypertension is known to involve a diverse range of contributing factors including genetic, environmental, hormonal, hemodynamic and inflammatory forces, to name a few. There is mounting evidence to suggest that the gut microbiome plays an important role in the development and pathogenesis of hypertension. The gastrointestinal tract, which houses the largest compartment of immune cells in the body, represents the intersection of the environment and the host. Accordingly, lifestyle factors shape and are modulated by the microbiome, modifying the risk for hypertensive disease. One well-studied example is the consumption of dietary fibers, which leads to the production of short-chain fatty acids and can contribute to the expansion of anti-inflammatory immune cells, consequently protecting against the progression of hypertension. Dietary interventions such as fasting have also been shown to impact hypertension via the microbiome. Studying the microbiome in hypertensive disease presents a variety of unique challenges to the use of traditional model systems. Integrating microbiome considerations into preclinical research is crucial, and novel strategies to account for reciprocal host-microbiome interactions, such as the wildling mouse model, may provide new opportunities for translation. The intricacies of the role of the microbiome in hypertensive disease is a matter of ongoing research, and there are several technical considerations which should be accounted for moving forward. In this review we provide insights into the host-microbiome interaction and summarize the evidence of its importance in the regulation of blood pressure. Additionally, we provide recommendations for ongoing and future research, such that important insights from the microbiome field at large can be readily integrated in the context of hypertension.

trips4health: a single-blinded randomised controlled trial incentivising adult public transport use for physical activity gain.

BACKGROUND: Public transport users tend to accumulate more physical activity than non-users; however, whether physical activity is increased by financially incentivising public transport use is unknown. The trips4health study aimed to determine the impact of an incentive-based public transport intervention on physical activity. METHODS: A single-blinded randomised control trial of a 16-week incentive-based intervention involved Australian adults who were infrequent bus users (≥ 18 years; used bus ≤ 2 times/week) split equally into intervention and control groups. The intervention group were sent weekly motivational text messages and awarded smartcard bus credit when targets were met. The intervention group and control group received physical activity guidelines. Accelerometer-measured steps/day (primary outcome), self-reported transport-related physical activity (walking and cycling for transport) and total physical activity (min/week and MET-min/week) outcomes were assessed at baseline and follow-up. RESULTS: Due to the COVID pandemic, the trial was abandoned prior to target sample size achievement and completion of all assessments (N = 110). Steps/day declined in both groups, but by less in the intervention group [-557.9 steps (-7.9%) vs.-1018.3 steps/week (-13.8%)]. In the intervention group, transport-related physical activity increased [80.0 min/week (133.3%); 264.0 MET-min/week (133.3%)] while total physical activity levels saw little change [35.0 min/week (5.5%); 25.5 MET-min/week (1.0%)]. Control group transport-related physical activity decreased [-20.0 min/week (-27.6%); -41.3 MET-min/week (-17.3%)], but total physical activity increased [260.0 min/week (54.5%); 734.3 MET-min/week (37.4%)]. CONCLUSION: This study found evidence that financial incentive-based intervention to increase public transport use is effective in increasing transport-related physical activity These results warrant future examination of physical activity incentives programs in a fully powered study with longer-term follow-up. TRIAL REGISTRATION: This trial was registered with the Australian and New Zealand Clinical Trials Registry August 14th, 2019: ACTRN12619001136190; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377914&isReview=true.

How transdisciplinary research teams learn to do knowledge translation (KT), and how KT in turn impacts transdisciplinary research: a realist evaluation and longitudinal case study.

BACKGROUND: Transdisciplinary research and knowledge translation are increasingly regarded as key concepts underpinning applied research across the health and social sciences, due to their presumed potential in addressing complex, "wicked" problems and improving the use of research in practice and policy, respectively. Despite sharing an impact mandate, the relationship between transdisciplinary research collaboration and knowledge translation remains unclear. In response, we examined the relationship between transdisciplinary collaboration and knowledge translation to generate these understandings with a view towards maximizing the impact of collaborative efforts. METHODS: We undertook a realist evaluation and longitudinal case study of a 5-year National Health and Medical Research Council-funded Centre of Research Excellence in Transdisciplinary Frailty Research. Data were collected between February 2017 and March 2020 over three rounds of theory development, refinement and testing using interviews, observation, document review and visual elicitation as data sources. The Human Research Ethics Committee of the University of Adelaide approved this study. RESULTS: Iterative analysis of narrative interviews and visual data led to the development of three overarching programme theories explicating the reciprocal relationship between KT understandings and transdisciplinary team process. These programme theories revolve around the concept of a network, which we define in alignment with extant theoretical literature on network mechanisms and complex networks as graphically representable networks of agents/people (nodes) joined by social relationships (links). Our findings demonstrate that under the right contextual conditions, transdisciplinary team members respond through an improved ability to (1) navigate the network, (2) negotiate the network and (3) mobilize the network. CONCLUSIONS: This research demonstrates the reciprocity and mutually supportive relationship between transdisciplinary research and knowledge translation. Our findings suggest that embedding a collaborative knowledge translation framework and providing resources such as facilitation and distributed leadership within a transdisciplinary team can improve collaboration and support transdisciplinary research objectives.

Multicancer early detection test: Preclinical, translational, and clinical evidence-generation plan and provocative questions.

Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case-control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.

Exploring the translational challenge for medical applications of ionising radiation and corresponding radiation protection research.

BACKGROUND: Medical applications of ionising radiation and associated radiation protection research often encounter long delays and inconsistent implementation when translated into clinical practice. A coordinated effort is needed to analyse the research needs for innovation transfer in radiation-based high-quality healthcare across Europe which can inform the development of an innovation transfer framework tailored for equitable implementation of radiation research at scale. METHODS: Between March and September 2021 a Delphi methodology was employed to gain consensus on key translational challenges from a range of professional stakeholders. A total of three Delphi rounds were conducted using a series of electronic surveys comprised of open-ended and closed-type questions. The surveys were disseminated via the EURAMED Rocc-n-Roll consortium network and prominent medical societies in the field. Approximately 350 professionals were invited to participate. Participants' level of agreement with each generated statement was captured using a 6-point Likert scale. Consensus was defined as median ≥ 4 with ≥ 60% of responses in the upper tertile of the scale. Additionally, the stability of responses across rounds was assessed. RESULTS: In the first Delphi round a multidisciplinary panel of 20 generated 127 unique statements. The second and third Delphi rounds recruited a broader sample of 130 individuals to rate the extent to which they agreed with each statement as a key translational challenge. A total of 60 consensus statements resulted from the iterative Delphi process of which 55 demonstrated good stability. Ten statements were identified as high priority challenges with ≥ 80% of statement ratings either 'Agree' or 'Strongly Agree'. CONCLUSION: A lack of interoperability between systems, insufficient resources, unsatisfactory education and training, and the need for greater public awareness surrounding the benefits, risks, and applications of ionising radiation were identified as principal translational challenges. These findings will help to inform a tailored innovation transfer framework for medical radiation research.

Incentivising public transport use for physical activity gain: process evaluation of the COVID-19 disrupted trips4health randomised controlled trial.

BACKGROUND: Partnering with a public transport (PT) provider, state government, and local government, the single-blinded randomised controlled trial, trips4health, investigated the impact of PT use incentives on transport-related physical activity (PA) in Tasmania, Australia. The intervention involved 16-weeks of incentives (bus trip credits) for achieving weekly PT use targets, supported by weekly text messages. This study objective was to conduct a process evaluation of the COVID-19 disrupted trips4health study. METHODS: The Medical Research Council UK's framework for complex public health interventions guided the process evaluation. Participant reach, acceptability, fidelity and feasibility were evaluated. Administrative and post-intervention survey data were analysed descriptively. Semi-structured interviews with intervention participants (n = 7) and PT provider staff (n = 4) were analysed thematically. RESULTS: Due to COVID-19, trips4health was placed on hold (March 2020) then stopped (May 2020) as social restrictions impacted PT use. At study cessation, 116 participants (approximately one third of target sample) had completed baseline measures, 110 were randomised, and 64 (n = 29 in the intervention group; n = 35 in the control group) completed post-intervention measures. Participants were 18 - 80 years (average 44.5 years) with females (69%) and those with tertiary education (55%) over-represented. The intervention was delivered with high fidelity with 96% of bus trip credits and 99% of behavioural text messages sent as intended. Interviewed PT staff said implementation was highly feasible. Intervention participant acceptability was high with 90% reporting bus trip incentives were helpful and 59% reporting the incentives motivated them to use PT more. From a total of 666 possible bus trip targets, 56% were met with 38% of intervention participants agreeing and 41% disagreeing that 'Meeting the bus trip targets was easy'. Interviews and open-ended survey responses from intervention participants revealed incentives motivated bus use but social (e.g., household member commitments) and systemic (e.g., bus availability) factors made meeting bus trip targets challenging. CONCLUSIONS: trips4health demonstrated good acceptability and strong fidelity and feasibility. Future intervention studies incentivising PT use will need to ensure a broader demographic is reached and include more supports to meet PT targets. TRIAL REGISTRATION: ACTRN12619001136190 .

Urinary sodium concentration predicts time to major adverse coronary events and all-cause mortality in men with heart failure over a 28-33-year period: a prospective cohort study.

BACKGROUND: Lower urinary sodium concentrations (UNa) may be a biomarker for poor prognosis in chronic heart failure (HF). However, no data exist to determine its prognostic association over the long-term. We investigated whether UNa predicted major adverse coronary events (MACE) and all-cause mortality over 28-33 years. METHODS: One hundred and eighty men with chronic HF from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) were included. Baseline data was collected between 1984 and 1989. MACE and all-cause outcomes were obtained using hospital linkage data (1984-2017) with a follow-up of 28-33 years. Cox proportional hazards models were generated using 24-h UNa tertiles at baseline (1 ≤ 173 mmol/day; 2 = 173-229 mmol/day; 3 = 230-491 mmol/day) as a predictor of time-to-MACE outcomes, adjusted for relevant covariates. RESULTS: Overall, 63% and 83% of participants (n = 114 and n = 150) had a MACE event (median 10 years) and all-cause mortality event (median 19 years), respectively. On multivariable Cox Model, relative to the lowest UNa tertile, no significant difference was noted in MACE outcome for individuals in tertiles 2 and 3 with events rates of 28% (HR:0.72; 95% CI: 0.46-1.12) and 21% (HR 0.79; 95% CI: 0.5-1.25) respectively.. Relative to the lowest UNa tertile, those in tertile 2 and 3 were 39% (HR: 0.61; 95% CIs: 0.41, 0.91) and 10% (HR: 0.90; 95% CIs: 0.62, 1.33) less likely to experience to experience all-cause mortality. The multivariable Cox model had acceptable prediction precision (Harrell's C concordance measure 0.72). CONCLUSION: UNa was a significant predictor of all-cause mortality but not MACE outcomes over 28-33 years with 173-229 mmol/day appearing to be the optimal level. UNa may represent an emerging long-term prognostic biomarker that warrants further investigation.

Community-Based Exercise Programs for Cancer Survivors: A Scoping Review of Program Characteristics Using the Consolidated Framework for Implementation Research.

OBJECTIVE: To describe the characteristics of exercise programs for survivors of cancer conducted outside of a research laboratory (ie, home-based or community-based settings). DATA SOURCES: A systematic search of published literature was conducted using Medline, Pubmed, Cumulative Index of Nursing and Allied Health Literature, PsycINFO, SPORTdiscus, and Embase from 1980 to January 2021. Where conference abstracts were identified, authors were contacted for other articles. STUDY SELECTION: Two independent reviewers screened titles and abstracts and full texts of potentially relevant studies to determine eligibility, with discrepancies resolved by discussion. Included studies were reports of exercise programs or interventions in which participants exercise at home or in a community-based setting and including individuals diagnosed with cancer either undergoing treatment or who had completed treatment. DATA EXTRACTION: Data were extracted using the Oxford Implementation Index and coded under the 5 domains of the Consolidated Framework for Implementation Research (CFIR). Extraction and coding were completed by 2 independent reviewers, with discrepancies resolved through discussion. Data were synthesized narratively according to CFIR. DATA SYNTHESIS: A total of 58 publications describing 34 individual programs from around the world were included. Of these, only 14 publications had the specific goal of reporting on program implementation and development. A variety of intervention characteristics and characteristics of individuals involved in the intervention were described. Reporting of factors related to the CFIR domains of inner setting, outer setting, and implementation process were minimal. CONCLUSIONS: This review summarizes the characteristics of existing programs that have been reported in the literature and finds that partnerships and collaboration occur in the inner and outer settings and as part of the process of implementation. This review highlights key knowledge gaps to be answered to support the development of future community-based interventions.

Commentary on the Challenges and Benefits of Implementing Standardized Outcome Measures.

The Institute of Medicine (now the National Academy of Medicine) has proposed a Learning Heath system (LHS) as a model to improve health care. A LHS focuses on capturing data from the clinical encounter and applying those data to improve practice. The process can be described as an iterative learning cycle composed of 3 areas: performance to data, data to knowledge, and knowledge to performance or often knowledge translation. Adoption of new knowledge in medicine is notoriously slow, and the relatively new field of knowledge translation is systematically examining the critical success factors. In this issue of the Archives, Moore reports a knowledge translation project in a key aspect of rehabilitation: implementing standardized outcome measures. We report on the challenges and benefits of that project from a practical perspective and identify the critical success ingredient, leadership for implementation, which was composed of 3 key behaviors: setting clear expectations, engaging stakeholders, and providing support. Furthermore, the additional benefits, challenges, and costs are addressed.

Knowledge Translation in Physical Medicine and Rehabilitation: A Citation Analysis of the Knowledge-to-Action Literature.

OBJECTIVES: To (1) provide an overview of the use of the Knowledge-to-Action Cycle (KTA) to guide a clinical implementation project; (2) identify activities performed in each phase of the KTA; and (3) provide suggestions to improve KTA activities in physical medicine and rehabilitation. DATA SOURCES: Google Scholar and PubMed were searched through December 31, 2019. STUDY SELECTION: Two reviewers screened titles, abstracts, and full-text articles to identify published studies that used the KTA to implement a project. DATA EXTRACTION: Two reviewers examined full-text articles. Data extraction included activities performed in each phase of the KTA, including measurements used to evaluate the project's effectiveness. DATA SYNTHESIS: Commonly performed KTA activities were identified and country of study, area of rehabilitation, and other factors related to the use of the KTA in rehabilitation were described. A total of 46 articles that met the study's inclusion criteria provided an overview of the use of the KTA in rehabilitation. Strengths and weaknesses of the articles are discussed and recommendations for improved KTA use are provided. CONCLUSIONS: Implementation of evidence-based practice requires focused engineering and efforts. This review provides an overview of the knowledge translation activities occurring in physical medicine and rehabilitation and considerations to improve knowledge translation research and practice.

Knowledge Translation Research to Promote Behavior Changes in Rehabilitation: Use of Theoretical Frameworks and Tailored Interventions: A Scoping Review.

OBJECTIVE: To describe knowledge translation (KT) research as a means of changing practice behaviors in rehabilitation. We specifically aimed to explore how theories, models, and frameworks (TMFs) are used to guide KT, guide methods to tailor KT interventions, and evaluate outcomes. We hypothesized these methods would have increased over the past 10 years. DATA SOURCES: We identified articles through searches conducted using databases Cumulative Index to Nursing and Allied Health, MEDLINE, PubMed, Academic Search Premier, and previous reviews from January 2000 to April 2020. Search terms included physical therapy, occupational therapy, speech-language pathology, knowledge translation, and knowledge-to-action (KTA). STUDY SELECTION: Two authors interpedently screened titles, abstracts, and full-text articles. Studies were included if behavior change of rehabilitation practitioners was measured. Systematic reviews, protocols, and capacity-building interventions were excluded. DATA EXTRACTION: Three authors extracted information on study design, theoretical frameworks, intervention strategies, and outcome evaluation. DATA SYNTHESIS: Fifty-six studies were included in the review. Sixteen (29%) reported the use of a theoretical framework to guide the KT process. Since 2013, the KTA framework was used 35% of the time. Twenty-two studies (39%) reported barrier assessments to tailor interventions, and 82% were published after 2013. However, barrier assessment in the local context was only conducted 64% of the time. Outcomes of tailored interventions were most frequently measured using chart audits (50%) and questionnaires (41%). Further, the link between KT theory, specific barriers, and selection of intervention strategies was not consistently described. CONCLUSIONS: Over the past 7 years, there has been an increase in the use of KT TMFs and tailored interventions. Recommendations for future research include the use of TMFs to guide local barrier assessment, KT strategy selection, intervention development, and overall KT process and mapping barriers to selected intervention strategies.

Gait and Balance Outcome Measures Are Responsive in Severely Impaired Individuals Undergoing Inpatient Stroke Rehabilitation.

OBJECTIVE: To investigate whether gait and balance outcome measures in patients with severe gait and balance impairments at admission to inpatient rehabilitation provided additional and meaningful information beyond customary measures. Specifically, this study investigated whether individuals who obtained low scores at admission exhibited improvements that exceeded the established minimal detectable change during inpatient rehabilitation. We also investigated whether gait outcomes would capture changes in function not identified by customary measures. DESIGN: Secondary analysis of a knowledge translation project aimed at increasing the systematic collection of these outcome measures in a poststroke cohort. SETTING: Subacute inpatient rehabilitation facility. PARTICIPANTS: Individuals<2 months poststroke (N=157) with 34-43 with severe deficits including Berg Balance Scale≤5, 10-meter walk test=0 m/s, or 6-minute walk test=0 m. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Berg Balance Scale, 10-meter walk test, 6-minute walk test. RESULTS: After 1 week of rehabilitation, 41%-53% of severely impaired individuals had changes above minimal detectable changes in gait and balance outcomes, which increased to 68%-84% at discharge. Across the entire cohort, FIM locomotion scores failed to identify changes in gait function for 35% of participants after 1 week of rehabilitation. CONCLUSIONS: Routine assessment of gait and balance outcome measures in patients with severe deficits early poststroke may be beneficial. These measures were responsive after 1 week of rehabilitation and detected changes not captured by customary measures. Routine use of a standardized gait and balance assessments may provide clinicians with important information to guide clinical decision making.

Applying the Knowledge-to-Action Framework to Implement Gait and Balance Assessments in Inpatient Stroke Rehabilitation.

OBJECTIVES: The overall objectives of this project were to implement and sustain use of a gait assessment battery (GAB) that included the Berg Balance Scale, 10-meter walk test, and 6-minute walk test during inpatient stroke rehabilitation. The study objective was to assess the effect of the study intervention on clinician adherence to the recommendations and its effect on clinician perceptions and the organization. DESIGN: Pre- and post-training intervention study. SETTING: Subacute inpatient rehabilitation facility. PARTICIPANTS: Physical therapists (N=6) and physical therapist assistants (N=2). INTERVENTION: The intervention comprised a bundle of activities, including codeveloping and executing the plan with clinicians and leaders. The multicomponent implementation plan was based on the Knowledge-to-Action Framework and included implementation facilitation, implementation leadership, and a bundle of knowledge translation interventions that targeted barriers. Implementation was an iterative process in which results from one implementation phase informed planning of the next phase. MAIN OUTCOME MEASURES: Clinician administration adherence, surveys of perceptions, and organizational outcomes. RESULTS: Initial adherence to the GAB was 46% and increased to more than 85% after 6 months. These adherence levels remained consistent 48 months after implementation. Clinician perceptions of measure use were initially high (>63%), with significant improvements in knowledge and use of one measure after implementation. CONCLUSIONS: We successfully implemented the assessment battery with high levels of adherence to recommendations, likely because of using the bundle of knowledge translation activities, facilitation, and use of a framework to codevelop the plan. These changes in practice were sustainable, as determined by a 4-year follow-up.

Research Needs for Inpatient Management of Severe Alcohol Withdrawal Syndrome: An Official American Thoracic Society Research Statement.

Background: Severe alcohol withdrawal syndrome (SAWS) is highly morbid, costly, and common among hospitalized patients, yet minimal evidence exists to guide inpatient management. Research needs in this field are broad, spanning the translational science spectrum. Goals: This research statement aims to describe what is known about SAWS, identify knowledge gaps, and offer recommendations for research in each domain of the Institute of Medicine T0-T4 continuum to advance the care of hospitalized patients who experience SAWS. Methods: Clinicians and researchers with unique and complementary expertise in basic, clinical, and implementation research related to unhealthy alcohol consumption and alcohol withdrawal were invited to participate in a workshop at the American Thoracic Society 2019 International Conference. The committee was subdivided into four groups on the basis of interest and expertise: T0-T1 (basic science research with translation to humans), T2 (research translating to patients), T3 (research translating to clinical practice), and T4 (research translating to communities). A medical librarian conducted a pragmatic literature search to facilitate this work, and committee members reviewed and supplemented the resulting evidence, identifying key knowledge gaps. Results: The committee identified several investigative opportunities to advance the care of patients with SAWS in each domain of the translational science spectrum. Major themes included 1) the need to investigate non-γ-aminobutyric acid pathways for alcohol withdrawal syndrome treatment; 2) harnessing retrospective and electronic health record data to identify risk factors and create objective severity scoring systems, particularly for acutely ill patients with SAWS; 3) the need for more robust comparative-effectiveness data to identify optimal SAWS treatment strategies; and 4) recommendations to accelerate implementation of effective treatments into practice. Conclusions: The dearth of evidence supporting management decisions for hospitalized patients with SAWS, many of whom require critical care, represents both a call to action and an opportunity for the American Thoracic Society and larger scientific communities to improve care for a vulnerable patient population. This report highlights basic, clinical, and implementation research that diverse experts agree will have the greatest impact on improving care for hospitalized patients with SAWS.

Toward scientific dissemination of undergraduate thesis in physical therapy programs - a cross-sectional study.

BACKGROUND: The execution of undergraduate thesis is a period in which students have an opportunity to develop their scientific knowledge. However, many barriers could prevent the learning process. This cross-sectional study aimed to analyze the scientific dissemination of results from undergraduate theses in physical therapy programs and verify the existence of barriers and challenges in the preparation of undergraduate thesis. Second, to investigate whether project characteristics and thesis development barriers were associated with the dissemination of undergraduate thesis results. METHODS: Physical therapists who graduated as of 2015, from 50 different educational institutions, answered an online questionnaire about barriers faced during the execution of undergraduate thesis and about scientific dissemination of their results. RESULTS: Of 324 participants, 43% (n = 138) of participants disseminated their results, and the main form of dissemination was publishing in national journals (18%, n = 58). Regarding the barriers, 76% (n = 246) of participants reported facing some difficulties, and the main challenge highlighted was the lack of scientific knowledge (28%, n = 91). Chances of dissemination were associated with barriers related to scientific understanding and operational factors, such as the type of institution, institutional facilities, and involvement with other projects. CONCLUSION: Scientific knowledge seems to be a determining factor for the good development of undergraduate theses. In addition, it is clear the need to stimulate more qualified dissemination that reaches a larger audience. Changes in operational and teaching factors may improve the undergraduate thesis quality. However, the importance of rethinking scientific education within physical therapy programs draws attention.

Endotyping chronic rhinosinusitis based on olfactory cleft mucus biomarkers.

BACKGROUND: Although chronic rhinosinusitis (CRS) is considered the most treatable form of olfactory dysfunction, there has been relatively little clinical attention focused on assessing endotypes as they pertain to olfactory loss. OBJECTIVES: The goal of this study was to explore inflammatory endotypes in CRS using an unsupervised cluster analysis of olfactory cleft (OC) biomarkers in a phenotype-free approach. METHODS: Patients with CRS were prospectively recruited and psychophysical olfactory testing, Questionnaire of Olfactory Dysfunction (QOD-NS), and bilateral OC endoscopy were obtained. Mucus was collected from the OC and evaluated for 26 biomarkers using principal component analysis. Cluster analysis was performed using only OC biomarkers and differences in olfactory measures were compared across clusters. RESULTS: A total of 198 subjects (128 with CRS and 70 controls) were evaluated. Evaluation of OC biomarkers indicated 6 principal components, explaining 69.50% of the variance, with type 2, mixed type 1/Th17-cell, growth factor, and neutrophil chemoattractant inflammatory signatures. A total of 10 clusters were identified that differed significantly in frequency of controls, and subjects with CRS with nasal polyps, and subjects with CRS without nasal polyps across the clusters (likelihood ratio test, χ182=178.64; P < .001). Olfactory measures differed significantly across clusters, including olfactory testing, QOD-NS, and OC endoscopy (P < .001 for all). CONCLUSIONS: Clustering based solely on OC biomarkers can organize patients into clinically meaningful endotypes that discriminate between subjects with CRS and controls. Validation studies are necessary to confirm these findings and further refine olfactory endotypes.

Thrombin Preconditioning Improves the Therapeutic Efficacy of Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage Induced Neonatal Rats.

Severe intraventricular hemorrhage (IVH) remains a major cause of high mortality and morbidity in extremely preterm infants. Mesenchymal stem cell (MSC) transplantation is a possible therapeutic option, and development of therapeutics with enhanced efficacy is necessary. This study investigated whether thrombin preconditioning improves the therapeutic efficacy of human Wharton's jelly-derived MSC transplantation for severe neonatal IVH, using a rat model. Severe neonatal IVH was induced by injecting 150 µL blood into each lateral ventricle on postnatal day (P) 4 in Sprague-Dawley rats. After 2 days (P6), naïve MSCs or thrombin-preconditioned MSCs (1 × 105/10 µL) were transplanted intraventricularly. After behavioral tests, brain tissues and cerebrospinal fluid of P35 rats were obtained for histological and biochemical analyses, respectively. Thrombin-preconditioned MSC transplantation significantly reduced IVH-induced ventricular dilatation on in vivo magnetic resonance imaging, which was coincident with attenuations of reactive gliosis, cell death, and the number of activated microglia and levels of inflammatory cytokines after IVH induction, compared to naïve MSC transplantation. In the behavioral tests, the sensorimotor and memory functions significantly improved after transplantation of thrombin-preconditioned MSCs, compared to naïve MSCs. Overall, thrombin preconditioning significantly improves the therapeutic potential and more effectively attenuates brain injury, including progressive ventricular dilatation, gliosis, cell death, inflammation, and neurobehavioral functional impairment, in newborn rats with induced severe IVH than does naïve MSC transplantation.

Translating Functional Connectivity After Stroke: Functional Magnetic Resonance Imaging Detects Comparable Network Changes in Mice and Humans.

Background and Purpose: The translational roadblock has long impeded the implementation of experimental therapeutic approaches for stroke into clinical routine. Considerable interspecies differences, for example, in brain anatomy and function, render comparisons between rodents and humans tricky, especially concerning brain reorganization and recovery of function. We tested whether stroke-evoked changes in neural networks follow similar patterns in mice and patients using a systems-level perspective. Methods: We acquired resting-state functional magnetic resonance imaging data during the early poststroke phase in a sample of human patients and compared the observed network changes with data from 2 mouse stroke models, that is, photothrombosis and distal middle cerebral artery occlusion. Importantly, data were subjected to the same processing steps, allowing a direct comparison of global network changes using graph theory. Results: We found that network parameters computed for both mouse models of stroke and humans follow a similar pattern in the postacute stroke phase. Parameters indicating the global communication structure's facilitation, such as small worldness and characteristic path length, were similarly changed in humans and mice in the first days after stroke. Additionally, small worldness correlated with concurrent motor impairment in humans. Longitudinal observation in the subacute phase revealed a negative correlation between initial small worldness and motor recovery in mice. Conclusions: We show that network measures based on resting-state functional magnetic resonance imaging data after stroke obtained in mice and humans share notable features. The observed network alterations could serve as therapeutic readout parameters for future translational studies in stroke research.