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Implementation Science and Pediatric Diabetes: A Scoping Review of the State of the Literature and Recommendations for Future Research
Get PDFPurpose of Review: This scoping review aimed to identify implementation science (IS) research in pediatric diabetes, report
integration of IS theory and terminology, and offer guidance for future research.
Recent Findings: Of 23 papers identified, 19 were published since 2017 and 21 focused on type 1 diabetes. Most involved
medical evidence-based practices (EBPs; n = 15), whereas fewer focused on psychosocial (n = 7) and diabetes education
(n = 2). The majority either identified barriers and facilitators of implementing an EBP (n = 11) or were implementation trials
(n = 11). Fewer studies documented gaps in EBP implementation in standard care (n = 7) or development of implementation
strategies (n = 1). Five papers employed IS theories and two aimed to improve equity.
Summary: There is a paucity of IS research in pediatric diabetes care literature. Few papers employed IS theory, used consis-
tent IS terminology, or described IS strategies or outcomes. Guidance for future research to improve IS research in pediatric
diabetes is offered.No embarg
Developing an Adeno-Associated Viral Gene Therapy for Sialidosis Using Small and Large Animal Models
Get PDFSialidosis is a rare, fatal lysosomal storage disease caused by mutations in NEU1, encoding neuraminidase 1 (NEU1) resulting in toxic accumulation of sialylated glycoproteins. Type I patients have adolescent onset with myoclonus, ataxia, seizures, cherry-red spot, and vision loss, with death in midlife. Type II patients are more severe with the addition of hepatosplenomegaly, coarse facial features, dysostosis multiplex, developmental delay, and death in childhood. There are no approved therapies for sialidosis. We developed three adeno-associated viral (AAV) gene therapy vector strategies to treat sialidosis encoding: Neu1 alone (AAV9-Neu1), Neu1 modified to enhance secretion (AAV9-Idua-Neu1) or Neu1 in combination with its chaperone protein cathepsin A (AAV9-Ctsa-Bici-Neu1). Neonatal Neu1-KO mice were injected by intracerebroventricular injection. Increased survival and significant improvement in motor ability was noted for all vectors, however seizures were observed in AAV9-Neu1 treated mice at 10 months of age. Reduced sialic acid and PPCA were found in peripheral organs and brains of treated mice. NEU1 was increased in peripheral organs and the brain, however AAV9-Ctsa-Bici-Neu1 treated mice had NEU1 levels similar to WT mice. Pathology of peripheral organs were markedly ameliorated with AAV gene therapy. We generated a sialidosis type II sheep using CRISPR-SpCas9 (A320del), which is in the same location as the amino acid change in patients (A319V). Importantly, the A320del sheep exhibits a neurological phenotype unlike the Neu1-KO mouse. Overall, the most efficacious vector is AAV9-Ctsa-Bici-Neu1, which will be further tested in the sialidosis sheep model. These studies will inform future clinical trials for this devastating disease.Neuroscienc
Isolated Limb Infusion as First, Second, or Third or Later-Line Therapy for Metastatic In-Transit Melanoma
Get PDFBACKGROUND: Ten percent of patients with melanoma develop in-transit metastases (ITM). Isolated limb infusion (ILI) is a well-established therapy for unresectable ITM on the extremities, but the ideal sequencing/line of therapy of ILI has not been defined. This study evaluates ILI as first-line, second-line, or third or later-line therapy.
METHODS: A retrospective review included all patients with unresectable ITM who underwent ILI from 2006-2023.
RESULTS: A total of 130 patients were identified, 61% female, median age of 71 (31-89) years. Median follow-up was 37.5 months. ILI was first-line therapy in 80% (n = 104), second-line in 15% (n = 19), and third or later-line in 5.4% (n = 7). Overall response rate (ORR) and complete response (CR) rates for ILI as any line of therapy were 74% and 41%, respectively. ORR for ILI as first, second, or third or later-line therapy were 78%, 63%, and 57%, respectively. CR rates for ILI as first, second, or third or later-line therapy were 42%, 37%, and 43%, respectively. There were no significant differences in ORR, progression-free survival (PFS), overall survival, or disease-free survival between therapy lines. Median PFS for ILI as first, second, or third or later-line therapy were 6.9, 5.4, and 18 months, respectively.
CONCLUSION: Patients responded well to ILI, whether or not they received previous therapies for unresectable ITM. First-line ILI appears to have a better ORR than later lines of ILI. Although sample size limited statistical significance, there was a 21% improvement in ORR when ILI was used as first-line vs third-line therapy, which is clinically meaningful. ILI is effective for unresectable melanoma ITM and can be used as salvage therapy.
Isolated limb infusion (ILI) is an excellent treatment option for patients with in-transit melanoma. In this study, patients responded notably well when ILI was used as first-line therapy, and also responded well when ILI was used as a salvage therapy.No embarg
The feasibility of wildlife immersion experiences for Veterans with PTSD
Get PDFINTRODUCTION: Animal-assisted interventions (AAI) offer potential physical and psychological health benefits that may assist Veterans with post-traumatic stress disorder. However, more feasibility studies are needed regarding intervention details, adverse events, reasons for study withdrawal, and animal welfare.
METHODS: This mixed methods feasibility trial involved a modified crossover study in which Veterans with PTSD/PTSD symptoms were provided a series of 8 nature and wildlife immersion experiences to evaluate feasibility and preliminary efficacy. The sample included 19 Veterans with PTSD/PTSD symptoms who were followed for a mean of 15.1 weeks. The intervention was comprised of a baseline forest walk, assisting with wildlife rehabilitation, observation in a wildlife sanctuary, and bird watching. Post study bird feeders were provided for sustainability.
RESULTS: This AAI nature/wildlife immersion intervention was feasible, acceptable, and safe to administer to Veterans with PTSD/PTSD symptoms with appropriate support. Logistical and relational facilitators were identified that supported the wildlife immersion activities. Participants reported greatly enjoying the activities. Attention to animal welfare and care was an important ethical foundation that also contributed to feasibility.
DISCUSSION: AAI immersion experiences with wildlife are feasible and can safely be administered to Veterans with PTSD/PTSD symptoms. Logistical and relational facilitators are important to support nature and wildlife immersion activities.No embarg
Molecular Analysis of Neural Mechanisms Controlling Organismal Responses to Oxidative Stress
No full textOrganisms have evolved protective strategies for limiting cellular damage and enhancing organismal survival during stress, in particular oxidative stress. My thesis work investigated previously underappreciated links between neuronal activity, neurotransmission, and oxidative stress responses in the nematode Caenorhabditis elegans.
I demonstrated a requirement for neural activity in regulating organismal survival during oxidative stress using a genetic strategy for neuronal silencing. From a survey of evolutionarily conserved neurotransmitter systems, I showed that cholinergic transmission from motor neurons was important for protection from prolonged oxidative stress. I showed that prolonged oxidative stress mobilizes a widespread transcriptional response. A deficiency in cholinergic transmission strikingly reduces the scope of this response. I found that cholinergic involvement is primarily mediated through activation of the Gq-coupled muscarinic acetylcholine receptor GAR-3. Interestingly, gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mutants, suggesting that cholinergic activation of GAR-3 may be critical for stress-responsive upregulation of protein degradation pathways. In parallel, I investigated the impact of oxidative stress on neuronal integrity and observed progressive neurodegeneration during prolonged oxidative stress. Curiously, I found that a deficiency in cholinergic transmission does not enhance the severity of neurodegeneration during the early stages of prolonged oxidative stress, perhaps suggesting that neurodegeneration and organismal survival are not precisely linked. My research provides key insights into neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling systems and transcriptional activation of protective pathways, suggesting potential targets to combat oxidative damage and related inflammatory, systemic and neurodegenerative diseases.Neuroscience2 years2026-12-1
Reverse Correlation Characterizes More Complete Tinnitus Spectra in Patients
Get PDFWe validate a recent reverse correlation approach to tinnitus characterization by applying it to individuals with clinically-diagnosed tinnitus. Two tinnitus patients assessed the subjective similarity of their non-tonal tinnitus percepts and random auditory stimuli. Regression of the responses onto the stimuli yielded reconstructions which were evaluated qualitatively by playing back resynthesized waveforms to the subjects and quantitatively by response prediction analysis. Subject 1 preferred their resynthesis to white noise; subject 2 did not. Response prediction balanced accuracies were significantly higher than chance across subjects: subject 1: 0.5963, subject 2: 0.6922. Reverse correlation can provide the foundation for reconstructing accurate representations of complex, non-tonal tinnitus in clinically diagnosed subjects. Further refinements may yield highly similar waveforms to individualized tinnitus percepts.No embarg
On approximate equality of Z-values of the statistical tests for win statistics (win ratio, win odds, and net benefit)
No full textDong et al. (2023) showed that the win statistics (win ratio, win odds, and net benefit) can complement each another to demonstrate the strength of treatment effects in randomized trials with prioritized multiple outcomes. This result was built on the connections among the point and variance estimates of the three statistics, and the approximate equality of Z-values in their statistical tests. However, the impact of this approximation was not clear. This Discussion refines this approach and shows that the approximate equality of Z-values for the win statistics holds more generally. Thus, the three win statistics consistently yield closely similar p-values. In addition, our simulations show an example that the naive approach without adjustment for censoring bias may produce a completely opposite conclusion from the true results, whereas the IPCW (inverse-probability-of-censoring weighting) approach can effectively adjust the win statistics to the corresponding true values (i.e. IPCW-adjusted win statistics are unbiased estimators of treatment effect).No embarg
Use of the pRESET LITE thrombectomy device in combined approach for medium vessel occlusions: A multicenter evaluation
No full textPurpose: Our purpose was to assess the efficacy and safety of the pRESET LITE stent retriever (Phenox, Bochum, Germany), designed for medium vessel occlusion (MeVO) in acute ischemic stroke (AIS) patients with a primary MeVO.
Methods: We performed a retrospective analysis of the MAD MT Consortium, an integration of prospectively maintained databases at 37 academic institutions in Europe, North America, and Asia, of AIS patients who underwent mechanical thrombectomy with the pRESET LITE stent retriever for a primary MeVO. We subcategorized occlusions into proximal MeVOs (segments A1, M2, and P1) vs. distal MeVOs/DMVO (segments A2, M3-M4, and P2). We reviewed patient and procedural characteristics, as well as angiographic and clinical outcomes.
Results: Between September 2016 and December 2021, 227 patients were included (50% female, median age 78 [65-84] years), of whom 161 (71%) suffered proximal MeVO and 66 (29%) distal MeVO. Using a combined approach in 96% of cases, successful reperfusion of the target vessel (mTICI 2b/2c/3) was attained in 85% of proximal MeVO and 97% of DMVO, with a median of 2 passes (IQR: 1-3) overall. Periprocedural complications rate was 7%. Control CT at day 1 post-MT revealed a hemorrhagic transformation in 63 (39%) patients with proximal MeVO and 24 (36%) patients with DMVO, with ECASS-PH type hemorrhagic transformations occurring in 3 (1%) patients. After 3 months, 58% of all MeVO and 63% of DMVO patients demonstrated a favorable outcome (mRS 0-2).
Conclusion: Mechanical thrombectomy using the pRESET LITE in a combined approach with an aspiration catheter appears effective for primary medium vessel occlusions across several centers and physicians
Exploring Deep Learning Applications using Ultrasound Single View Cines in Acute Gallbladder Pathologies: Preliminary results
Get PDFRationale and objectives: In this preliminary study, we aimed to develop a deep learning model using ultrasound single view cines that distinguishes between imaging of normal gallbladder, non-urgent cholelithiasis, and acute calculous cholecystitis requiring urgent intervention.
Methods: Adult patients presenting to the emergency department between 2017-2022 with right-upper-quadrant pain were screened, and ultrasound single view cines of normal imaging, non-urgent cholelithiasis, and acute cholecystitis were included based on final clinical diagnosis. Longitudinal-view cines were de-identified and gallbladder pathology was annotated for model training. Cines were randomly sorted into training (70%), validation (10%), and testing (20%) sets and divided into 12-frame segments. The deep learning model classified cines as normal (all segments normal), cholelithiasis (normal and non-urgent cholelithiasis segments), and acute cholecystitis (any cholecystitis segment present).
Results: A total of 186 patients with 266 cines were identified: Normal imaging (52 patients; 104 cines), non-urgent cholelithiasis (73;88), and acute cholecystitis (61;74). The model achieved a 91% accuracy for Normal vs. Abnormal imaging and an 82% accuracy for Urgent (acute cholecystitis) vs. Non-urgent (cholelithiasis or normal imaging). Furthermore, the model identified abnormal from normal imaging with 100% specificity, with no false positive results.
Conclusion: Our deep learning model, using only readily obtained single-view cines, exhibited a high degree of accuracy and specificity in discriminating between non-urgent imaging and acute cholecystitis requiring urgent intervention
Understanding Onset, Dynamic Transitions, and Associated Inequality Risk Factors for Adverse Posttraumatic Neuropsychiatric Sequelae After Trauma Exposure
Get PDFObjective: Several gaps remain in the understanding of the onset, dynamic transitions, and associated risk factors of adverse posttraumatic neuropsychiatric sequelae (APNS) in the acute post-trauma window. Based on serial assessments of symptoms from a large cohort study, we identified homogeneous statuses across multiple APNS symptom domains and investigated the dynamic transitions among these statuses during the first 2 months after trauma exposure. Furthermore, we studied how symptom onset and transitions are affected by equity-relevant characteristics.
Methods: The analysis was based on 2557 participants enrolled in the Advancing Understanding of RecOvery afteR traumA (AURORA). APNS symptoms comprised pain, depression, sleep discontinuity, nightmares, avoidance, re-experience, anxiety, hyperarousal, somatic symptoms, and mental fatigue. We identified the homogeneous status of APNS symptoms at baseline, 1 month, and 2 months, and explored transition probabilities among these statuses using latent transition analysis. Equity-relevant characteristics included gender, race, education, family income, childhood trauma, and area deprivation.
Results: Three homogeneous statuses-low-, moderate-, and severe-symptom-were identified. While the majority of trauma survivors with severe- or moderate-symptom status maintained the same status over time, some transitioned to a less severe symptom status, particularly within the first month. Specifically, females, non-whites, and those with higher childhood trauma were associated with a decreased likelihood of transitioning to a less severe symptom status. From one to 2 months, lower income was associated with a decreased likelihood of transitioning from moderate-to low-symptom status.
Conclusions: The findings can inform early intervention strategies for APNS, potentially reducing health disparities among trauma survivors.No embarg