Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Endoscopic endonasal approach for olfactory groove meningioma resection: Strategies and outcomes in a retrospective case series.

OBJECTIVE: Though the endoscopic endonasal approach (EEA) is a widely accepted treatment for skull base tumors, the specific use of EEA for olfactory groove meningiomas (OGMs) is debated, with variable outcomes reported in the literature. We review the surgical results of OGM resections for one surgeon including the operative approach, surgical nuances, and outcomes, with a focus on factors relating to patient selection which favor EEA over transcranial approaches. METHODS: We retrospectively reviewed thirteen cases of endoscopic endonasal resection of olfactory groove meningiomas. Patient characteristics, clinical characteristics, surgical outcomes, and complications were analyzed. Extent of resection was determined based on volumetric analysis of pre- and postoperative MRI. RESULTS: Anatomic characteristics that render a tumor difficult to access fully are lateral extension beyond the mid-orbit and anterior extension to the falx. Simpson Grade I resection was achieved in 11/13 (84.6 %) cases. Mean pre-operative tumor volume was 8.99 cm3 (range 2.19-16.79 cm3), and 92 % of tumors were WHO grade I. We demonstrate 2 cases of smell preservation, possible with small unilateral tumors and tumors that are confined to either the anterior or posterior portion of the cribriform plate. The post-operative CSF leak rate was 7.7 %, without prophylactic lumbar CSF drainage. The mortality rate was 7.7 % (n = 1) after infectious complications following CSF leak. CONCLUSIONS: Endoscopic endonasal resection of olfactory groove meningiomas is an effective and safe operative method with outcomes and complication rates comparable to transcranial approaches. Key considerations include careful patient selection and familiarity with technical nuances of endoscopic endonasal approach for this specific tumor type.

Overcoming brain-derived therapeutic resistance in HER2+ breast cancer brain metastasis.

Brain metastasis of HER2+ breast cancer occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with Trastuzumab +/-HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis (BCBM). The scarcity of suitable patient-derived in-vivo models for HER2+ BCBM has compromised the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. We have generated and characterized new HER2+ BCBM cells (BCBM94) isolated from a patient HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated BCBM in mice. The clinically used receptor tyrosine kinase inhibitor (RTKi) Lapatinib blocked phosphorylation of all ErbB1-4 receptors and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin-1 (NRG1), a ligand for ErbB3 and ErbB4 that is abundantly expressed in the brain, was able to rescue Lapatinib-induced apoptosis and clonogenic ability in BCBM94 and in HER2+ BT474. ErbB3 was essential to mediate the NRG1-induced survival pathway that involved PI3K-AKT signalling and the phosphorylation of BAD at serine 136 to prevent apoptosis. High throughput RTKi screening identified the brain penetrable Poziotinib as highly potent compound to reduce cell viability in HER2+ BCBM in the presence of NRG1. Successful in-vivo ablation of BCBM94- and BT474-derived HER2+ brain tumors was achieved upon two weeks of treatment with Poziotinib. MRI revealed BCBM remission upon poziotinib, but not with Lapatinib treatment. In conclusion, we have established a new patient-derived HER2+ BCBM in-vivo model and identified Poziotinib as highly efficacious RTKi with excellent brain penetrability that abrogated HER2+ BCBM brain tumors in our mouse models.

Provider-reported experiences, barriers, and perspectives on genetic testing as part of autism diagnosis.

Several professional organizations recommend conducting genetic testing as part of the autism diagnosis process, as it can provide additional information and benefits for autistic people and their families. However, there is disagreement among autism communities about whether genetic testing reflects autistic people's best interests. In practice, rates of clinical genetic testing for autism are much lower than diagnoses, creating a large gap between clinical guidelines and real clinical encounters. To investigate one potential source of this gap, we interviewed 14 healthcare providers about the autism diagnostic process and their actions related to autism genetic testing. We recruited a sample of primarily Ph.D. level-psychologists and analyzed our qualitative data using a five-step framework analysis method. Participants generally had positive or mixed views of genetic testing in autism. They described their current experiences of implementation of genetic testing, including that they did not often find it changed their clinical practice. Only some providers recommended it to everyone receiving an autism diagnosis. They also listed factors which discourage families from getting testing, including high costs, families feeling overwhelmed, other support needs taking priority, and ethical implications. Notably, providers highlighted a trend of referring patients to research genetic testing rather than clinical testing, which may provide a cheaper and easier alternative but is not likely to return results to participants. Finally, participants felt they needed more training in genetics and listed specific topics of uncertainty. Our research highlights a need to further educate clinicians in the uses and limitations of genetic testing for autism and suggests content areas of focus for genetics educators.

An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers.

CONTEXT: Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC). OBJECTIVE: We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo. DESIGN: A35 (NCATS-SM4420; NCGC00241808) was selected from a sub-library of >200 TSHR ligands. Cell proliferation assays including BrdU incorporation and WST-1, along with molecular docking studies were done. In vivo activity of A35 was assessed in TC cell-derived xenograft (CDX) models with immunocompromised (NSG) mice. FFPE sections of tumor and lung tissues were observed for the extent of cell death and metastasis. RESULTS: A35 was shown to stimulate cAMP production in some cell types by activating TSHR but not in TC cells, MDA-T32 and MDA-T85. A35 inhibited proliferation of MDA-T32 & MDA-T85 in vitro and in vivo, and pulmonary metastasis of MDA-T85F1 in mice. In vitro, A35 inhibition of proliferation was reduced by a selective TSHR antagonist. Inhibition of CDX tumor growth without decreases in mouse weights and liver function showed A35 to be efficacious without apparent toxicity. Lastly, A35 reduced levels of Ki67 in the tumors and metastatic markers in lung tissues. CONCLUSION: We conclude that A35 is a TSHR-selective inhibitor of TC cell proliferation and metastasis, and suggest that A35 may be a promising lead drug candidate for the treatment of differentiated thyroid cancer in humans.

A systematic review of nanocarriers for treatment of urologic cancers.

Nanocarriers (NCs) are a form of nanotechnology widely investigated in cancer treatment to improve the safety and efficacy of systemic therapies by increasing tumor specificity. Numerous clinical trials have explored the use of NCs in urologic cancers since the approval of the first NCs for cancer treatment over 20 years ago. The objective of this systematic review is to examine the effectiveness and safety of NCs in treating urological cancers. This paper summarizes the state of the field by investigating peer-reviewed, published results from 43 clinical trials involving the use of NCs in bladder, prostate, and kidney cancer patients with a focus on safety and efficacy data. Among the 43 trials, 16 were phase I, 20 phase II, and 4 phase I/II. No phase III trials have been reported. While both novel and classic NCs have been explored in urologic cancers, NCs already approved for the treatment of other cancers were more widely represented. Trials in prostate cancer and mixed trials involving both urologic and non-urologic cancer patients were the most commonly reported trials. Although NCs have demonstrable efficacy with adequate safety in non-urologic cancer patient populations, current clinical stage NC options appear to be less beneficial in the urologic cancer setting. For example, nab-paclitaxel and liposomal doxorubicin have proven ineffective in the treatment of urologic cancers despite successes in other cancers. However, several ongoing pre-clinical studies using targeted and locally applied improved NCs may eventually improve their utility.

Novel venous balloon for compliance measurement and stent sizing in a post-thrombotic swine model.

Objective: Real-time accurate venous lesion characterization is needed during endovenous interventions for stent deployment. The goal of this study is to validate a novel device for venoplasty sizing and compliance measurements. Methods: A compliance measuring sizing balloon (CMSB) uses real-time electrical conductance measurements based on Ohm's Law to measure the venous size and compliance in conjunction with pressure measurement. The sizing accuracy and repeatability of the CMSB system were performed with phantoms on the bench and in a swine model with an induced post thrombotic (PT) stenosis in the common femoral vein of swine. Results: The accuracy and repeatability of the CMSB system were validated with phantom bench studies of known dimensions in the range of venous diameters. In 9 swine (6 experimental and 3 control animals), the luminal cross-sectional areas (CSA) increased heterogeneously along the PT stenosis when the CMSB system was inflated by stepwise pressures. The PT stenosis showed lower compliance compared to the non-PT vein segments (5 mm2 vs. 10 mm2 and 13 mm2 at a pressure change of 40 cm H2O). Compliance had no statistical difference between venous hypertension (VHT) and Control. Compliance at PT stenosis, however, was significantly smaller than that at Control and VHT (p < 0.05, ANOVA). Conclusion: The CMSB system provides accurate, repeatable, real-time measurements of CSA and compliance for assessment of venous lesions to guide interventions. These findings provide the impetus for future first-in-human studies.

Acute kidney injury during extracorporeal life support in cardiogenic shock: Does flow matter?

BACKGROUND: This study examines the role of extracorporeal life support flow in the development of acute kidney injury in cardiogenic shock. METHODS: We performed a retrospective analysis of 465 patients placed on extracorporeal life support at our institution between January 2015 and December 2020 for cardiogenic shock. Flow index was calculated by dividing mean flow by body surface. Stages of acute kidney injury were determined according to Kidney Disease: Improving Global Outcomes (KDIGO) organization guidelines. RESULTS: There were 179 (38.5%) patients who developed acute kidney injury, 63.1% of which were classified as Stage 3--the only subgroup associated with 1-year mortality (hazard ratio = 2.03, p < .001). Risk of kidney injury increased up to a flow index of 1.6 L/min/m2, and kidney injury was more common among patients with flow index greater than 1.6 L/min/m2 (p = .034). Those with kidney injury had higher baseline lactate levels (4.4 vs 3.1, p = .04), and Stage 3 was associated wit higher baseline creatinine (p < .001). CONCLUSIONS: In our cohort, kidney injury was common and Stage 3 kidney injury was associated with worse outcomes compared to other stages. Low flow was not associated with increased risk of kidney injury. Elevated baseline lactate and creatinine among patients with acute kidney injury suggest underlying illness severity, rather than flow, may influence kidney injury risk.

Development and validation of PAMPA-BBB QSAR model to predict brain penetration potential of novel drug candidates.

Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in the development of drugs that target the central nervous system. Although there are several methods to determine BBB permeability of small molecules, the Parallel Artificial Membrane Permeability Assay (PAMPA) is one of the most common assays in drug discovery due to its robust and high-throughput nature. Drug discovery is a long and costly venture, thus, any advances to streamline this process are beneficial. In this study, ∼2,000 compounds from over 60 NCATS projects were screened in the PAMPA-BBB assay to develop a quantitative structure-activity relationship model to predict BBB permeability of small molecules. After analyzing both state-of-the-art and latest machine learning methods, we found that random forest based on RDKit descriptors as additional features provided the best training balanced accuracy (0.70 ± 0.015) and a message-passing variant of graph convolutional neural network that uses RDKit descriptors provided the highest balanced accuracy (0.72) on a prospective validation set. Finally, we correlated in vitro PAMPA-BBB data with in vivo brain permeation data in rodents to observe a categorical correlation of 77%, suggesting that models developed using data from PAMPA-BBB can forecast in vivo brain permeability. Given that majority of prior research has relied on in vitro or in vivo data for assessing BBB permeability, our model, developed using the largest PAMPA-BBB dataset to date, offers an orthogonal means to estimate BBB permeability of small molecules. We deposited a subset of our data into PubChem bioassay database (AID: 1845228) and deployed the best performing model on the NCATS Open Data ADME portal (https://opendata.ncats.nih.gov/adme/). These initiatives were undertaken with the aim of providing valuable resources for the drug discovery community.

Symptomatic perianeursymal cyst development 20 years after endovascular treatment of a ruptured giant aneurysm: Case report and updated review.

Perianeurysmal cysts are a rare and poorly understood finding in patients both with treated and untreated aneurysms. While the prior literature suggests that a minority of perianeurysmal cysts develop 1-4 years following endovascular aneurysm treatment, this updated review demonstrates that nearly half of perianeurysmal cysts were diagnosed following aneurysm coiling, with the other half diagnosed concurrently with an associated aneurysm prior to treatment. 64% of perianeurysmal cysts were surgically decompressed, with a 39% rate of recurrence requiring re-operation. We report a case of a 71-year-old woman who presented with vertigo and nausea and was found to have a 3.4 cm perianeurysmal cyst 20 years after initial endovascular coiling of a ruptured giant ophthalmic aneurysm. The cyst was treated with endoscopic fenestration followed by open fenestration upon recurrence. The case represents the longest latency from initial aneurysm treatment to cyst diagnosis reported in the literature and indicates that the diagnosis of perianeurysmal cyst should remain on the differential even decades after treatment. Based on a case discussion and updated literature review, this report highlights proposed etiologies of development and management strategies for a challenging lesion.

Simultaneous heart-kidney transplant compared with heart transplant alone in patients with borderline renal function who are not dialysis dependent.

OBJECTIVE: This study assessed characteristics and outcomes of patients who are not dependent on dialysis receiving simultaneous heart kidney transplantation versus heart transplantation alone (HTA) to identify optimal eGFR threshold where combined transplant strategy may be superior. METHODS: This study retrospectively analyzed 7896 adult patients with estimated glomerular filtration rate (eGFR) <60 mL/minute from the United Network for Organ Sharing database who received HTA or simultaneous heart kidney transplant between 2005 and 2021, excluding those who received pretransplant dialysis. Subjects were further stratified into 3 groups based on chronic kidney disease stage at time of transplant: Stage 3A (eGFR 45-59 mL/minute; n = 5044), Stage 3B (eGFR 30-44 mL/minute; n = 2193), and Stage 4 or 5 (eGFR <30 mL/minute; n = 659). Outcomes of interest were all-cause mortality, cardiac allograft failure, and freedom from chronic dialysis or renal transplant following heart transplant. RESULTS: Simultaneous heart kidney transplant and HTA recipients differed in various baseline characteristics. Simultaneous heart kidney transplant recipients with eGFR <45 mL/minute had greater short- and long-term overall survival and cardiac allograft survival compared with HTA, as well as greater long-term freedom from chronic dialysis or renal transplant. These results were consistent with both propensity matched analyses and multivariable Cox regression analysis of 10 year outcomes. Optimal cutoff value for pretransplant eGFR in predicting elevated risk of renal failure in recipients of heart transplant alone was found to be eGFR ∼45 mL/minute. CONCLUSIONS: Similar to patients with eGFR <30 mL/minute, patients with eGFR 30 to 44 mL/minute who underwent simultaneous heart kidney transplant had superior outcomes compared with HTA, suggesting possible benefit of combined transplant strategy for this subset of heart transplant candidates.

In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.

Disheveled-1 Interacts with Claudin-5 and Contributes to Norrin-Induced Endothelial Barrier Restoration.

Previous studies have revealed that norrin can reverse vascular endothelial-growth-factor (VEGF)-induced permeability in a ß-catenin-dependent pathway. Here, we have explored the contribution of disheveled-1 (DVL1) in norrin-induced blood-retinal barrier (BRB) restoration. We provide evidence that in addition to canonical signaling, DVL1 promotes tight junction (TJ) stabilization through a novel, non-canonical signaling pathway involving direct claudin-5 (CLDN5) binding. Immunofluorescence staining of rat retinal cross-sections showed enriched expression of DVL1 and 3 at endothelial capillaries and co-localization with CLDN5 and ZO-1 at the TJ complex in primary bovine retinal endothelial cells (BRECs). Barrier properties of BRECs were determined via measurements of trans-endothelial electrical resistance (TEER) or permeability to 70 kDa RITC-dextran. These studies demonstrated that norrin restoration of barrier properties after VEGF treatment required DVL1 as an siRNA knockdown of Dvl1 but not Dvl2 or Dvl3, reduced basal barrier properties and ablated norrin-induced barrier restoration. However, loss of Dvl1 did not decrease ß-catenin signaling activity as measured by Axin2 mRNA expression, suggesting the contribution of a non-canonical pathway. DVL and TJ protein interactions were analyzed via co-immunoprecipitation of endogenous protein in BRECs, which demonstrated that DVL1 interacts with both CLDN5 and ZO-1, while DVL3 interacts only with ZO-1. These interactions were most abundant after inducing BRB restoration by treating BRECs with VEGF and norrin. DVL has previously been shown to form intramolecular bindings between the C-terminal PDZ-binding motif (PDZ-BM) with an internal PDZ domain. Co-transfection of HEK293 cells with DVL1 and CLDN5 or relevant mutants revealed that DVL1 interacts with CLDN5 through the DVL PDZ domain binding, CLDN5 PDZ-BM, in competition with DVL1 PDZ-BM, since DVL/CLDN5 interaction increases with deletion of the DVL1 PDZ-BM and decreases by co-expressing the C-terminal fragment of DVL1 containing the PDZ-BM or through deletion of CLDN5 PDZ-BM. In BREC cells, transfection of the C-terminal fragment of DVL1 downregulates the expression of CLDN5 but does not affect the expression of other proteins of the TJs, including ZO-1, occludin, CLDN1 or VE-cadherin. Blocking DVL1/CLDN5 interaction increased basal permeability and prevented norrin induction of barrier properties after VEGF. Combined with previous data, these results demonstrate that norrin signals through both a canonical ß-catenin pathway and a non-canonical signaling pathway by which DVL1 directly binds to CLDN5 to promote barrier properties.

Multilingual COVID-19 vaccination videos in NSW, Australia: a case study of cultural-responsiveness on social media.

Multimodal communication via social media employed by governments as a COVID-19 communication strategy with multilingual populations hopes to alter behaviours and attitudes. However, there is presently no understanding about the responsiveness of these videos to the needs of culturally and linguistically diverse (CaLD) populations in Australia. This study aimed to analyse the cultural responsiveness of content in multilingual videos shared via a government social media page from NSW, Australia. A systematic search of videos shared between June 2021 and October 2021 was conducted. Using quantitative methods, 37 videos were analysed using a modified version of the Patient-oriented and culturally-adapted (POCA) healthcare translation model and readability indexes. Of these, 5/37 were classified as culturally responsive. The culturally responsive videos scored higher than those that were not culturally responsive. While credible sources, positive language and cultural symbols were observed in several of the videos, there was a lack of familiar experiences and economically viable vaccine uptake behaviours. Videos favoured generic examples of vaccine practices and failed to address concerns about vaccine eligibility, cost, and transport. All videos exceeded recommended readability indices for CaLD populations. Removing complex and abstract terminology and including familiar vaccine experiences could improve multilingual communication for CaLD communities.

Loss of microRNA-30a and sex-specific effects on the neonatal hyperoxic lung injury.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions. METHODS: Wild-type and miR-30a-/- neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a-/- mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a-/- male and female lung transcriptome data. RESULTS: Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a-/- mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a-/- female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a-/- female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium. CONCLUSIONS: miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.

Bronchopulmonary dysplasia (BPD) is a lung condition that affects babies born prematurely, causing problems with their lung development. Interestingly, BPD tends to affect boys more than girls, but we do not fully understand why. To investigate this, we conducted a study using mice. Female mice had better lung development and blood vessel formation when exposed to high oxygen levels. We found higher expression of a molecule called miR-30a in the female mice and seemed to be protective. So, we wanted to see if removing miR-30a would have the same effect on both male and female mice. To test this, we exposed newborn mice without miR-30a and normal mice to high oxygen levels or regular room air. Interestingly, the differences between normal males and females were no longer present in the mice without miR-30a. This suggested that miR-30a plays an important role in lung development. We also identified that the female mice without miR-30a, when exposed to high oxygen, had the greatest number of genes affected, and these gene changes were like those seen in blood samples from premature babies with BPD. Finally, we report that miR-30a was in a specific part of the lung called the bronchiolar epithelium. Overall, this study suggests that miR-30a is crucial in protecting premature lungs from damage caused by high oxygen levels. By understanding how miR-30a affects lung development, we may be able to develop new treatments for BPD in the future.

A systematic review of the evidence for effectiveness of interventions to address transport and other unintentional injuries among adolescents.

INTRODUCTION: Globally, injuries are a leading cause of mortality and morbidity for adolescents, which disproportionately affect the disadvantaged. To build an investment case for adolescent injury prevention, evidence is needed as to effective interventions. METHODS: A systematic review of peer-reviewed original research published between 2010-2022 was conducted. CINAHL, Cochrane Central, Embase, Medline and PsycINFO databases were searched for studies reporting the effectiveness of unintentional injury prevention interventions for adolescents (10-24 years), with assessment of study quality and equity (e.g., age, gender, ethnicity, socio-economic status). RESULTS: Sixty-two studies were included; 59 (95.2%) from high-income countries (HIC). Thirty-eight studies (61.3%) reported no aspect of equity. Thirty-six studies (58.1%) reported prevention of sports injuries (commonly neuromuscular training often focused on soccer-related injuries, rule changes and protective equipment). Twenty-one studies (33.9%) reported prevention of road traffic injury, with legislative approaches, commonly graduated driver licensing schemes, found to be effective in reducing fatal and nonfatal road traffic injury. Seven studies reported interventions for other unintentional injuries (e.g., falls). DISCUSSION: Interventions were strongly biased towards HIC, which does not reflect the global distribution of adolescent injury burden. Low consideration of equity in included studies indicates current evidence largely excludes adolescent populations at increased risk of injury. A large proportion of studies evaluated interventions to prevent sports injury, a prevalent yet low severity injury mechanism. Findings highlight the importance of education and enforcement alongside legislative approaches for preventing adolescent transport injuries. Despite drowning being a leading cause of injury-related harm among adolescents, no interventions were identified. CONCLUSION: This review provides evidence to support investment in effective adolescent injury prevention interventions. Further evidence of effectiveness is needed, especially for low- and middle-income countries, populations at increased risk of injury who would benefit from greater consideration of equity and for high lethality injury mechanisms like drowning.

Effectiveness of system navigation programs linking primary care with community-based health and social services: a systematic review.

BACKGROUND: Fragmented delivery of health and social services can impact access to high-quality, person-centred care. The goal of system navigation is to reduce barriers to healthcare access and improve the quality of care. However, the effectiveness of system navigation remains largely unknown. This systematic review aims to identify the effectiveness of system navigation programs linking primary care with community-based health and social services to improve patient, caregiver, and health system outcomes. METHODS: Building on a previous scoping review, PsychInfo, EMBASE, CINAHL, MEDLINE, and Cochrane Clinical Trials Registry were searched for intervention studies published between January 2013 and August 2020. Eligible studies included system navigation or social prescription programs for adults, based in primary care settings. Two independent reviewers completed study selection, critical appraisal, and data extraction. RESULTS: Twenty-one studies were included; studies had generally low to moderate risk of bias. System navigation models were lay person-led (n = 10), health professional-led (n = 4), team-based (n = 6), or self-navigation with lay support as needed (n = 1). Evidence from three studies (low risk of bias) suggests that team-based system navigation may result in slightly more appropriate health service utilization compared to baseline or usual care. Evidence from four studies (moderate risk of bias) suggests that either lay person-led or health professional-led system navigation models may improve patient experiences with quality of care compared to usual care. It is unclear whether system navigation models may improve patient-related outcomes (e.g., health-related quality of life, health behaviours). The evidence is very uncertain about the effect of system navigation programs on caregiver, cost-related, or social care outcomes. CONCLUSIONS: There is variation in findings across system navigation models linking primary care with community-based health and social services. Team-based system navigation may result in slight improvements in health service utilization. Further research is needed to determine the effects on caregiver and cost-related outcomes.

Shear wave ultrasound elastography of the biceps brachii can be used as a precise proxy for passive elbow torque in individuals with hemiparetic stroke.

Muscle tissue is prone to changes in composition and architecture following stroke. Changes in muscle tissue of the extremities are thought to increase resistance to muscle elongation or joint torque under passive conditions. These effects likely compound neuromuscular impairments, exacerbating movement function. Unfortunately, conventional rehabilitation is devoid of precise measures and relies on subjective assessments of passive joint torques. Shear wave ultrasound elastography, a tool to measure muscle mechanical properties, may be readily available for use in the rehabilitation setting as a precise measure, albeit at the muscle-tissue level. To support this postulation, we evaluated the criterion validity of shear wave ultrasound elastography of the biceps brachii; we investigated its relationship with a laboratory-based criterion measure for quantifying elbow joint torque in individuals with moderate to severe chronic stroke. Additionally, we evaluated construct validity, with the specific sub-type of hypothesis testing of known groups, by testing the difference between arms. Measurements were performed under passive conditions at seven positions spanning the arc of elbow joint flexion-extension in both arms of nine individuals with hemiparetic stroke. Surface electromyography was utilized for threshold-based confirmation of muscle quiescence. A moderate relationship between the shear wave velocity and elbow joint torque was identified, and both metrics were greater in the paretic arm. Data supports the progression toward a clinical application of shear wave ultrasound elastography in evaluating altered muscle mechanical properties in stroke, while acknowledging that undetectable muscle activation or hypertonicity may contribute to the measurement. Shear wave ultrasound elastography may augment the conventional method of manually testing joint mobility by providing a high-resolution precise value. Tissue-level measurement may also assist in identifying new therapeutic targets for patient-specific impairment-based interventions.

Use of physiological based pharmacokinetic modeling for cross-species prediction of pharmacokinetic and tissue distribution profiles of a novel niclosamide prodrug.

Introduction: Niclosamide (Nc) is an FDA-approved anthelmintic drug that was recently identified in a drug repurposing screening to possess antiviral activity against SARS-CoV-2. However, due to the low solubility and permeability of Nc, its in vivo efficacy was limited by its poor oral absorption. Method: The current study evaluated a novel prodrug of Nc (PDN; NCATS-SM4705) in improving in vivo exposure of Nc and predicted pharmacokinetic profiles of PDN and Nc across different species. ADME properties of the prodrug were determined in humans, hamsters, and mice, while the pharmacokinetics (PK) of PDN were obtained in mice and hamsters. Concentrations of PDN and Nc in plasma and tissue homogenates were measured by UPLC-MS/MS. A physiologically based pharmacokinetic (PBPK) model was developed based on physicochemical properties, pharmacokinetic and tissue distribution data in mice, validated by the PK profiles in hamsters and applied to predict pharmacokinetic profiles in humans. Results: Following intravenous and oral administration of PDN in mice, the total plasma clearance (CLp) and volume of distribution at steady-state (Vdss) were 0.061-0.063 L/h and 0.28-0.31 L, respectively. PDN was converted to Nc in both liver and blood, improving the systemic exposure of Nc in mice and hamsters after oral administration. The PBPK model developed for PDN and in vivo formed Nc could adequately simulate plasma and tissue concentration-time profiles in mice and plasma profiles in hamsters. The predicted human CLp/F and Vdss/F after an oral dose were 2.1 L/h/kg and 15 L/kg for the prodrug respectively. The predicted Nc concentrations in human plasma and lung suggest that a TID dose of 300 mg PDN would provide Nc lung concentrations at 8- to 60-fold higher than in vitro IC50 against SARS-CoV-2 reported in cell assays. Conclusion: In conclusion, the novel prodrug PDN can be efficiently converted to Nc in vivo and improves the systemic exposure of Nc in mice after oral administration. The developed PBPK model adequately depicts the mouse and hamster pharmacokinetic and tissue distribution profiles and highlights its potential application in the prediction of human pharmacokinetic profiles.

Preclinical validation of a novel therapeutic strategy for choroid plexus carcinoma.

Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC.