Association of large core middle cerebral artery stroke and hemorrhagic transformation with hospitalization outcomes.

Historically, investigators have not differentiated between patients with and without hemorrhagic transformation (HT) in large core ischemic stroke at risk for life-threatening mass effect (LTME) from cerebral edema. Our objective was to determine whether LTME occurs faster in those with HT compared to those without. We conducted a two-center retrospective study of patients with ≥ 1/2 MCA territory infarct between 2006 and 2021. We tested the association of time-to-LTME and HT subtype (parenchymal, petechial) using Cox regression, controlling for age, mean arterial pressure, glucose, tissue plasminogen activator, mechanical thrombectomy, National Institute of Health Stroke Scale, antiplatelets, anticoagulation, temperature, and stroke side. Secondary and exploratory outcomes included mass effect-related death, all-cause death, disposition, and decompressive hemicraniectomy. Of 840 patients, 358 (42.6%) had no HT, 403 (48.0%) patients had petechial HT, and 79 (9.4%) patients had parenchymal HT. LTME occurred in 317 (37.7%) and 100 (11.9%) had mass effect-related deaths. Parenchymal (HR 8.24, 95% CI 5.46-12.42, p < 0.01) and petechial HT (HR 2.47, 95% CI 1.92-3.17, p < 0.01) were significantly associated with time-to-LTME and mass effect-related death. Understanding different risk factors and sequelae of mass effect with and without HT is critical for informed clinical decisions.

Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

Multimodal Imaging of Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer-A State-of-the-Art Review.

BACKGROUND: This review focuses on multimodality imaging of cardiotoxicity in cancer patients, with the aim of evaluating the effectiveness of different techniques in detecting and monitoring cardiac changes associated with cancer therapy. METHODS: Eight studies were included in the review, covering various imaging modalities such as cardiac magnetic resonance imaging, echocardiography, and multigated acquisition scanning. RESULTS: Cardiac magnetic resonance imaging emerged as the most definitive modality, offering real-time detection, comprehensive assessment of cardiac function, the ability to detect early myocardial changes, and superior detection of cardiotoxicity when compared to the other imaging modalities. The studies also emphasize the importance of parameters such as left ventricular ejection fraction and global longitudinal strain in assessing cardiac function and predicting cardiotoxicity. CONCLUSION: Due to the common use of HER2 agents and anthracyclines within the breast cancer population, the LVEF as a critical prognostic measurement for assessing heart health and estimating the severity of left-sided cardiac malfunction is a commonly used endpoint. CTRCD rates differed between imaging modalities, with cardiac MRI the most sensitive. The use of multimodal cardiac imaging remains a nuanced area, influenced by local availability, the clinical question at hand, body habits, and medical comorbidities. All of the imaging modalities listed have a role to play in current care; however, focus should be given to increasing the provision of cardiac MRI for breast cancer patients in the future to optimize the detection of CTRCD and patient outcomes thereafter.

M2pep-Modified Cyclodextrin-siRNA Nanoparticles Modulate the Immunosuppressive Tumor Microenvironment for Prostate Cancer Therapy.

Prostate cancer (PCa) is the most prevalent cause of cancer deaths in men. Conventional strategies, such as surgery, radiation, or chemotherapy, face challenges including poor prognosis and resistance. Therefore, the development of new improved strategies is vital to enhance patient outcomes. Recently, immunotherapy has shown potential in the treatment of a range of cancers, including PCa. Tumor-associated macrophages (TAMs) play an important role in the tumor microenvironment (TME) and reprogramming of TAMs is associated with remodeling the TME. The colony-stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) signaling pathway is closely related to the polarization of TAMs. The downregulation of CSF-1R, using small interfering RNA (siRNA), has been shown to achieve the reprogramming of TAMs, from the immunosuppressive M2 phenotype to the immunostimulatory M1 one. To maximize specific cellular delivery an M2 macrophage-targeting peptide, M2pep, was formulated with an amphiphilic cationic ß-Cyclodextrin (CD) incorporating CSF-1R siRNA. The resulting nanoparticles (NPs) increased M2 macrophage targeting both in vitro and in vivo, promoting the release of M1 factors and simultaneously downregulating the levels of M2 factors through TAM reprogramming. The subsequent remodeling of the TME resulted in a reduction in tumor growth in a subcutaneous PCa mouse model mainly mediated through the recruitment of cytotoxic T cells. In summary, this M2pep-targeted CD-based delivery system demonstrated significant antitumor efficacy, thus presenting an alternative immunotherapeutic strategy for PCa treatment.

Sialic acid-targeted cyclodextrin-based nanoparticles deliver CSF-1R siRNA and reprogram tumour-associated macrophages for immunotherapy of prostate cancer.

Prostate cancer remains a serious condition threatening the health of men. Due to the complicated nature of the tumour microenvironment (TME), conventional treatments face challenges including poor prognosis and tumour resistance, therefore new therapeutic strategies are urgently needed. Small interfering RNA (siRNA), a double-stranded non-coding RNA, regulates specific gene expression through RNA interference. Tumour-associated macrophages (TAMs) are a potential therapeutic target in cancer immunotherapy. Colony stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) signaling pathway plays a crucial role in the polarization of the immunosuppressive TAMs, M2 macrophages. Downregulation of CSF-1R is known to reprogram the immunosuppressive TAMs, M2 macrophages, to the immunostimulatory phenotype, M1 macrophages. Sialic acid is a ligand for Siglec-1 (CD169) which is overexpressed on M2 macrophages with little expression in other phenotypes. Therefore, a sialic acid-targeted cyclodextrin-based nanoparticle was developed to specifically deliver CSF-1R siRNA to M2 macrophages. The nanoparticles were studied in vitro using both human and mouse prostate cancer cell lines. Results show that the targeted nanoparticles achieved cell specific delivery to M2 macrophages via the sialic acid-CD169 axis. The expression of CSF-1R was significantly downregulated in M2 macrophages (29.64% for targeted vs 19.31% for non-targeted nanoparticles in THP-1-derived M2 macrophages and 38.94% for targeted vs 18.51% for non-targeted nanoparticles in RAW 264.7-derived M2 macrophages, n = 4, p < 0.01). The resulting reprograming of M2 macrophages to M1 enhanced the level of apoptosis in the prostate cancer cells in a Transwell model (49.17% for targeted vs 37.68% for non-targeted nanoparticles in PC-3 cells and 69.15% for targeted vs 44.73% for non-targeted nanoparticles in TRAMP C1 cells, n = 3, p < 0.01). Thus, this targeted cyclodextrin-based siRNA drug delivery system provides a potential strategy for prostate cancer immunotherapy.

Cyclodextrin-Based Nanoparticles for Delivery of Antisense Oligonucleotides Targeting Huntingtin.

Huntington's disease (HD) is a progressive inherited neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene, which is translated into the pathologic mutant huntingtin (mHTT) protein. Despite the great potential of HTT lowering strategies and the numerous antisense oligonucleotides (ASOs) in pre- and clinical trials, sustained silencing of mHTT has not been achieved. As a strategy to improve ASO delivery, cyclodextrin-based nanoparticles (CDs) offer a promising approach. Here, three CDs with distinct chemical structures were designed and their efficacies were compared as potential platforms for the delivery of ASO targeting HTT. Results using striatal neurons and HD patient-derived fibroblasts indicate that modified γ-CDs exhibited the best uptake efficiency and successfully downregulated mHTT at protein and allele levels. The incorporation of the brain-targeting peptide RVG into the modified γ-CDs showed greater downregulation of mHTT protein and HD-causing allele SNP1 than untargeted ones in an in vitro blood-brain barrier model. Although the ASO sequence was designed as a nonallele-specific therapeutic approach, our strategy gives an additional benefit of some mHTT selectivity. Overall, this study demonstrated the CD platform's feasibility for delivering ASO-based therapeutics for HD treatment.

Improving the Post-Operative Prediction of BCR-Free Survival Time with mRNA Variables and Machine Learning.

Predicting the risk of, and time to biochemical recurrence (BCR) in prostate cancer patients post-operatively is critical in patient treatment decision pathways following surgical intervention. This study aimed to investigate the predictive potential of mRNA information to improve upon reference nomograms and clinical-only models, using a dataset of 187 patients that includes over 20,000 features. Several machine learning methodologies were implemented for the analysis of censored patient follow-up information with such high-dimensional genomic data. Our findings demonstrated the potential of inclusion of mRNA information for BCR-free survival prediction. A random survival forest pipeline was found to achieve high predictive performance with respect to discrimination, calibration, and net benefit. Two mRNA variables, namely ESM1 and DHAH8, were identified as consistently strong predictors with this dataset.

Heart Failure Association-International Cardio-Oncology Society Risk Score Validation in HER2-Positive Breast Cancer.

BACKGROUND: This paper looks to validate the risk score from the Heart Failure Association of the European Society of Cardiology and the International Cardio-Oncology Society (HFA-ICOS) for predicting potential cardiotoxicity from anticancer therapy for patients positive for human epidermal growth factor receptor 2. METHODS: A total of 507 patients with at least five years since index diagnosis of breast cancer were retrospectively divided according to the HFA-ICOS risk proforma. According to level of risk, these groups were assessed for rates of cardiotoxicity via mixed-effect Bayesian logistic regression model. RESULTS: A follow-up of five years observed cardiotoxicity of 3.3% (n = 3) in the low-risk, 3.3% (n = 10) in the medium-risk, 4.4% (n = 6) in the high-risk, and 38% (n = 6) in the very-high-risk groups respectively. For cardiac events related to treatment, the risk was significantly higher for the very-high-risk category of HFA-ICOS compared to other categories (Beta = 3.1, 95% CrI: 1.5, 4.8). For overall cardiotoxicity related to treatment, the area under the curve was 0.643 (CI 95%: 0.51, 0.76), with 26.1% (95% CI: 8%, 44%) sensitivity and 97.9% (95% CI: 96%, 99%) specificity. CONCLUSIONS: The HFA-ICOS risk score has moderate power in predicting cancer therapy-related cardiotoxicity in HER2-positive breast cancer patients.

A machine learning eye movement detection algorithm using electrooculography.

STUDY OBJECTIVES: Eye movement quantification in polysomnograms (PSG) is difficult and resource intensive. Automated eye movement detection would enable further study of eye movement patterns in normal and abnormal sleep, which could be clinically diagnostic of neurologic disorders, or used to monitor potential treatments. We trained a long short-term memory (LSTM) algorithm that can identify eye movement occurrence with high sensitivity and specificity. METHODS: We conducted a retrospective, single-center study using one-hour PSG samples from 47 patients 18-90 years of age. Team members manually identified and trained an LSTM algorithm to detect eye movement presence, direction, and speed. We performed a 5-fold cross validation and implemented a "fuzzy" evaluation method to account for misclassification in the preceding and subsequent 1-second of gold standard manually labeled eye movements. We assessed G-means, discrimination, sensitivity, and specificity. RESULTS: Overall, eye movements occurred in 9.4% of the analyzed EOG recording time from 47 patients. Eye movements were present 3.2% of N2 (lighter stages of sleep) time, 2.9% of N3 (deep sleep), and 19.8% of REM sleep. Our LSTM model had average sensitivity of 0.88 and specificity of 0.89 in 5-fold cross validation, which improved to 0.93 and 0.92 respectively using the fuzzy evaluation scheme. CONCLUSION: An automated algorithm can detect eye movements from EOG with excellent sensitivity and specificity. Noninvasive, automated eye movement detection has several potential clinical implications in improving sleep study stage classification and establishing normal eye movement distributions in healthy and unhealthy sleep, and in patients with and without brain injury.

Scoping Review: Neurocognitive Outcome Assessments After Critical Illness in Children.

OBJECTIVES: To map the literature regarding assessment of neurocognitive outcomes in PICU survivors. Secondary objectives were to identify literature gaps and to provide data for development of a Core Outcome Measures Set in the domain. METHODS: Planned, a priori analysis was performed of data from an over-all scoping review of Post-Intensive Care Syndrome-pediatrics (PICS-p) functional outcomes. English-language databases and registries from 1970 to 2017 were searched by a medical librarian to identify manuscripts reporting on Post Intensive Care Syndrome-pediatrics (PICS-p). Further, detailed data extraction for neurocognitive outcomes was performed focusing on study characteristics, instruments used, and populations. RESULTS: 114 instruments evaluated neurocognitive function in 183 manuscripts. 83% of manuscripts were published after 2000. Median of 3 (IQR 2-5) neurocognitive instruments per manuscript were reported. Wechsler Scales (45%), clinical neurologic evaluations (21%), Pediatric Cerebral Performance Category (20%), Bayley Scales of Infant Development (16%), and Vineland Adaptive Behavior Scales (11%) were the most commonly used instruments. Median sample size was 65 (IQR 32-129) subjects. Most (63%) assessments were conducted in-person and parents/guardians (40%) provided the information. Patients with congenital heart disease and traumatic brain injury were most commonly evaluated (31% and 24% of manuscripts, respectively). Adolescents were the most commonly studied age group (34%). Baseline function was infrequently assessed (11% of manuscripts); most studies assessed patients at only one time point after PICU discharge. Within studies, neurocognitive assessments were often combined with others - especially social (18%) and physical (8%). CONCLUSIONS: 183 manuscripts studied the neurocognitive domain of PICS-p. Studies were quantitative and tended to focus on populations with anticipated cognitive impairment. Considerable variability exists among the chosen 114 instruments used; however, 4 instruments were frequently chosen with focus on intelligence, cerebral functioning, and developmental and adaptive behavior. The literature is marked by lack of agreement on methodologies but reflects the burgeoning interest in studying PICS-p neurocognitive outcomes.

Case Report: Carcinoid heart disease with severe tricuspid regurgitation and concomitant patent foramen ovale causing severe hypoxia.

This case report demonstrates a unique case of managing complex concomitant structural cardiac issues using transcatheter techniques in a frail patient. The primary regurgitant lesion in this case caused significant right to left shunting with severely debilitating hypoxaemia for the patient, requiring high volumes of ambulatory oxygen to compensate. We would like to highlight the role of multi-modality cardiac imaging demonstrated in this case, as well as the limited surgical data and poor outcomes in advanced disease with higher peri-operative complications. Finally, it should be noted that percutaneous correction of structural lesions may provide palliative relief but carries an uncertain risk of recurrence.

Supervision of Surgical Trainees During Operative Procedures: Implementation of a Formal Preoperative Surgical Checklist.

Background Trainers in surgery have an educational obligation to train trainees in performing operative procedures. Objective We hypothesized that poor concordance manifests as discrepancies between the trainee and the trainer, with an associated reduction in satisfaction with the training experience, perception of training quality, and completion of workplace-based assessments (WBAs). This study also aimed to validate the novel Supervised Training Operative Procedure (STOP) online tool. Method We developed an online proforma (STOP online tool) and conducted a prospective, single-blinded study of 53 orthopedic operative procedures with 53 trainees between January 19, 2019, and August 27, 2019. Results Forty-four (82%) trainees were listed as the primary surgeon. The overall mean trainee satisfaction (on a 0-10 Likert scale) was 8.25 (range: 3-10), and the mean trainer satisfaction was 8.28 (range: 4-10). A preoperative discussion between the trainee and the trainer occurred in 96.2% of the cases. Forty-eight (91%) trainers preoperatively established trainees' objectives and 91% (n = 48) of the cases showed postoperative completion of objectives. Forty-four (83%) trainers anticipated workplace-based assessment (WBA) completion for trainees, and this translated into 41 (77%) completed WBAs. Overall, 47 (92.9%) trainees felt that the STOP tool would be useful as a surgical training checklist and in the completion of WBAs. Conclusion The STOP checklist is useful in understanding qualitative and quantitative measures of the overall trainee performance of an operative case. This holistic approach will enable us to establish a structured perioperative surgical training checklist, as trainee and trainer requirements are dependent on one another.

Co-Formulation of Amphiphilic Cationic and Anionic Cyclodextrins Forming Nanoparticles for siRNA Delivery in the Treatment of Acute Myeloid Leukaemia.

Non-viral delivery of therapeutic nucleic acids (NA), including siRNA, has potential in the treatment of diseases with high unmet clinical needs such as acute myeloid leukaemia (AML). While cationic biomaterials are frequently used to complex the nucleic acids into nanoparticles, attenuation of charge density is desirable to decrease in vivo toxicity. Here, an anionic amphiphilic CD was synthesised and the structure was confirmed by Fourier-transform infrared spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR), and high-resolution mass spectrometry (HRMS). A cationic amphiphilic cyclodextrin (CD) was initially used to complex the siRNA and then co-formulated with the anionic amphiphilic CD. Characterisation of the co-formulated NPs indicated a significant reduction in charge from 34 ± 7 mV to 24 ± 6 mV (p < 0.05) and polydispersity index 0.46 ± 0.1 to 0.16 ± 0.04 (p < 0.05), compared to the cationic CD NPs. Size was similar, 161−164 nm, for both formulations. FACS and confocal microscopy, using AML cells (HL-60), indicated a similar level of cellular uptake (60% after 6 h) followed by endosomal escape. The nano co-formulation significantly reduced the charge while maintaining gene silencing (21%). Results indicate that blending of anionic and cationic amphiphilic CDs can produce bespoke NPs with optimised physicochemical properties and potential for enhanced in vivo performance in cancer treatment.

Patient Navigation Can Improve Breast Cancer Outcomes among African American Women in Chicago: Insights from a Modeling Study.

African American (AA) women experience much greater mortality due to breast cancer (BC) than non-Latino Whites (NLW). Clinical patient navigation is an evidence-based strategy used by healthcare institutions to improve AA women's breast cancer outcomes. While empirical research has demonstrated the potential effect of navigation interventions for individuals, the population-level impact of navigation on screening, diagnostic completion, and stage at diagnosis has not been assessed. An agent-based model (ABM), representing 50-74-year-old AA women and parameterized with locally sourced data from Chicago, is developed to simulate screening mammography, diagnostic resolution, and stage at diagnosis of cancer. The ABM simulated three counterfactual scenarios: (1) a control setting without any navigation that represents the "standard of care"; (2) a clinical navigation scenario, where agents receive navigation from hospital-affiliated staff; and (3) a setting with network navigation, where agents receive clinical navigation and/or social network navigation (i.e., receiving support from clinically navigated agents for breast cancer care). In the control setting, the mean population-level screening mammography rate was 46.3% (95% CI: 46.2%, 46.4%), the diagnostic completion rate was 80.2% (95% CI: 79.9%, 80.5%), and the mean early cancer diagnosis rate was 65.9% (95% CI: 65.1%, 66.7%). Simulation results suggest that network navigation may lead up to a 13% increase in screening completion rate, 7.8% increase in diagnostic resolution rate, and a 4.9% increase in early-stage diagnoses at the population-level. Results suggest that systems science methods can be useful in the adoption of clinical and network navigation policies to reduce breast cancer disparities.

Natural Language Processing of Radiology Reports to Detect Complications of Ischemic Stroke.

BACKGROUND: Abstraction of critical data from unstructured radiologic reports using natural language processing (NLP) is a powerful tool to automate the detection of important clinical features and enhance research efforts. We present a set of NLP approaches to identify critical findings in patients with acute ischemic stroke from radiology reports of computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: We trained machine learning classifiers to identify categorical outcomes of edema, midline shift (MLS), hemorrhagic transformation, and parenchymal hematoma, as well as rule-based systems (RBS) to identify intraventricular hemorrhage (IVH) and continuous MLS measurements within CT/MRI reports. Using a derivation cohort of 2289 reports from 550 individuals with acute middle cerebral artery territory ischemic strokes, we externally validated our models on reports from a separate institution as well as from patients with ischemic strokes in any vascular territory. RESULTS: In all data sets, a deep neural network with pretrained biomedical word embeddings (BioClinicalBERT) achieved the highest discrimination performance for binary prediction of edema (area under precision recall curve [AUPRC] > 0.94), MLS (AUPRC > 0.98), hemorrhagic conversion (AUPRC > 0.89), and parenchymal hematoma (AUPRC > 0.76). BioClinicalBERT outperformed lasso regression (p < 0.001) for all outcomes except parenchymal hematoma (p = 0.755). Tailored RBS for IVH and continuous MLS outperformed BioClinicalBERT (p < 0.001) and linear regression, respectively (p < 0.001). CONCLUSIONS: Our study demonstrates robust performance and external validity of a core NLP tool kit for identifying both categorical and continuous outcomes of ischemic stroke from unstructured radiographic text data. Medically tailored NLP methods have multiple important big data applications, including scalable electronic phenotyping, augmentation of clinical risk prediction models, and facilitation of automatic alert systems in the hospital setting.

Angiotensin-Converting Enzyme Inhibitor-Induced Oropharyngeal edema with Subsequent Stress-Cardiomyopathy.

Intramuscular adrenaline is a standard treatment approach for the symptomatic patient presenting with distress and oropharyngeal edema, requiring subsequent doses if oedema persists. This case demonstrates a delayed side-effect of stress-induced cardiomyopathy after adrenaline administration. A 62-year-old suffered acute oropharyngeal angioedema secondary to angiotensin-converting-enzyme inhibitor use. Two standard doses of intramuscular adrenaline 2 hours apart were administered, and she was monitored for 2 days. On day three post discharge, she represented with acute hypervolaemia. Transthoracic echocardiogram showed a globally dilated, poorly functioning left ventricle. Cardiac magnetic resonance imaging described takotsubo cardiomyopathy. One month later, left ventricular function had normalised with optimal medical treatment. Cardiomyopathy with a temporal relationship to a hypersensitivity reaction is thought to occur due to one of three mechanisms: Stress (takotsubo) cardiomyopathy, allergic acute coronary (Kounis) Syndrome, and hypersensitive myocarditis. If a clinical presentation of hypersensitivity is such that it requires treatment with epinephrine, it is particularly challenging to determine the exact cause of cardiomyopathy.

Modified cyclodextrin-based nanoparticles mediated delivery of siRNA for huntingtin gene silencing across an in vitro BBB model.

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, leading to a toxic version of the HTT protein. There are currently no disease-modifying therapies available. In this scenario, gene-based treatments for HD aimed at lowering HTT levels have become one of the most promising emerging therapeutic options. To date, however, promising results have only been achieved following direct intrathecal or intracranial injections designed to circumvent the blood-brain barrier (BBB). Consequently, efforts to develop less invasive delivery platforms are highly desirable. Here, we described a novel delivery system based on modified cyclodextrin nanoparticles (CDs) loaded with small interfering RNAs (siRNAs) targeting HTT andcomplexed with the rabies virus glycoprotein(RVG), a BBB-shuttle peptide. Results using an in vitro BBB model, indicate the formulation successfully crosses the brain endothelial cells, releases the encapsulated siRNAs into the cytoplasm of neuronal cells, and mediates downregulation of HTT. In conclusion, the CD platform is a promising option for delivery of siRNA-based therapeutics for HD with wider potential to treat other diseases with a genetically validated target in the central nervous system.

Type 1 diabetes patients increase CXCR4+ and CXCR7+ haematopoietic and endothelial progenitor cells with exercise, but the response is attenuated.

Exercise mobilizes angiogenic cells, which stimulate vascular repair. However, limited research suggests exercise-induced increase of endothelial progenitor cell (EPCs) is completely lacking in type 1 diabetes (T1D). Clarification, along with investigating how T1D influences exercise-induced increases of other angiogenic cells (hematopoietic progenitor cells; HPCs) and cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), is needed. Thirty T1D patients and 30 matched non-diabetes controls completed 45 min of incline walking. Circulating HPCs (CD34+, CD34+CD45dim) and EPCs (CD34+VEGFR2+, CD34+CD45dimVEGFR2+), and subsequent expression of CXCR4 and CXCR7, were enumerated by flow cytometry at rest and post-exercise. Counts of HPCs, EPCs and expression of CXCR4 and CXCR7 were significantly lower at rest in the T1D group. In both groups, exercise increased circulating angiogenic cells. However, increases was largely attenuated in the T1D group, up to 55% lower, with CD34+ (331 ± 437 Δcells/mL vs. 734 ± 876 Δcells/mL p = 0.048), CD34+VEGFR2+ (171 ± 342 Δcells/mL vs. 303 ± 267 Δcells/mL, p = 0.006) and CD34+VEGFR2+CXCR4+ (126 ± 242 Δcells/mL vs. 218 ± 217 Δcells/mL, p = 0.040) significantly lower. Exercise-induced increases of angiogenic cells is possible in T1D patients, albeit attenuated compared to controls. Decreased mobilization likely results in reduced migration to, and repair of, vascular damage, potentially limiting the cardiovascular benefits of exercise.Trial registration: ISRCTN63739203.

A sono-anatomical and cadaveric study of ultrasound-guided retrolaminar block.

AIM: Retrolaminar block (RB) is known to confer chest wall analgesia but, its mechanism has not been established. Our primary objective was to determine if the spread of injectate following RB extends to the paravertebral space (PVS). Second-ary objectives were to determine the predefined anatomical areas and nervous tissues contacted by injectate; the effect of volume on spread; and the extent to which experts can predict PVS spread based on examination of US videos of the injection. MATERIAL AND METHODS: US-guided RB was performed on cadavers using a single injection technique of 10, 20 or 30 ml dye. Anatomical dissection was performed to identify the extent of spread of injectate to the retrolaminar, intercostal and PVS. Ultrasound recordings of the injection were independently evaluated by experts in US-guided regional anaesthesia. RESULTS: Spread of injectate to the ipsilateral PVS was identified in 6/10 dissected regions (0/1, 1/3 and 5/6 when injectate volumes of 10, 20 and 30ml were administered respectively). The extent of cephalad-caudad spread within the PVS varied from 1 to 3 levels. Expert interpretation of ultrasound images regarding spread to the PVS demonstrated poor correlation with dye staining observed on dissection. CONCLUSIONS: Injectate spread following RB demonstrated substantial variability. Inconsistent spread to the ipsilateral PVS may account for clinically occurring incomplete blocks. The likelihood of spread to the ipsilateral PVS was greater when a larger volume was injected. Expert evaluation of the dynamic ultrasound images obtained at injection can-not reliably predict spread to the PVS.

Real-World Experience With Antiplatelet Agents After Percutaneous Coronary Intervention in Patients With an Indication for an Oral Anticoagulant.

ABSTRACT: Patients undergoing percutaneous coronary intervention (PCI) with a clinical indication for oral anticoagulation (OAC) in addition to antiplatelet therapy (APT) necessitate rigorous evaluation of bleeding and ischemic risk to guide therapy. The optimal OAC/APT drug combination and duration of treatment is not known. This study aimed to evaluate the incidence of patients undergoing PCI with an OAC indication and the rationale for post-PCI combined OAC/APT selection in clinical practice. Consecutive patients undergoing PCI with an indication for combined OAC/APT were included in a 12-month retrospective case series. Patient demographics, clinical characteristics, prescribed OAC/APT regimens, and rationale for drug selection were reviewed. PCI was performed in 1650 patients during the study period, with an indication for OAC/APT in 133 (8.1%). A combination of aspirin, P2Y12 inhibitor, and OAC was the most frequently prescribed regime on discharge (n = 103, 81%). Dual antiplatelet therapy (DAPT) in combination with OAC was continued for a mean duration of 6.4 ± 4.4 weeks (range 3-52 weeks) before one antiplatelet was discontinued. There was no significant difference between the mean CHA2DS2-VASc or HAS-BLED score of patients with atrial fibrillation discharged on OAC/DAPT compared with alternate combinations (DAPT alone or OAC/single APT), 3.6 ± 1.3 versus 3.8 ± 1, P = 0.37 and 2.04 ± 0.7 versus 2.05 ± 1.0, P = 0.98, respectively. This case series identifies high variability in OAC/APT treatment duration and limited application of risk scoring systems and high-risk PCI characteristics in the selection of OAC/APT regimens. A more systematic patient assessment is needed to help standardize OAC/APT prescribing for this important patient cohort.