Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Retrograde intrarenal surgery for asymptomatic incidental renal stones: a retrospective, real-world data analysis.

OBJECTIVE: To determine surgical outcomes and stone-free rates (SFRs) when offering upfront retrograde intrarenal surgery (RIRS) to patients with asymptomatic incidental renal stones (AIRS), as active surveillance, shockwave lithotripsy or upfront intervention in patients with AIRS is still a debate among urologists. PATIENTS AND METHODS: This retrospective FLEXible Ureteroscopy Outcomes Registry (FLEXOR), supported by the Team of Worldwide Endourological Researchers (TOWER), examines adult patients who underwent RIRS. We analysed a subset of asymptomatic patients with renal stones on imaging who were treated with RIRS. Data includes patient characteristics, stone specifications, anaesthesia type, perioperative details, complications, and SFR. A multivariable logistic regression analysis was performed to assess factors associated with the SFR. RESULTS: Among 679 patients with AIRS, 640 met the inclusion criteria. The median age was 55 years, with 33.4% being female. In all, 22.1% had positive urine cultures. The median stone diameter was 12 mm, commonly in lower and interpolar locations. RIRS was preferentially performed under general anaesthesia using a reusable scope in 443 cases. Prophylactic antibiotics were administered to 314 patients. The median operation time was 58 min and the median laser time was 24 min. The SFR was 68.8%. The use of holmium laser (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.06-0.63; P < 0.01) and multiple stones (OR 0.38, 95% CI 0.19-0.76; P < 0.01) were factors associated with lower odds of being stone free. Overall complications were minimal, with sepsis in 1.6% of patients. Re-interventions were performed in 76 cases (11.8%), with RIRS being the most common in 67 cases (10.6%). CONCLUSION: Our multicentre real-world study is the first of its kind that highlights the pros and cons of offering RIRS to patients with AIRS and demonstrates a favourable SFR with acceptable complications. Pre-emptively discussing potential re-intervention helps patients make informed decisions, particularly in cases involving large and multiple stones.

Comparing Same-Sitting Bilateral vs Unilateral Retrograde Intrarenal Surgery in the Elderly.

OBJECTIVE: To compare same-sitting bilateral vs unilateral retrograde intrarenal surgery (RIRS) in elderly patients, focusing on postoperative complications and stone-free rates (SFR). METHODS: Data from 2 multicenter databases, FLEXible ureteroscopy Outcomes Registry (FLEXOR) (unilateral RIRS) and same sitting bilateral-retrograde intrarenal surgery (SSB-RIRS) (bilateral RIRS), were analyzed, considering only patients aged 70+ with preoperative computed tomography. Patients were categorized into Group 1 (bilateral RIRS) and Group 2 (unilateral RIRS). Follow-up included imaging assessments and secondary treatments as needed. RESULTS: Group 1 included 146 patients, while group 2 had 495. Group 1's patients were slightly older and had a higher prevalence of recurrent stone formation. Group 2 often underwent RIRS for incidental stones. Group 1 had larger and more pelvic stones. Laser lithotripsy and total operation times were significantly longer in Group 1. Group 2 had significantly higher overall stone-free rates, although there were no significant differences in ancillary procedures for residual fragments. Group 1 experienced more pelvicalyceal injuries needing stenting, postoperative fever, and post-op hematuria not requiring transfusion. CONCLUSION: In conclusion, bilateral RIRS can be carefully considered in elderly patients. Preoperative counseling is essential for both primary and repeat RIRS procedures, and further research is needed to optimize instrument and laser strategies for better outcomes in elderly RIRS patients.

Influence of pre-stenting on RIRS outcomes. Inferences from patients of the Global Multicentre Flexible Ureteroscopy Outcome Registry (FLEXOR).

BACKGROUND: Retrograde Intrarenal Surgery (RIRS) is recommended as an alternative to percutaneous nephrolithotomy for stones up to 2 cm. Pre-stenting before RIRS remains controversial with various studies differing in outcomes and recommendations. We aim to understand how pre-stenting influences surgical outcomes. METHODS: A number of 6579 patients from the TOWER group registry were divided into pre-stented (group 1) and non-pre-stented groups (group 2). Patients aged ≥18 years old, with normal calyceal anatomy were enrolled. Patients with ureteric stones, anomalous kidneys, bilateral stones, planned for ECIRS were excluded. RESULTS: Patients are homogeneously distributed in both groups (3112 vs. 3467). The predominant indication for pre-stenting was symptom relief. Overall stone size was comparable, whilst group 1 had a significantly more multiple (1419 vs. 1283, P<0.001) and lower-pole (LP) stones (1503 vs. 1411, P<0.001). The mean operative time for group 2 was significantly longer (68.17 vs. 58.92, P<0.001). Stone size, LP stones, age, recurrence and multiple stones are contributing factors for residual fragments at the multivariable analysis. The incidence of postoperative day 1 fever and sepsis was significantly higher in group 2, indicating that pre-stenting is associated with a lower risk of post-RIRS infection and a lower overall complications rate (13.62% vs. 15.89%) (P<0.001). CONCLUSIONS: RIRS without pre-stenting can be considered safe without significant morbidity. Multiple, lower-pole and large stone is a significant contributor towards residual fragments. Patients who were not pre-stented had significantly higher but low-grade complications, especially for lower pole and large volume stones. While we do not advocate routine pre-stenting, a tailored approach for these patients should include proper counselling regarding pre-stenting.

Scratch-AID, a deep learning-based system for automatic detection of mouse scratching behavior with high accuracy.

Mice are the most commonly used model animals for itch research and for development of anti-itch drugs. Most laboratories manually quantify mouse scratching behavior to assess itch intensity. This process is labor-intensive and limits large-scale genetic or drug screenings. In this study, we developed a new system, Scratch-AID (Automatic Itch Detection), which could automatically identify and quantify mouse scratching behavior with high accuracy. Our system included a custom-designed videotaping box to ensure high-quality and replicable mouse behavior recording and a convolutional recurrent neural network trained with frame-labeled mouse scratching behavior videos, induced by nape injection of chloroquine. The best trained network achieved 97.6% recall and 96.9% precision on previously unseen test videos. Remarkably, Scratch-AID could reliably identify scratching behavior in other major mouse itch models, including the acute cheek model, the histaminergic model, and a chronic itch model. Moreover, our system detected significant differences in scratching behavior between control and mice treated with an anti-itch drug. Taken together, we have established a novel deep learning-based system that could replace manual quantification for mouse scratching behavior in different itch models and for drug screening.

Early outcomes of short-course low intensity shockwave therapy (LiSWT) for erectile dysfunction: A prospective, randomized, double-blinded, sham-controlled study in Malaysia.

Low-intensity shockwave therapy (LiSWT) has emerged as a promising non-invasive treatment modality for erectile dysfunction (ED) yet the well-designed randomized clinical trials are still lacking to prove its claimed benefits. A randomized, prospective, double-blinded sham-controlled study was conducted to evaluate the effectiveness and safety profile of short course LiSWT on vasculogenic ED patients. The International Index of Erectile Function-5 (IIEF-5) and Erection Hardness Score (EHS) questionnaires were used for evaluation. Patients underwent weekly sessions for 4 weeks and were re-assessed at 1, 3 and 6 months post therapy. Fifty one patients were recruited and randomized into sham and treatment arms. The mean IIEF-5 scores were significantly improved in the treatment arm compared to worsening of scores in the sham arm after 1 month (14.1 vs. 9.3 p < 0.001), 3 months (14.9 vs. 8.6, p < 0.001) and 6 months (14.2 vs. 7.9, p < 0.001) post treatment. A significant improvement of EHS was demonstrated at 1 month (2.4 vs. 1.8, p = 0.001, 3 months 2.7 vs. 1.7, p < 0.001) and 6 months (2.7 vs. 1.6, p < 0.001) in the treatment arm compared to sham arm. The success rate based on IIEF score increment more than five points was 26% in treatment arm and 0% in sham arm. Improvement in EHS score ≥3 in the treatment versus sham arm was 63% and 4%, respectively. There was no adverse effect reported. This 4-week LiSWT protocol reflects better treatment compliance, and it prevents further deterioration of erectile function among this cohort of patients. This study proves that LiSWT is a well-tolerated treatment with modest improvements in erectile function and hardness, among patients with vasculogenic ED.

Intravesical Chemohyperthermia vs. Bacillus Calmette-Guerin Instillation for Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette-Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation. Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC. Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24-36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61-1.13; moderate certainty of evidence) and the 24-36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26-1.49; low certainty of evidence). There were also no significant differences in grade 1-2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93-1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69-1.43; low certainty of evidence). Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.

Delayed surgery for localised and metastatic renal cell carcinoma: a systematic review and meta-analysis for the COVID-19 pandemic.

PURPOSE: The COVID-19 pandemic has led to the cancellation or deferment of many elective cancer surgeries. We performed a systematic review on the oncological effects of delayed surgery for patients with localised or metastatic renal cell carcinoma (RCC) in the targeted therapy (TT) era. METHOD: The protocol of this review is registered on PROSPERO(CRD42020190882). A comprehensive literature search was performed on Medline, Embase and Cochrane CENTRAL using MeSH terms and keywords for randomised controlled trials and observational studies on the topic. Risks of biases were assessed using the Cochrane RoB tool and the Newcastle-Ottawa Scale. For localised RCC, immediate surgery [including partial nephrectomy (PN) and radical nephrectomy (RN)] and delayed surgery [including active surveillance (AS) and delayed intervention (DI)] were compared. For metastatic RCC, upfront versus deferred cytoreductive nephrectomy (CN) were compared. RESULTS: Eleven studies were included for quantitative analysis. Delayed surgery was significantly associated with worse cancer-specific survival (HR 1.67, 95% CI 1.23-2.27, p < 0.01) in T1a RCC, but no significant difference was noted for overall survival. For localised ≥ T1b RCC, there were insufficient data for meta-analysis and the results from the individual reports were contradictory. For metastatic RCC, upfront TT followed by deferred CN was associated with better overall survival when compared to upfront CN followed by deferred TT (HR 0.61, 95% CI 0.43-0.86, p < 0.001). CONCLUSION: Noting potential selection bias, there is insufficient evidence to support the notion that delayed surgery is safe in localised RCC. For metastatic RCC, upfront TT followed by deferred CN should be considered.

Cell Membrane-Coated Electrospun Fibers Enhance Keratinocyte Growth through Cell-Type Specific Interactions.

Although cell membrane-coated fiber scaffolds can be useful for regenerative medicine by presenting both cell surface antigens and topographical cues, it remains unknown whether changes in cellular behavior on cell membrane-coated scaffolds are due to specific cell-cell interactions. In this work, the effects of scaffold fiber diameters and surface charges on the cell membrane coating efficiency were explored. Furthermore, fibroblast membrane-coated scaffolds improved the growth of human keratinocytes as compared to red blood cell membrane-coated and plain scaffolds. These results suggest the biofunctionality of cell membrane-coated scaffolds and the specific cell-cell interactions that are preserved to modulate cellular response.

Oriented and sustained protein expression on biomimicking electrospun fibers for evaluating functionality of cells.

A proper protein orientation is often required in order to achieve specific protein-receptor interaction to elicit a desired biological response. Here, we present a Protein A-based biomimicking platform that is capable of efficiently orienting proteins for evaluating cellular behaviour. By absorbing Protein A onto aligned bio-mimicking polycaprolactone (PCL) fibers, we demonstrate that protein binding could be retained on these fibers for at least 7 days under physiologically relevant conditions. We further show that Protein A served as a molecular orientor to arrange the recombinant proteins in similar orientations. Such protein-orienting scaffolds were further verified to be biologically functional by using sensitive primary rat cortical neurons (CNs) and oligodendrocyte progenitor cells (OPCs), as model neural cells for a stringent proof of concept. Specifically, CNs that were seeded on fibers coated with Protein A and a known enhancer of neurite growth (L1 Cell Adhesion Molecular L1CAM) displayed the longest total neurite length (462.77 ± 100.79 µm, p < 0.001) as compared to the controls. Besides that, OPCs seeded on fibers coated with Protein A and Neuregulin-1 Type III (Nrg1 type III) (myelin enhancer) produced the longest myelin ensheathment length (19.8 ± 11.69 µm). These results demonstrate the efficacy of this platform for protein screening applications.

Telemedicine Usage Among Urologists During the COVID-19 Pandemic: Cross-Sectional Study.

BACKGROUND: Prior to the COVID-19 pandemic, urology was one of the specialties with the lowest rates of telemedicine and videoconferencing use. Common barriers to the implementation of telemedicine included a lack of technological literacy, concerns with reimbursement, and resistance to changes in the workplace. In response to the COVID-19 pandemic declared in March 2020, the delivery of urological services globally has quickly shifted to telemedicine to account for the mass clinical, procedural, and operative cancellations, inadequate personal protective equipment, and shortage of personnel. OBJECTIVE: The aim of this study was to investigate current telemedicine usage by urologists, urologists' perceptions on the necessity of in-person clinic appointments, the usability of telemedicine, and the current barriers to its implementation. METHODS: We conducted a global, cross-sectional, web-based survey to investigate the use of telemedicine before and after the COVID-19 pandemic. Urologists' perceived usability of telemedicine was assessed using a modified Delphi approach to create questions based on a modified version of the validated Telehealth Usability Questionnaire (TUQ). For the purposes of this study, telemedicine was defined as video calls only. RESULTS: A total of 620 urologists from 58 different countries and 6 continents participated in the survey. Prior to COVID-19, 15.8% (n=98) of urologists surveyed were using telemedicine in their clinical practices; during the pandemic, that proportion increased to 46.1% (n=283). Of the urologists without telemedicine experience, interest in telemedicine usage increased from 43.7% (n=139) to 80.8% (n=257) during the COVID-19 pandemic. Among urologists that used telemedicine during the pandemic, 80.9% (n=244) were interested in continuing to use it in their practice. The three most commonly used platforms were Zoom, Doxy.me, and Epic, and the top three barriers to implementing telemedicine were patients' lack of technological comprehension, patients' lack of access to the required technology, and reimbursement concerns. CONCLUSIONS: This is the first study to quantify the use, usability, and pervading interest in telemedicine among urologists during the COVID-19 pandemic. In the face of this pandemic, urologists' usage of telemedicine nearly tripled, demonstrating their ability to adopt and adapt telemedicine into their practices, but barriers involving the technology itself are still preventing many from utilizing it despite increasing interest.

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-Dependent Regulation.

A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes-associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.

A Global Survey on the Impact of COVID-19 on Urological Services.

BACKGROUND: The World Health Organization (WHO) declared coronavirus disease-19 (COVID-19) as a pandemic on March 11, 2020. The impact of COVID-19 on urological services in different geographical areas is unknown. OBJECTIVE: To investigate the global impact of COVID-19 on urological providers and the provision of urological patient care. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, web-based survey was conducted from March 30, 2020 to April 7, 2020. A 55-item questionnaire was developed to investigate the impact of COVID-19 on various aspects of urological services. Target respondents were practising urologists, urology trainees, and urology nurses/advanced practice providers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the degree of reduction in urological services, which was further stratified by the geographical location, degree of outbreak, and nature and urgency of urological conditions. The secondary outcome was the duration of delay in urological services. RESULTS AND LIMITATIONS: A total of 1004 participants responded to our survey, and they were mostly based in Asia, Europe, North America, and South America. Worldwide, 41% of the respondents reported that their hospital staff members had been diagnosed with COVID-19 infection, 27% reported personnel shortage, and 26% had to be deployed to take care of COVID-19 patients. Globally, only 33% of the respondents felt that they were given adequate personal protective equipment, and many providers expressed fear of going to work (47%). It was of concerning that 13% of the respondents were advised not to wear a surgical face mask for the fear of scaring their patients, and 21% of the respondents were advised not to discuss COVID-19 issues or concerns on media. COVID-19 had a global impact on the cut-down of urological services, including outpatient clinic appointments, outpatient investigations and procedures, and urological surgeries. The degree of cut-down of urological services increased with the degree of COVID-19 outbreak. On average, 28% of outpatient clinics, 30% of outpatient investigations and procedures, and 31% of urological surgeries had a delay of >8 wk. Urological services for benign conditions were more affected than those for malignant conditions. Finally, 47% of the respondents believed that the accumulated workload could be dealt with in a timely manner after the COVID-19 outbreak, but 50% thought the postponement of urological services would affect the treatment and survival outcomes of their patients. One of the limitations of this study is that Africa, Australia, and New Zealand were under-represented. CONCLUSIONS: COVID-19 had a profound global impact on urological care and urology providers. The degree of cut-down of urological services increased with the degree of COVID-19 outbreak and was greater for benign than for malignant conditions. One-fourth of urological providers were deployed to assist with COVID-19 care. Many providers reported insufficient personal protective equipment and support from hospital administration. PATIENT SUMMARY: Coronavirus disease-19 (COVID-19) has led to significant delay in outpatient care and surgery in urology, particularly in regions with the most COVID-19 cases. A considerable proportion of urology health care professionals have been deployed to assist in COVID-19 care, despite the perception of insufficient training and protective equipment.

Effects of miR-219/miR-338 on microglia and astrocyte behaviors and astrocyte-oligodendrocyte precursor cell interactions.

MiR-219 and miR-338 (miR-219/miR-338) are oligodendrocyte-specific microRNAs. The overexpression of these miRs in oligodendrocyte precursor cells promotes their differentiation and maturation into oligodendrocytes, which may enhance axonal remyelination after nerve injuries in the central nervous system (CNS). As such, the delivery of miR-219/miR-338 to the CNS to promote oligodendrocyte precursor cell differentiation, maturation and myelination could be a promising approach for nerve repair. However, nerve injuries in the CNS also involve other cell types, such as microglia and astrocytes. Herein, we investigated the effects of miR-219/miR-338 treatment on microglia and astrocytes in vitro and in vivo. We found that miR-219/miR-338 diminished microglial expression of pro-inflammatory cytokines and suppressed astrocyte activation. In addition, we showed that miR-219/miR-338 enhanced oligodendrocyte precursor cell differentiation and maturation in a scratch assay paradigm that re-created a nerve injury condition in vitro. Collectively, our results suggest miR-219/miR-338 as a promising treatment for axonal remyelination in the CNS following nerve injuries. All experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC), Nanyang Technological University (approval No. A0309 and A0333) on April 27, 2016 and October 8, 2016.

Correction: Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells.

Correction for 'Scaffold mediated gene knockdown for neuronal differentiation of human neural progenitor cells' by Wai Hon Chooi et al., Biomater. Sci., 2018, 6, 3019-3029.

Scaffold-mediated non-viral delivery platform for CRISPR/Cas9-based genome editing.

Genome editing, especially via the simple and versatile type II CRISPR/Cas9 system, offers an effective avenue to precisely control cell fate, an important aspect of tissue regeneration. Unfortunately, most CRISPR/Cas9 non-viral delivery strategies only utilise micro-/nano-particle delivery methods. While these approaches provide reasonable genomic editing efficiencies, their systemic delivery may lead to undesirable off-target effects. For in vivo applications, a more localized and sustained delivery approach may be useful, particularly in the context of tissue regeneration. Here, we developed a scaffold that delivers the CRISPR/Cas9 components (i.e. single guide RNA (sgRNA) and Cas9 protein complexes) in a localized and non-viral manner. Specifically, using mussel-inspired bioadhesive coating, polyDOPA-melanin (pDOPA), we adsorbed Cas9:sgRNA lipofectamine complexes onto bio-mimicking fiber scaffolds. To evaluate the genome-editing efficiency of this platform, U2OS.EGFP cells were used as the model cell type. pDOPA coating was essential in allowing Cas9:sgRNA lipofectamine complexes to adhere onto the scaffolds with a higher loading efficiency, while laminin coating was necessary for maintaining cell viability and proliferation on the pDOPA-coated fibers for effective gene editing (21.5% editing efficiency, p < 0.001). Importantly, U2OS.EGFP cells took up Cas9:sgRNA lipofectamine complexes directly from the scaffolds via reverse transfection. Overall, we demonstrate the efficacy of such fiber scaffolds in providing localized, sustained and non-viral delivery of Cas9:sgRNA complexes. Such genome editing scaffolds may find useful applications in tissue regeneration. STATEMENT OF SIGNIFICANCE: Currently, there is a lack of effective non-viral means to deliver CRISPR/Cas9 components for genome editing. Most existing approaches only utilize micro-/nano-particles by injection or systemic delivery, which may lead to undesirable off-target effects. Here, we report a platform that delivers the CRISPR/Cas9 components (i.e. single guide RNA (sgRNA) and Cas9 protein complexes) in a localized and sustained manner. We used mussel-inspired bioadhesive coating to functionalize the bio-mimicking fiber scaffolds with Cas9:sgRNA lipofectamine complexes, to allow effective gene editing for the cells seeded on the scaffolds. Importantly, the cells took up Cas9:sgRNA lipofectamine complexes directly from the scaffolds. Such genome editing scaffolds may find useful applications in tissue regeneration.

Scaffold-mediated sequential drug/gene delivery to promote nerve regeneration and remyelination following traumatic nerve injuries.

Neural tissue regeneration following traumatic injuries is often subpar. As a result, the field of neural tissue engineering has evolved to find therapeutic interventions and has seen promising outcomes. However, robust nerve and myelin regeneration remain elusive. One possible reason may be the fact that tissue regeneration often follows a complex sequence of events in a temporally-controlled manner. Although several other fields of tissue engineering have begun to recognise the importance of delivering two or more biomolecules sequentially for more complete tissue regeneration, such serial delivery of biomolecules in neural tissue engineering remains limited. This review aims to highlight the need for sequential delivery to enhance nerve regeneration and remyelination after traumatic injuries in the central nervous system, using spinal cord injuries as an example. In addition, possible methods to attain temporally-controlled drug/gene delivery are also discussed for effective neural tissue regeneration.

Digital Health Professions Education on Diabetes Management: Systematic Review by the Digital Health Education Collaboration.

BACKGROUND: There is a shortage of health care professionals competent in diabetes management worldwide. Digital education is increasingly used in educating health professionals on diabetes. Digital diabetes self-management education for patients has been shown to improve patients' knowledge and outcomes. However, the effectiveness of digital education on diabetes management for health care professionals is still unknown. OBJECTIVE: The objective of this study was to assess the effectiveness and economic impact of digital education in improving health care professionals' knowledge, skills, attitudes, satisfaction, and competencies. We also assessed its impact on patient outcomes and health care professionals' behavior. METHODS: We included randomized controlled trials evaluating the impact of digitalized diabetes management education for health care professionals pre- and postregistration. Publications from 1990 to 2017 were searched in MEDLINE, EMBASE, Cochrane Library, PsycINFO, CINAHL, ERIC, and Web of Science. Screening, data extraction and risk of bias assessment were conducted independently by 2 authors. RESULTS: A total of 12 studies met the inclusion criteria. Studies were heterogeneous in terms of digital education modality, comparators, outcome measures, and intervention duration. Most studies comparing digital or blended education to traditional education reported significantly higher knowledge and skills scores in the intervention group. There was little or no between-group difference in patient outcomes or economic impact. Most studies were judged at a high or unclear risk of bias. CONCLUSIONS: Digital education seems to be more effective than traditional education in improving diabetes management-related knowledge and skills. The paucity and low quality of the available evidence call for urgent and well-designed studies focusing on important outcomes such as health care professionals' behavior, patient outcomes, and cost-effectiveness as well as its impact in diverse settings, including developing countries.

Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination.

The loss of oligodendrocytes (OLs) and subsequently myelin sheaths following injuries or pathologies in the CNS leads to debilitating functional deficits. Unfortunately, effective methods of remyelination remain limited. Here, we present a scaffolding system that enables sustained non-viral delivery of microRNAs (miRs) to direct OL differentiation, maturation, and myelination. We show that miR-219/miR-338 promoted primary rat OL differentiation and myelination in vitro. Using spinal cord injury as a proof-of-concept, we further demonstrate that miR-219/miR-338 could also be delivered non-virally in vivo using an aligned fiber-hydrogel scaffold to enhance remyelination after a hemi-incision injury at C5 level of Sprague-Dawley rats. Specifically, miR-219/miR-338 mimics were incorporated as complexes with the carrier, TransIT-TKO (TKO), together with neurotrophin-3 (NT-3) within hybrid scaffolds that comprised poly(caprolactone-co-ethyl ethylene phosphate) (PCLEEP)-aligned fibers and collagen hydrogel. After 1, 2, and 4 weeks post-treatment, animals that received NT-3 and miR-219/miR-338 treatment preserved a higher number of Olig2+ oligodendroglial lineage cells as compared with those treated with NT-3 and negative scrambled miRs (Neg miRs; p < 0.001). Additionally, miR-219/miR-338 increased the rate and extent of differentiation of OLs. At the host-implant interface, more compact myelin sheaths were observed when animals received miR-219/miR-338. Similarly within the scaffolds, miR-219/miR-338 samples contained significantly more myelin basic protein (MBP) signals (p < 0.01) and higher myelination index (p < 0.05) than Neg miR samples. These findings highlight the potential of this platform to promote remyelination within the CNS.