Brain repair mechanisms after cell therapy for stroke.

Cell-based therapies hold great promise for brain repair after stroke. While accumulating evidence confirms the preclinical and clinical benefits of cell therapies, the underlying mechanisms by which they promote brain repair remain unclear. Here, we briefly review endogenous mechanisms of brain repair after ischemic stroke and then focus on how different stem and progenitor cell sources can promote brain repair. Specifically, we examine how transplanted cell grafts contribute to improved functional recovery either through direct cell replacement or by stimulating endogenous repair pathways. Additionally, we discuss recently implemented preclinical refinement methods, such as preconditioning, microcarriers, genetic safety switches, and universal (immune evasive) cell transplants, as well as the therapeutic potential of these pharmacologic and genetic manipulations to further enhance the efficacy and safety of cell therapies. By gaining a deeper understanding of post-ischemic repair mechanisms, prospective clinical trials may be further refined to advance post-stroke cell therapy to the clinic.

The relationship between hair cortisol concentration and autism diagnosis.

BACKGROUND: Autistic children are prone to experience heightened levels of distress and physiological reactivity to a range of sensory, social, and emotional stimuli. In line with this, multiple studies have demonstrated that autistic children have higher acute cortisol stress responses to adverse or threatening stimuli and altered cortisol awakening responses. However, few studies have examined whether this sensitivity may relate to heightened levels of chronic stress and persistently elevated hypothalamic-pituitary-adrenal (HPA) axis activity. The measurement of cortisol accumulation in hair is considered a non-invasive biomarker of chronic stress and has been associated with several childhood diseases. Here, we investigated whether hair cortisol concentration in a large sample of autistic children differed from non-autistic children, and after accounting for a range of child, parental and family-level characteristics. METHODS: Hair cortisol concentration was measured in 307 autistic children and 282 non-autistic controls aged between 2 and 17 years recruited from four Australian states who participated in providing hair samples and demographic data to the Australian Autism Biobank. Independent samples t-test or one-way analysis of variance (ANOVA) were conducted to determine significant differences in the mean hair cortisol concentration (pg/mg) between potential covariates. Primary analysis included multivariable regression modelling of the collapsed sample to identify variables that were significantly associated with hair cortisol concentration after controlling for covariates. We also accounted for the potential interaction of multiple biological (e.g., age, sex, BMI) and psychosocial characteristics at the level of the child, the mother and the father, and the family unit. RESULTS: Our findings suggest that the diagnosis of autism was not a significant predictor of chronic stress, as measured by hair cortisol concentration. However, findings of the multivariable regression analysis showed that key factors such as area of residence (Queensland vs Victorian state of residence) and decrease in child's age were significantly associated with higher hair cortisol concentration whereas lower family income was significantly associated with higher hair cortisol concentration. CONCLUSION: To our knowledge, this is the first study to show that socioeconomic factors such as family annual income affect hair cortisol status in autistic children, indicating that the psychosocial environment may be a potential mediator for chronic stress in autistic children just as it has been demonstrated in non-autistic children.

Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula: OCELOT task group study protocol.

INTRODUCTION: Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. METHODS AND ANALYSIS: A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. ETHICS AND DISSEMINATION: Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children's NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum.

Development of audio-guided deep breathing and auditory Go/No-Go task on evaluating its impact on the wellness of young adults: a pilot study.

OBJECTIVES: Numerous studies indicate that deep breathing (DB) enhances wellbeing. Multiple deep breathing methods exist, but few employ audio to reach similar results. This study developed audio-guided DB and evaluated its immediate impacts on healthy population via self-created auditory Go/No-Go task, tidal volume changes, and psychological measures. METHODS: Audio-guided DB with natural sounds to guide the DB was developed. Meanwhile, audio-based Go/No-Go paradigm with Arduino was built to measure the attention level. Thirty-two healthy young adults (n=32) were recruited. Psychological questionnaires (Rosenberg's Self-Esteem Scale (RSES), Cognitive and Affective Mindfulness Scale-Revised (CAMS-R), Perceived Stress Scale (PSS)), objective measurements with tidal volume and attention level with auditory Go/No-Go task were conducted before and after 5 min of DB. RESULTS: Results showed a significant increment in tidal volume and task reaction time from baseline (p=0.003 and p=0.033, respectively). Significant correlations were acquired between (1) task accuracy with commission error (r=-0.905), (2) CAMS-R with task accuracy (r=-0.425), commission error (r=0.53), omission error (r=0.395) and PSS (r=-0.477), and (3) RSES with task reaction time (r=-0.47), task accuracy (r=-0.362), PSS (r=-0.552) and CAMS-R (r=0.591). CONCLUSIONS: This pilot study suggests a link between it and young adults' wellbeing and proposes auditory Go/No-Go task for assessing attention across various groups while maintaining physical and mental wellness.

Leakage beyond the primary lesion: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke.

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-ß accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-ß around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the co-localisation of amyloid-ß with vasculature and blood-brain barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that were exacerbated in vessels with amyloid-ß deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

Solitary pulmonary nodule in an early adolescent.

An early adolescent boy presented with 1-week history of left-sided chest pain, localised to the anterior aspect of seventh intercostal space. A chest radiograph revealed a round opacity measuring 2.6×2.4 cm in the left mid zone. A CT scan of the chest confirmed a solitary well-circumscribed pulmonary nodule measuring 2.7×2.4 cm in the central left upper lobe, adjacent to the anterior segmental bronchus. Positron emission tomography scan showed mild to moderate fluorodeoxyglucose uptake (maximum standardized uptake value 5.2) in the nodule. He underwent a video-assisted left upper lobectomy. Histology of the nodule was consistent with sclerosing pneumocytoma, a rare benign lung neoplasm that occurs predominantly in middle-aged women of Asian descent. This case highlights the challenges in diagnosis and management of solitary pulmonary nodules in children, especially those who remain symptomatic or only have minimal symptoms and provides a pragmatic approach to this condition.

Retrograde ureteral sheathed forceps technique to retrieve a proximally migrated stent in a young infant.

Ureteral stents are commonly externalised retrogradely by cystoscopy and exchanged under imaging guidance. When a ureteral stent has migrated proximally into the ureter, it may be snared by ureteroscopy or antegrade percutaneous access; however, ureteroscopy can be challenging in young infants where there is difficulty visualizing the ureteral orifice or a small-calibre ureter. The presented case describes a radiologic technique for retrieval of a proximally migrated ureteral stent in a young infant using a 0.025-in. hydrophilic wire, 4-Fr angiographic catheter, 8-Fr vascular sheath and cystoscopic forceps, without requiring transrenal antegrade access or surgical ureteral meatotomy.

Gastrointestinal transit time of radiopaque ingested foreign bodies in children: experience of two paediatric tertiary centres.

Introduction: Foreign body (FB) ingestion is a common paediatric emergency. While guidelines exist for urgent intervention, less is known of the natural progress of FBs passing through the gastrointestinal tract (GIT). We reviewed these FB transit times in an outpatient cohort. Methods: A retrospective review was performed on all children (≤18 years) treated for radiopaque FB ingestion at two major tertiary paediatric centres from 2015 to 2016. Demographic data, FB types, outcomes and hospital visits (emergency department [ED] and outpatient) were recorded. All cases discharged from the ED with outpatient follow-up were included. We excluded those who were not given follow-up appointments and those admitted to inpatient wards. We categorised the outcomes into confirmed passage (ascertained via abdominal X-ray or reported direct stool visualisation by patients/caregivers) and assumed passage (if patients did not attend follow-up appointments). Results: Of the 2,122 ED visits for FB ingestion, 350 patients who were given outpatient follow-up appointments were reviewed (median age 4.35 years [range: 0.5-14.7], 196 [56%] male). The largest proportion (16%) was aged 1-2 years. Coins were the most common ingested FB, followed by toys. High-risk FB (magnets or batteries) formed 9% of cases (n=33). The 50th centile for FB retention was 8, 4 and 7 days for coins, batteries and other radiopaque FBs, respectively; all confirmed passages occurred at 37, 7 and 23 days, respectively. Overall, 197 (68%) patients defaulted on their last given follow-up. Conclusion: This study provides insight into the transit times of FB ingested by children, which helps medical professionals to decide on the optimal time for follow-up visits and provide appropriate counsel to caregivers.

Covid-19 Pandemic Strategy for Treatment of Acute Uncomplicated Appendicitis with Antibiotics- Risk Categorization and Shared Decision-Making.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, a protocol was adopted by our department on antibiotics treatment for Acute Uncomplicated Appendicitis (AUA). Our study aimed to determine the feasibility and safety of non-operative treatment (NOT), compared to upfront laparoscopic appendectomy (LA), for AUA in children during the pandemic. METHOD: Our prospective comparative study was conducted from May 1, 2020 to January 31, 2021. Patient selection criteria included: age ≥5 years, abdominal pain duration ≤48 h, ultrasound (US)/Computered Tomography scan confirmation of AUA, US appendiceal diameter 6-11 mm with no features of perforation/abscess collection and no faecolith. For NOT patients, intravenous antibiotics were administered for 24-48 h followed by oral for 10-day course. Comparison was performed between patients whose parents preferred NOT to those who opted for up-front appendectomy. Primary outcomes were NOT success at index admission, early and late NOT failure rates till 27 months. Secondary outcomes were differences in complication rate, hospital length of stay (LOS) and cost between groups. RESULTS: 77 patients were recruited: 43 (55.8%) underwent NOT while 34 (44.2%) patients opted for LA. Success of NOT at index admission was 90.7% (39/43). Overall, NOT failure rate at 27 months' follow-up was 37.2% (16/43). Of the NOT failures, 1 appendix was normal on histology while only 1 was perforated. There were no significant differences in secondary outcomes between both groups except for LOS of late NOT failure. Cost for upfront LA was nearly thrice that of NOT. CONCLUSION: Our stringent COVID protocol together with shared decision-making with parents is a safe and feasible treatment option during a crisis situation. LEVEL OF EVIDENCE: Treatment study, Level II.

Management of acute testicular pain in children: changing trends with improvements in scrotal ultrasonography over 18 years.

Introduction: Doppler scrotal ultrasonography (US) is the modality of choice in diagnosing testicular torsion. We aimed to evaluate the performance of scrotal US in diagnosing testicular torsion over the past 18 years in our institution and determine the factors contributing to the length of wait times for it. Methods: A retrospective review was conducted of boys who presented with acute scrotal pain from 2014 to 2015. US reports, operative findings, final diagnosis and key time points of the patients' journey (time to emergency department consultation, time to admission, time to US and time to operating theatre [OT]) were collected. US performance results were compared with those observed in a historical cohort from 1998 to 2004. Wait times were compared between operated and non-operated patients. Results: Data from 519 boys with a mean age of 9.15 years was collected. Of these, 438 (84.4%) boys had undergone initial scrotal US; of these scrotal US cases, 28 were surgically explored, with 23 confirmed to have torsion. Another five cases were explored without prior US, and all were confirmed to have torsion. Performance analysis of US showed a sensitivity of 100% and a specificity of 98.8%. There was no significant difference between wait times of operated and non-operated patients. Time to US (P < 0.0001, r = 0.96) and time to OT (P < 0.0001, r = 0.64) correlated significantly with the total time from presentation to surgery. Conclusion: There has been an improvement in the diagnostic performance of scrotal US for testicular torsion over the past 18 years. Quality improvement programmes targeted at reducing wait times for patients presenting with acute scrotum should target time to US and time to OT.

Beyond the Primary Infarction: Focus on Mechanisms Related to Secondary Neurodegeneration after Stroke.

Recently, a growing body of evidence has indicated that secondary neurodegeneration after stroke occurs at remote regions of the brain that are connected to the primary infarction site [...].

Conservative antibiotic treatment of pediatric acute uncomplicated appendicitis during the COVID-19 pandemic: a prospective comparative cohort study.

BACKGROUND: Our study aimed to compare the clinical outcomes and cost-efficiency of antibiotic management versus laparoscopic appendectomy for acute uncomplicated appendicitis (AUA) in children during the COVID-19 pandemic when resources were limited and transmission risks uncertain. METHOD: In this prospective comparative cohort study, we analyzed the data of 139 children diagnosed with AUA meeting the following inclusion criteria: 5-18 years of age, symptoms duration of ≤ 48 h, appendix diameter ≤ 11 mm and no appendicolith. Treatment outcomes between non-operative management group (78/139) and upfront laparoscopic appendectomy group (61/139) were compared. Antibiotic regimes were intravenous ceftriaxone/metronidazole or amoxicillin/clavulanic acid for 48 h, followed by oral antibiotics to complete total 10-days course. RESULTS: 8/78 (10.3%) children had early failure (within 48 h) requiring appendectomy. 17/70 (24.3%) patients experienced late recurrence within mean follow-up time of 16.2 ± 4.7 months. There were no statistical differences in peri-operative complications, negative appendicectomy rate, and incidence of perforation and hospitalization duration between antibiotic and surgical treatment groups. Cost per patient in upfront surgical group was significantly higher ($6208.5 ± 5284.0) than antibiotic group ($3588.6 ± 3829.8; p = 0.001). CONCLUSION: Despite 24.3% risk of recurrence of appendicitis in 16.2 ± 4.7 months, antibiotic therapy for AUA appears to be a safe and cost-effective alternative to upfront appendectomy.

Extravesical vs. intravesical ureteric reimplantation for primary vesicoureteral reflux: A systematic review and meta-analysis.

Purpose: This study aims to compare the outcomes of extravesical (EVUR) and intravesical (IVUR) ureteric reimplantation for primary vesicoureteral reflux (VUR) via systematic review and meta-analysis. Methods: Literature review from Medline, Embase, and Cochrane since inception to March 2022 was performed. Meta-analysis was conducted on eligible randomized controlled trials (RCT) and observational cohort studies (OCS) comparing outcomes between EVUR and IVUR. Results: Twelve studies were included, comprising 577 patients (778 ureters) operated by EVUR and 395 patients (635 ureters) by IVUR. Pre-operative VUR grade, postoperative VUR persistence and hydronephrosis was not statistically significant. EVUR had shorter operative time [mean differences (MD) -22.91 min; 95% confidence interval (CI), -44.53 to -1.30, P = 0.04] and hospital stay (MD -2.09 days; 95% CI, -2.82 to -1.36, P < 0.00001) compared to IVUR. Bilateral EVUR had higher risk of postoperative acute urinary retention (ARU) (8.1%) compared to bilateral IVUR (1.7%) (OR = 4.40; 95% CI, 1.33-14.58, P = 0.02). No patient undergoing unilateral EVUR or IVUR experienced ARU. Conclusion: Both EVUR and IVUR are equally effective in correcting primary VUR. Operative time and hospital stay are shorter after EVUR compared to IVUR. However, bilateral EVUR is associated with higher risk of postoperative ARU.

Meckel's Diverticulum - Clinical Presentation and Pitfalls in Diagnosis in the Pediatric Age Group in Singapore.

Purpose: The purpose of this study was to study the presentation of patients who underwent Meckel's diverticulectomy (MD) and utility of pertechnetate Meckel's scan in the diagnosis of MD. Methods: The clinical presentation of a retrospective cohort of patients who underwent MD from January 2007 to December 2019 was studied. The modes of presentation, treatment, and the diagnostic utility of pertechnetate Meckel's scans were evaluated. False-positive and false-negative scans were reviewed. The presence of gastric mucosa on histology of Meckel's was correlated with presentation as gastrointestinal bleeding and positive scan results. Results: Ninety-nine patients underwent MD. Thirty-five out of 263 (13.3%) Meckel's scans done were positive. There was a male preponderance (86.9%). The peak age of presentation was 0-4 years (rectal bleeding or intestinal obstruction). Only a third of the patients with Meckel's diverticulum Meckel's had a preoperative diagnosis of Meckel's. The sensitivity/specificity of Meckel's scan was higher in patients presenting with painless rectal bleeding. Seven patients were false positive (weak tracer uptake or ectopic uptake) and five were false negative. Two patients with false-negative Meckel's scan, having gastrointestinal bleeding had gastric mucosa on histology of Meckel's. Conclusion: Meckel's diverticulum has a male predominance. Meckel's scan has a high sensitivity in the children presenting with fresh painless rectal bleeding but is of limited use in the diagnosis of Meckel's diverticulum in other forms of presentations. False-positive scans can be anticipated in the presence of weak or ectopic uptake. False-negative scans can occur even in the presence of bleeding and in spite of the presence of gastric mucosa in the Meckel's diverticulum. Laparoscopy is a useful tool in diagnosis and treatment.

Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice.

Aims: We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods: Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 µl/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results: r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p < 0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p < 0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p < 0.05). Conclusion: r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke.

Dynamic Bayesian Belief Network for long-term monitoring and system barrier failure analysis: Decommissioned wells.

There is increasing interest to consider dependent failures and human errors in the offshore industry. Permanently abandoned wells dot most of the subsea environment. The nature of a well plugging and abandonment (Well P&A) run - usually the lowest-cost contractor engaged to plug several wells tapping the same reservoir makes it an ideal case study for incorporating failures based on common causes. The heavy use of operators during a cementing job also provides the case for analysis of human error in such tasks. One proposed method to analyse the above-mentioned is the use of Bayesian Belief Networks to achieve the following objectives (1) to capture better estimates of a well PA event by incorporating dependencies, and meet regulatory requirements by authorities; and (2) to use the same model to provide long term monitoring of a group of wells linked by common dependencies. This model has not only captured the dependencies of multiple variables, but also projected it in a dynamic manner to provide a risk profile for the next decade where well integrity failure is likely to happen. • Proposed adapted method capture better estimates of a well PA event by incorporating dependencies • Method allows for extension of model to long term monitoring of a group of wells linked by common dependencies.

Outcome of boys with posterior urethral valves from a single tertiary hospital in Singapore.

INTRODUCTION: Posterior urethral valve (PUV) is the most common congenital cause of bladder outflow obstruction in male infants. Despite timely treatment, renal damage can still occur in the long-term leading to chronic kidney disease (CKD). METHODS: A retrospective review of all PUV patients in a single tertiary institution between April 1998 and July 2019 was conducted to analyze their presentations, management and outcomes. Long-term renal function, radiologic scans and somatic growth were evaluated. RESULTS: A total of 16 patients were included in this study. Two patients who defaulted all follow-ups were excluded. Seven patients (43.7%) presented in the antenatal period; four patients (25%) presented in the neonatal period and five patients (31.3%) presented in the post-neonatal period. Primary transurethral fulguration of valves was done in 13 patients, while three had vesicostomies as the primary procedure. Three patients had associated anterior urethral valves (AUV), which were treated endoscopically. Nine boys had additional procedures for diversion and undiversion, VUR, non-functioning kidney and clean intermittent catheterization. Ten patients had urodynamic studies performed, of which eight patients received anticholinergic therapy. Eleven patients had DMSA scans, of which three patients had a normal study and eight patients showed unilateral reduced function. Four patients were diagnosed with CKD on long-term follow-up duration over 5 years. All patients were shown to have good somatic growth. CONCLUSION: Patients with PUV can suffer from complications despite primary treatment. In our small cohort, a quarter of our patients developed CKD on follow-up. Thus, patients need long-term follow-up to optimize bladder and renal function.