Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis

Frontotemporal dementia(FTD) and amyotrophic lateral sclerosis(ALS) are neurodegenerative diseases that belong to the same disease spectrum,with overlapping of genetic and pathological features.Genetic mutations in TARDBP,C9ORF72,MAPT,and GRN have been identified in these diseases.

Gestational diabetes mellitus: Challenges for different ethnic groups

Ethnicity is defined as"belonging to a social groupthat has a common national or cultural tradition".Membership of certain ethnic groups has long been associated with increased risk of gestational diabetes mellitus(GDM).Studies that examined ethnic differences amongst women with GDM were often conducted in western countries where women from various ethnic backgrounds were represented.The prevalence of GDM appears to be particularly high among women from South Asia and South East Asia,compared to Caucasian,African-American and Hispanic communities.For some,but not all ethnic groups,the body mass index is a risk factor for the development of GDM.Even within a particular ethnic group,those who were born in their native countries have a different risk profile for GDM compared to those born in western countries.In terms of treatment,medical nutrition therapy(MNT)plays a key role in the management of GDM and the prescription of MNT should be culturally sensitive.Limited studies have shown that women who live in an English-speaking country but predominantly speak a language other than English,have lower rates of dietary understanding compared with their English speaking counterparts,and this may affect compliance to therapy.Insulin therapy also plays an important role and there appears to be variation as to the progression of women who progress to requiring insulin among different ethnicities.As for peri-natal outcomes,women from Pacific Islander countries have higher rates of macrosomia,while women from Chinese backgrounds had lower adverse pregnancy outcomes.From a maternal outcome point of view,pregnant women from Asia with GDM have a higher incidence of abnormal glucose tolerance test results post-partum and hence a higher risk of future development of type2 diabetes mellitus.On the other hand,women from Hispanic or African-American backgrounds with GDM are more likely to develop hypertension post-partum.This review highlights the fact that management needs to be individualised and the clinician should be mindful of the impact that differences in ethnicity may have on the clinical characteristics and pregnancy outcomes inwomen affected by GDM,particularly those living in Western countries.Understanding these differences is critical in the delivery of optimal antenatal care for women from diverse ethnic backgrounds.

Pancreatic cancer and its stroma: A conspiracy theory

Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells(pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biologyand the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Indications and surgical options for small bowel, large bowel and perianal Crohn's disease

Despite advancements in medical therapy of Crohn's disease(CD), majority of patients with CD will eventually require surgical intervention, with at least a third of patients requiring multiple surgeries. It is important to understand the role and timing of surgery, with the goals of therapy to reduce the need for surgery without increasing the odds of emergency surgery and its associated morbidity, as well as to limit surgical recurrence and avoid intestinal failure. The profile of CD patients requiring surgical intervention has changed over the decades with improvements in medical therapy with immunomodulators and biological agents. The most common indication for surgery is obstruction from stricturing disease, followed by abscesses and fistulae. The risk of gastrointestinal bleeding in CD is high but the likelihood of needing surgery for bleeding is low. Most major gastrointestinal bleeding episodes resolve spontaneously, albeit the risk of re-bleeding is high. The risk of colorectal cancer associated with CD is low. While current surgical guidelines recommend a total proctocolectomy for colorectal cancer associated with CD, subtotal colectomy or segmental colectomy with endoscopic surveillance may be a reasonable option. Approximately 20%-40% of CD patients will need perianal surgery during their lifetime. This review assesses the practice parameters and guidelines in the surgical management of CD, with a focus on the indications for surgery in CD(and when not to operate), and a critical evaluation of the timing and surgical options available to improve outcomes and reduce recurrence rates.

Cryopreservation for delayed circulating tumor cell isolation is a valid strategy for prognostic association of circulating tumor cells in gastroesophageal cancer

AIM To demonstrate the feasibility of cryopreservation of peripheral blood mononuclear cells(PBMCs) for prognostic circulating tumor cell(CTC) detection in gastroesophageal cancer.METHODS Using 7.5 m L blood samples collected in EDTA tubes from patients with gastroesopheagal adenocarcinoma, CTCs were isolated by epithelial cell adhesion molecule based immunomagnetic capture using the Iso Flux platform. Paired specimens taken during the same blood draw(n = 15) were used to compare number of CTCs isolated from fresh and cryopreserved PBMCs. Blood samples were processed within 24 h to recover the PBMC fraction, with PBMCs used for fresh analysis immediately processed for CTC isolation. Cryopreservation of PBMCs lasted from 2 wk to 25.2 mo(median 14.6 mo). CTCs isolated from pre-treatment cryopreserved PBMCs(n = 43) were examined for associations with clinicopathological variables and survival outcomes.RESULTS While there was a significant trend to a decrease in CTC numbers associated with cryopreserved specimens(mean number of CTCs 34.4 vs 51.5, P = 0.04), this was predominately in samples with a total CTC count of > 50, with low CTC count samples less affected(P = 0.06). There was no significant association between the duration of cryopreservation and number of CTCs. In cryopreserved PBMCs from patient samples prior to treatment, a high CTC count(> 17) was associated with poorer overall survival(OS)(n = 43, HR = 4.4, 95%CI: 1.7-11.7, P = 0.0013). In multivariate analysis, after controlling for sex, age, stage, ECOG performance status, and primary tumor location, a high CTC count remained significantly associated with a poorer OS(HR = 3.7, 95%CI: 1.2-12.4, P = 0.03). CONCLUSION PBMC cryopreservation for delayed CTC isolation is a valid strategy to assist with sample collection, transporting and processing.

Coping strategies of family caregivers of patients with schizophrenia in Iran: A cross-sectional survey

Objectives: This study aimed to identify coping strategies used by family caregivers of patients with schizophrenia and their determinants.Methods: This was a descriptive correlational study.Participants were 225 family caregivers of patients with schizophrenia who were referred to the psychiatric clinic at one large teaching referral hospital in Iran.They were selected through purposive sampling method.Data collection tools were demographic and clinical data form,the Zarit Burden Interview (ZBI) and the Family Coping Questionnaire (FCQ).Results: The score of caregiver burden was 65.14 ± 9.17.Of 225 family caregivers,23.11% used an avoiding coping strategy.There was a significant relationship between caregiver burden and coping strategies (P < 0.001).The regression model showed that adaptive coping strategies were significantly associated with some demographic characteristics including age,education level,gender,employment status,losing the job because of caregiving responsibilities,perceived income adequacy,duration of illness,duration of caregiving and caregiver burden (P < 0.05).Conclusion: Family caregivers of patients with schizophrenia experience a high level of burden,which can put them at risk of using maladaptive coping strategies.Mental health professionals should plan programs that support both family caregivers and patients in clinical and community settings.

Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status

BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.

Alcoholic pancreatitis:A tale of spirits and bacteria

Alcohol is a major cause of chronic pancreatitis.About5%of alcoholics will ever suffer from pancreatitis,suggesting that additional co-factors are required to trigger an overt disease.Experimental work has implicated lipopolysaccharide,from gut-derived bacteria,as a potential co-factor of alcoholic pancreatitis.This review discusses the effects of alcohol on the gut flora,the gut barrier,the liver-and the pancreas and proposes potential interventional strategies.A better understanding of the interaction between the gut,the liver and the pancreas may provide valuable insight into the pathophysiology of alcoholic pancreatitis.

Prospective single-blinded single-center randomized controlled trial of Prep Kit-C and Moviprep:Does underlying inflammatory bowel disease impact tolerability and efficacy?

BACKGROUND Colonoscopy remains the gold standard for detection of colonic disease.An optimal evaluation depends on adequate bowel cleansing.Patients with inflammatory bowel disease(IBD),require frequent endoscopic assessment for both activity and dysplasia assessment.Two commonly used bowel preparations in Australia are Prep Kit-C(Pc)and Moviprep(Mp).Little is known about tolerability,efficacy and safety of split protocols of Mp and Pc in both IBD and non-IBD patients.AIM To primary aim was to compare the tolerability,efficacy and safety of split protocols of Mp and Pc in patients having a colonoscopy.The secondary aim was to compare the efficacy,tolerability and safety of either preparation in patients with or without IBD.METHODS Patients were randomized to Pc or Mp bowel preparation.Patients completed a questionnaire to assess tolerability.Efficacy was assessed using the Ottawa Bowel Preparation Score.Serum electrolytes and renal function were collected one week prior to colonoscopy and on the day of colonoscopy.RESULTS Of 338 patients met the inclusion criteria.Of 168 patients randomized to Mp and 170 to Pc.The efficacy of bowel preparation(mean Ottawa Bowel Preparation Score)was similar between Mp(5.4±2.4)and Pc(5.1±2.1)(P=0.3).Mean tolerability scores were similar in Mp(11.84±5.4)and Pc(10.99±5.2;P=0.17).125 patients had IBD(73 had Crohn’s Disease and 52 had Ulcerative colitis).Sixtyfour IBD patients were allocated to Mp and 61 to Pc.In non-IBD patients,104 were allocated to Mp and 109 to Pc.The mean tolerability score in the IBD group was lower than the non-IBD group(mean tolerability scores:IBD:10.3±5.1 and non-IBD:12.0±5.3;P=0.01).IBD patients described more abdominal pain with Mp when compared with Pc;(Mp:5.7±4.4 vs Pc:3.6±2.6,P=0.046).Serum magnesium level increased with Pc compared with Mp in all patients(mean increase in mmol/L:Mp:0.03±0.117 and Pc:0.11±0.106;P<0.0001).CONCLUSION In this study,the efficacy,tolerability and safety of Mp and Pc were similar in all patients.However,patients with IBD reported lower tolerability with both preparations.Specifically,IBD patients had more abdominal pain with Mp.These results should be considered when recommending bowel preparation especially to IBD patients.

Importance of investigating high-risk human papillomavirus in lymph node metastasis of esophageal adenocarcinoma

High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma.Tumor human papillomavirus status has been reported to confer a favorable prognosis in esophageal adenocarcinoma.The size of the primary tumor and degree of lymphatic spread determines the prognosis of esophageal carcinomas.Lymph node status has been found to be a predictor of recurrent disease as well as 5-year survival in esophageal malignancies.In human papillomavirus driven cancers,e.g.cervical,anogenital,head and neck cancers,associated lymph nodes with a high viral load suggest metastatic lymph node involvement.Thus,human papillomavirus could potentially be useful as a marker of micro-metastases.To date,there have been no reported studies regarding human papillomavirus involvement in lymph nodes of metastatic esophageal adenocarcinoma.This review highlights the importance of investigating human papillomavirus in lymph node metastasis of esophageal adenocarcinoma based on data derived from other human papillomavirus driven cancers.

Parenting preschoolers with autism: Socioeconomic influences on wellbeing and sense of competence

BACKGROUND Previous research suggests that parents raising a child with autism experience higher levels of psychological distress than parents of typically developing children and parents of children with other developmental disorders. Little is known, however, about the intersection between the effects of socioeconomic status(SES) on the wellbeing and sense of parental competency of parents of preschoolers with autism and how it relates to child symptom severity.AIM To examine the relationship between their child's symptom severity, SES, as measured by neighbourhood advantage and occupational status, on the psychological wellbeing and perceived parenting competence among parents of preschoolers with autism.METHODS Parents of 117 preschool-aged children with a diagnosis of autism spectrum disorder(ASD), 107 mothers and 54 fathers, completed questionnaires about their child's symptoms of ASD and functioning, their own perceptions of their wellbeing and parental competence on entry to an early intervention program in Sydney, Australia. Parents also provided demographic information pertaining to their occupation, level of education attained and address(postcode). All children were also assessed for their severity of symptoms using the Autism Diagnostic Observation Schedule. The Australian Socioeconomic Index of occupationalstatus as a measure of familial SES and the Index of Relative Socio-economic Advantage and Disadvantage as a measure of neighbourhood advantage were used to examine the impact of SES on parental sense of competence and wellbeing.RESULTS Compared to normative populations, both mothers and fathers in our sample reported significantly higher levels of parenting sense of efficacy but lower levels of interest in the parenting role. Mothers also displayed higher levels of satisfaction. Both mothers and fathers displayed higher levels of depression than normative populations with mothers also reporting greater levels of stress and anxiety. Child symptom severity was associated with maternal parenting competency with these relationships amplified among mothers with higher familial SES and who lived in areas of greater neighbourhood advantage.Increased adaptive functioning was associated with better maternal wellbeing,particularly among mothers who lived in areas of greater neighbourhood advantage. Contrastingly, paternal parenting competence was generally not influenced by child adaptive functioning or symptom severity, although for those in higher familial SES brackets, children's symptom severity and maladaptive symptoms were negatively related to paternal sense of parenting efficacy. There was a trend towards moderate relationships between lower familial SES and greater depression, stress and anxiety among fathers, but no relationship with their child's ASD symptom severity or functioning.CONCLUSION SES differentially impacts wellbeing and sense of parenting competence and its relationship to the impact of child symptoms for mothers and fathers of preschoolers with autism.

Characterisation of colonic dysplasia-like epithelial atypia in murine colitis

AIM To determine if exacerbation of pre-existing chronic colitis in Winnie(Muc2 mutant) mice induces colonic dysplasia.METHODS Winnie mice and C57BL6 as a genotype control, were administered 1% w/v dextran sulphate sodium(DSS) orally, followed by drinking water alone in weeklong cycles for a total of three cycles. After the third cycle, mice were killed and colonic tissue collected for histological and immunohistochemical evaluation. Inflammation and severity of dysplasia in the colonic mucosa were assessed in H&E sections of the colon. Epithelial cell proliferation was assessed using Ki67 and aberrant β-catenin signalling assessed with enzyme-based immunohistochemistry. Extracted RNA from colonic segments was used for the analysis of gene expression using real-time quantitative PCR. Finally, the distribution of Cxcl5 was visualised using immunohistochemistry.RESULTS Compared to controls, Winnie mice exposed to three cycles of DSS displayed inflammation mostly confined to the distal-mid colon with extensive mucosal hyperplasia and regenerative atypia resembling epithelial dysplasia. Dysplasia-like changes were observed in 100% of Winnie mice exposed to DSS, with 55% of these animals displaying changes similar to high-grade dysplasia, whereas high-grade changes were absent in wild-type mice. Occasional penetration of the muscularis mucosae by atypical crypts was observed in 27% of Winnie mice after DSS. Atypical crypts however displayed no evidence of oncogenic nuclear β-catenin accumulation, regardless of histological severity. Expression of Cav1, Trp53 was differentially regulated in the distal colon of Winnie relative to wild-type mice. Expression of Myc and Ccl5 was increased by DSS treatment in Winnie only. Furthermore, increased Ccl5 expression correlated with increased complexity in abnormal crypts. While no overall difference in Cxcl5 mucosal expression was observed between treatment groups, epithelial Cxcl5 protein appeared to be diminished in the atypical epithelium. CONCLUSION Alterations to the expression of Cav1, Ccl5, Myc and Trp53 in the chronically inflamed Winnie colon may influence the transition to dysplasia.

Exploration of Mutation and DNA Methylation of Polo-Like Kinase 1 (PLK1) in Colorectal Cancer

Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays critical roles in cell cycling and DNA damage response. Overexpression of PLK1 is associated with the poorer prognosis of cancers, including colorectal cancer (CRC). Although the downstream pathways of the overexpression that lead to oncogenesis have been extensively studied, little is known about the factors that cause the overexpression of PLK1 in CRC. DNA methylation was reported to be affecting the expression of PLK1 in some cancers. The study aims to investigate the contribution of genetic mutation and DNA methylation of the PLK1 gene to the overexpression of PLK1 in CRC. The study involves data mining from Catalogue of Somatic Mutations in Cancer (COSMIC) and UniProtKB, Sanger sequencing on DNA from the cell lines HCT116, SW48, Colo320DM and T84 to analyse the possible mutation of PLK1. Other than that methylation status of the PLK1 promoter in CRC are also analysed by using mass spectrometry (MS) and pyrosequencing. Data from the COSMIC show the low incidences of PLK1 mutation for CRC (3.02%) with 46 mutations identified. One of the mutation p.R337Q (c.1010G > A) is located in the D-box which is an important motif for protein ubiquitination and eventually proteasomal degradation. Hence this mutation may potentially result in stabilisation of the PLK1 protein. Mutations are detected at the upstream silencer region, the promoter region and Exon1 in HCT116 but are not located at the protein binding or functioning site. Similarly, the same mutation at promoter region is detected in SW48. Differential trends of changes in methylation status of PLK1 in the IR treated CRC cell lines detected by MS reveal the possible association between the methylation and the radiosensitivity. Furthermore, pyrosequencing shows that PLK1 methylation status in tumour tissues with high expression of PLK1 is not significantly different from those with no PLK1 expression. In conclusion, mutation of PLK1 gene is infrequent in CRC and the expression of PLK1 is unlikely to be dependent on DNA methylation in the promoter region of PLK1 in the CRC.

Initiative to Improve the Health Outcomes of Those at Risk of Perinatal Depression: Referral Characteristics and Psychosocial Determinants

In Australia, perinatal depression affects 15% - 20% of pregnant women. Depression does not go away on its own, getting help at early stages shown to be effective in treating antenatal depression. Aim of this study is to assess and describe the screening of women through the antenatal clinic and measure the outcome of services provided (such as counselling, social assistance) for those at risk of depression, in a general hospital setting in an ethnically diverse part of Sydney, Australia. Data from 193 women were obtained through accessing the psychosocial and screening assessments completed at the antenatal clinic between 2007 and 2008. Data regarding patients’ psychosocial characteristics, referrals and interventions were also gathered from hospital records. Data revealed that 60.4% of women screened scored ≥10 on the Edinburgh Postnatal Depression Scale (EDPS) which is indicative of significant depressive symptomatology. Of these women, 39.4% went on to receive a formal diagnosis. Women who indicated that they had planned their pregnancies (47.2%) were significantly less likely to report having major worries and stressors over the last 12 months (p < 0.05) in comparison to those who indicated that their pregnancies were unplanned. Data showed while screening methods are effective, regrettably a high proportion of women, despite presenting with “at risk” symptomatology levels, do not engage in intervention programs. Further research is required to explore the barriers in accessing both screening and intervention services (particularly in a culturally diverse area such as this), and how services can improve processes and patient participation.

Tenecteplase thrombolysis for stroke up to 24 hours after onset with perfusion imaging selection:the umbrella phase IIa CHABLIS-T randomised clinical trial

Background The performance of intravenous tenecteplase in patients who had an acute ischaemic stroke with large/medium vessel occlusion or severe stenosis in an extended time window remains unknown. We investigated the promise of efficacy and safety of different doses of tenecteplase manufactured in China, in patients who had an acute ischaemic stroke with large/ medium vessel occlusion beyond 4.5- hour time window. Methods The CHinese Acute tissue- Based imaging selection for Lysis In Stroke- Tenecteplase was an investigator- initiated, umbrella phase IIa, open- label, blinded- endpoint, Simon’s two- stage randomised clinical trial in 13 centres across China's Mainland. Participants who had salvageable brain tissue on automated perfusion imaging and presented within 4.5-24 hours from time of last seen well were randomised to receive 0.25 mg/ kg tenecteplase or 0.32 mg/kg tenecteplase, both with a bolus infusion over 5-10 s. The primary outcome was proportion of patients with promise of efficacy and safety defined as reaching major reperfusion without symptomatic intracranial haemorrhage at 24-48 hours after thrombolysis. Assessors were blinded to treatment allocation. All participants who received tenecteplase were included in the analysis. Results A total of 86 patients who had an acute ischaemic stroke identified with anterior large/medium vessel occlusion or severe stenosis were included in this study from November 2019 to December 2021. All of the 86 patients enrolled either received 0.25 mg/kg (n=43) or 0.32 mg/kg (n=43) tenecteplase, and were available for primary outcome analysis. Fourteen out of 43 patients in the 0.25 mg/kg tenecteplase group and 10 out of 43 patients in the 0.32 mg/kg tenecteplase group reached the primary outcome, providing promise of efficacy and safety for both doses based on Simon’s two- stage design. Discussion Among patients with anterior large/medium vessel occlusion and significant penumbral mismatch presented within 4.5-24 hours from time of last seen well, tenecteplase 0.25 mg/kg and 0.32 mg/kg both provided sufficient promise of efficacy and safety.

Movable typing of full-lumen personalized Vein-Chips to model cerebral venous sinus thrombosis

Cerebral venous sinus thrombosis(CVST)is a type of stroke associated with COVID-19 vaccine-induced immune thrombotic thrombocytopenia.The precise etiology of CVST often remains elusive due to the highly heterogeneous nature of its governing mechanisms,specifically,Virchow’s triad that involves altered blood flow,endothelial dysfunction,and hypercoagulability,which varies substantially amongst individuals.Existing diagnostic and monitoring approaches lack the capability to reflect the combination of these patient-specific thrombotic determinants.In response to this challenge,we introduce a Vein-Chip platform that recapitulates the CVST vascular anatomy from magnetic resonance venography and the associated hemodynamic flow profile using the“Chinese Movable Type-like”soft stereolithography technique.The resultant full-lumen personalized Vein-Chips,functionalized with endothelial cells,enable in-vitro thrombosis assays that can elucidate distinct thrombogenic scenarios between normal vascular conditions and those of endothelial dysfunction.The former displayed minimal platelet aggregation and negligible fibrin deposition,while the latter presented significant fibrin extrusion from platelet aggregations.The low-cost movable typing technique further enhances the potential for commercialization and broader utilization of personalized Vein-Chips in surgical labs and at-home monitoring.Future research and development in this direction will pave the way for improved management and prevention of CVST,ultimately benefiting both patients and healthcare systems.

Reflections on the Catastrophic 2019-2020 Australian Bushfires

While fire is an inherent part of the Australian landscape,the bushfires that occurred in eastern Australia from September 2019 to early February 2020 were unprecedented(Figure 1).Bushfires across the nation burned more than 12.6 million hectares(an area slightly bigger than Belgium,Denmark,and the Netherlands combined),emitted about 430 tonnes of carbon dioxide into the atmosphere(about three-quarters of the country's total annual carbon dioxide emissions),directly caused at least 33 deaths and over one billion animals were killed(https://www.abc.net.au/news/science/2020-03-05/bushfire-crisis-five-big-numbers/12007716).

儿童抽动症的评估

运动性和/或发声性抽动相对常见,可见于约1%的学龄期儿童。这也是图雷特(Tourette)综合征的特征之一,即一种持续1年以上的多种运动性抽动和一种或多种发声性抽动的神经发育障碍。抽动症常常被漏诊或误诊。

Mini-review on initiatives to interfere with the propagation and clearance of alphasynuclein in Parkinson’s disease

In this mini-review,we summarize recent findings relating to the prion-like propagation ofα-synuclein(α-syn)and the development of novel therapeutic strategies to target synucleinopathy in Parkinson’s disease(PD).We link the Braak’s staging hypothesis of PD with the recent evidence from in-vivo and in-vitro studies for the prion-like cell-to-cell propagation ofα-syn(via exocytosis and endocytosis).The classical accumulation of aggregatedα-syn in PD may result from an increased production or a failure in the mechanisms of clearance ofα-syn.We discuss novel agents,currently in clinical trial for PD including the ones that impact the aggregation ofα-syn and others that interfere withα-syn endocytosis as a means to target the progression of the disease.