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opencc-zeroDec 2016View details →

Data from: Reducing therapeutic misconception: a randomized intervention trial in hypothetical clinical trials

Background: Participants in clinical trials frequently fail to appreciate key differences between research and clinical care. This phenomenon, known as therapeutic misconception, undermines informed consent to clinical research, but to date there have been no effective interventions to reduce it and concerns have been expressed that to do so might impede recruitment. We determined whether a scientific reframing intervention reduces therapeutic misconception without significantly reducing willingness to participate in hypothetical clinical trials. Methods: This prospective randomized trial was conducted from 2015 to 2016 to test the efficacy of an informed consent intervention based on scientific reframing compared to a traditional informed consent procedure (control) in reducing therapeutic misconception among patients considering enrollment in hypothetical clinical trials modeled on real-world studies for one of five disease categories. Patients with diabetes mellitus, hypertension, coronary artery disease, head/neck cancer, breast cancer, and major depression were recruited from medical clinics and a clinical research volunteer database. The primary outcomes were therapeutic misconception, as measured by a validated, ten-item Therapeutic Misconception Scale (range=10-50), and willingness to participate in the clinical trial. Results: 154 participants completed the study (age range, 23-87 years; 92.3% white, 56.5% female); 74 (48.1%) had been randomized to receive the experimental intervention. Therapeutic misconception was significantly lower (p=0.004) in the scientific reframing group (26.4, 95% CI [23.7 to 29.1] compared to the control group (30.9, 95% CI [28.4 to 33.5], and remained so after controlling for education (p=0.017). Willingness to participate in the hypothetical trial was not significantly different (p=0.603) between intervention (52.1%, 95% CI [40.2 to 62.4]) and control (56.3%, 95% CI [45.3 to 66.6] groups. Conclusions: An enhanced educational intervention augmenting traditional informed consent led to a meaningful reduction in therapeutic misconception without a statistically significant change in willingness to enroll in hypothetical clinical trials. Additional study of this intervention is required in real-world clinical trials.

opencc-zeroAug 2019View details →

Data from: Scalable, semi-automated fluorescence reduction neutralization assay for qualitative assessment of Ebola virus-neutralizing antibodies in human clinical samples

Antibody titers against a viral pathogen are typically measured using an antigen binding assay, such as an enzyme-linked immunosorbent assay (ELISA), which only measures the ability of antibodies to identify a viral antigen of interest. Neutralization assays measure the presence of virus-neutralizing antibodies in a sample. Traditional neutralization assays, such as the plaque reduction neutralization test (PRNT), are often difficult to use on a large scale due to being both labor and resource intensive. Here we describe an Ebola virus fluorescence reduction neutralization assay (FRNA), which tests for neutralizing antibodies, that requires only a small volume of sample in a 96-well format and is easy to automate. The readout of the FRNA is the percentage of Ebola virus-infected cells measured with an optical reader or overall chemiluminescence that can be generated by multiple reading platforms and the readout is compatible with lytic and non-lytic viruses. Using blinded human clinical samples (EVD survivors or contacts) obtained in Liberia during the 2013–2016 Ebola virus disease outbreak, we demonstrate that FRNA-measured antibody titers are highly correlated with those measured by the Filovirus Animal Non-clinical Group (FANG) ELISA - the current standard for anti-EBOV antibody measurement with the important distinction of providing information on the neutralizing capabilities of the antibodies.

Data from: Pearls & Oy-sters: challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: clinical and imaging findings

PEARLS >Gerstmann-Straussler-Scheinker disease (GSS) is a rare prion disease characterized by cerebellar ataxia with progressive cognitive decline. >GSS is caused by a mutation within the prion protein gene (PRNP), which commonly exhibits autosomal dominant inheritance pattern. However, a significant portion of previously reported cases showed no family history of the disease, and GSS may also occur through de novo mutation of PRNP. OY-STERS >GSS is clinically heterogeneous and has no characteristic features on imaging. GSS could be considered in patients experiencing unexplained ataxia and subsequent cognitive decline even in those without a family history of the disease.

Data from: Digital gene expression analyses of mammary glands from meat ewes naturally infected with clinical mastitis

Clinical mastitis in sheep has gravely restrained production performance for a long time. Knowledge of mechanisms of its pathogenesis and resistance in meat sheep mammary gland with clinical mastitis are not yet understood, especially for clinical mastitis caused by natural infection. In this work, RNA-seq was firstly used to screen differentially expressed genes (DEGs) in clinical mastitic mammary tissues (CMMTs) as compared to healthy mammary tissues (HMTs) from meat sheep flocks. We identified 420 DEGs including 316 up-regulated and 104 down-regulated genes in CMMTs. Gene Ontology annotation revealed these DEGs were mainly engaged in immune response, inflammation response, etc. Pathway enrichment showed they were primarily enriched in pathways relevant to inflammation, immune response and metabolism. Alternative splicing analysis showed most common differential splicing genes (DSGs) in CMMTs and HMTs were implicated in immune response. Immunostaining for two immune response-related proteins encoded by DEGs were mainly observed in mammary epithelium between CMMTs and HMTs, and their positive signals were more intensive in CMMTs. These findings provide experimental basis and reference for further researching the molecular genetic mechanisms particularly immune defense mechanisms of mammary gland in clinical ovine mastitis.

Data from: Setup in a clinical workflow and impact on radiotherapy routine of an in vivo dosimetry procedure with an electronic portal imaging device

High conformal techniques such as intensity-modulated radiation therapy and volumetric-modulated arc therapy are widely used in overloaded radiotherapy departments. In vivo dosimetric screening is essential in this environment to avoid important dosimetric errors. This work examines the feasibility of introducing in vivo dosimetry (IVD) checks in a radiotherapy routine. The causes of dosimetric disagreements between delivered and planned treatments were identified and corrected during the course of treatment. The efficiency of the corrections performed and the added workload needed for the entire procedure were evaluated. The IVD procedure was based on an electronic portal imaging device. A total of 3682 IVD tests were performed for 147 patients who underwent head and neck, abdomen, pelvis, breast, and thorax radiotherapy treatments. Two types of indices were evaluated and used to determine if the IVD tests were within tolerance levels: the ratio R between the reconstructed and planned isocentre doses and a transit dosimetry based on the γ-analysis of the electronic portal images. The causes of test outside tolerance level was investigated and corrected and IVD test was repeated during subsequent fraction. The time needed for each step of the IVD procedure was registered. Pelvis, abdomen, and head and neck treatments had 10% of tests out of tolerance whereas breast and thorax treatments accounted for up to 25%. The patient setup was the main cause of 90% of the IVD tests out of tolerance and the remaining 10% was due to patient morphological changes. An average time of 42 min per day was sufficient to monitor a daily workload of 60 patients in treatment. This work shows that IVD performed with an electronic portal imaging device is feasible in an overloaded department and enables the timely realignment of the treatment quality indices in order to achieve a patient's final treatment compliant with the one prescribed.

opencc-zeroDec 2011View details →

Data from: A randomised trial comparing the clinical effectiveness of different emergency department healthcare professionals in soft tissue injury management

OBJECTIVE: To evaluate the clinical effectiveness of soft tissue injury management by emergency nurse practitioners (ENPs) and extended scope physiotherapists (ESPs) compared to the routine care provided by doctors in a UK emergency department (ED). DESIGN: Randomised, pragmatic trial of equivalence. SETTING: One adult ED in England. PARTICIPANTS: 372 patients were randomised; 126 to the ESP group, 123 to the ENP group and 123 to the doctor group. Participants were adults (older than 16 years) presenting to the ED with a peripheral soft tissue injury eligible for management by any of the three professional groups. Patients were excluded if they had any of the following: injury greater than 72 hours old; systemic disease; dislocated joints; recent surgery; unable to give informed consent (eg, dementia), open wounds; major deformities; opiate analgesia required; concurrent chest/rib injury; neurovascular deficits and associated fracture. INTERVENTIONS: Patients were randomised to treatment by ESPs, ENPs or routine care provided by doctors (of all grades). MAIN OUTCOME MEASURES: Upper-limb and lower-limb functional scores, quality of life, physical well-being, preference-based health measures and the number of days off work. RESULTS: The clinical outcomes of soft tissue injury treated by ESPs and ENPs in the ED were equivalent to routine care provided by doctors. CONCLUSIONS: As all groups were clinically equivalent it is other factors such as cost, workforce sustainability, service provision and skill mix that become important. This result validates the role of the ENP, which is becoming established as an integral part of minor injuries care, and demonstrates that the ESP should be considered as part of the clinical skill mix without detriment to outcomes. ISRCTN-ISRCTN trials register number 70891354.

Data from: Risk factors for suicidality in Huntington's disease: an analysis of the 2CARE clinical trial

Most suicidality literature in HD is based on natural history studies or retrospective reviews, but reports on risk factors from clinical trials are limited. We analyzed 609 participants from 2CARE, a randomized, double-blind, placebo controlled clinical trial with up to 5 years of follow-up, for risk factors related to suicidality. The primary outcome variable was the time from randomization until the first occurrence of either suicidal ideation or attempt. We also considered time from randomization until the first suicide attempt as a secondary outcome variable. Depression, anxiety, bipolar disorder, antidepressant or anxiolytic use, and prior suicide attempt at baseline were associated with time to ideation or attempt. Baseline employment status, marital status, CAG repeat length, tetrabenazine use, and treatment assignment (coenzyme Q10 or placebo) were not associated with suicidality. Time-dependent variables from the UHDRS Behavioral Assessment were associated with time to suicidal ideation or attempt, driven mainly by items related to depressed mood, low self-esteem/guilt, anxiety, suicidal thoughts, irritability, and compulsions. Variables associated with time to suicide attempt alone were generally similar. These data suggest psychiatric co-morbidities in HD are predictive of suicidal behavior while participating in clinical trials, reinforcing the importance of clinical surveillance and treatment towards lessening risk during participation and perhaps beyond. Designing a composite algorithm for early prediction of suicide attempts in HD may be of value, particularly given anticipated trials aimed at disease modification are likely to be long-term.

Data from: Difficult patient-doctor encounters in a Swiss university outpatient clinic: a cross-sectional study.

Introduction: Previous research has shown that multiple factors contribute to healthcare providers perceiving encounters as difficult, and are related to both medical and non-medical demands. Aim: To measure the prevalence and to identify predictors of encounters perceived as difficult by medical residents. Design and Setting: Cross-sectional study at the Department of Ambulatory Care and Community Medicine (DACCM), a university outpatient clinic with a long tradition of caring for vulnerable patients. Method: We identified difficult doctor-patient encounters using the validated Difficult Doctor-Patient Relationship Questionnaire (DDPRQ-10), and characterized patients using the Patient's Vulnerability Grid, a validated questionnaire measuring 5 domains of vulnerability, both completed by medical residents after each encounter. We used a multiple linear regression model with the outcome variable as the DDPRQ-10 score, controlling for resident characteristics. Participants: We analyzed 527 patient encounters performed by all 27 DACCM residents (17 women and 10 men). We asked each medical resident to evaluate 20 consecutive consultations starting on the same date. Outcome: One hundred and fifty-seven encounters (29,8%) were perceived as difficult. Results: After adjusting for differences among residents, all five domains of the Patient Vulnerability Grid were independently associated with a difficult encounter: frequent health care user; psychological comorbidity; health comorbidity; risky behaviors and a precarious social situation. Conclusion: Nearly a third of encounters were perceived as difficult by medical residents in our university outpatient clinic that cares for a high proportion of vulnerable patients. This represents twice the average ratio of difficult encounters in general practice. All five domains of patient vulnerability appear to have partial explanatory power on medical residents' perception of difficult patient encounters.

opencc-zeroDec 2016View details →

Data from: Known mutator alleles do not markedly increase mutation rate in clinical Saccharomyces cerevisiae strains

Natural selection has the potential to act on all phenotypes, including genomic mutation rate. Classic evolutionary theory predicts that in asexual populations, mutator alleles, which cause high mutation rates, can fix due to linkage with beneficial mutations. This phenomenon has been demonstrated experimentally and may explain the frequency of mutators found in bacterial pathogens. By contrast, in sexual populations, recombination decouples mutator alleles from beneficial mutations, preventing mutator fixation. In the facultatively sexual yeast Saccharomyces cerevisiae, segregating alleles of MLH1 and PMS1 have been shown to be incompatible, causing a high mutation rate when combined. These alleles had never been found together naturally, but were recently discovered in a cluster of clinical isolates. Here we report that the incompatible mutator allele combination only marginally elevates mutation rate in these clinical strains. Genomic and phylogenetic analyses provide no evidence of a historically elevated mutation rate. We conclude that the effect of the mutator alleles is dampened by background genetic modifiers. Thus, the relationship between mutation rate and microbial pathogenicity may be more complex than once thought. Our findings provide rare observational evidence that supports evolutionary theory suggesting that sexual organisms are unlikely to harbour alleles that increase their genomic mutation rate.

Data from: Automatic recognition of self-acknowledged limitations in clinical research literature

Objective: To automatically recognize self-acknowledged limitations in clinical research publications to support efforts in improving research transparency. Materials and Methods: To develop our recognition methods, we used a set of 8,431 sentences from 1,197 PubMed Central articles. A subset of these sentences was manually annotated for training/testing and inter-annotator agreement was calculated. We cast the recognition problem as a binary classification task, in which we determine whether a given sentence from a publication discusses self-acknowledged limitations or not. We experimented with three methods: a rule-based approach based on document structure, supervised machine learning, and a semi-supervised method that uses self-training to expand the training set in order to improve classification performance. The machine learning algorithms used were logistic regression (LR) and support vector machines (SVM). Results: Annotators had good agreement in labeling limitation sentences (Krippendorff's α=0.781). Of the three methods used, the rule-based method yielded the best performance with 91.5% accuracy (95% CI [90.1-92.9]), while self-training with SVM led to a small improvement over fully supervised learning (89.9%, 95% CI [88.4-91.4] vs. 89.6%, 95% CI [88.1-91.1]). Discussion: We attribute the effectiveness of the rule-based method to the highly localized and formulaic language used in reporting of limitations in clinical research publications. Experiments with training size and composition show that more data does not necessarily lead to higher accuracy in the machine learning-based approaches. Conclusion: The approach presented can be incorporated into the workflows of stakeholders focusing on research transparency to improve reporting of limitations in clinical studies.

opencc-zeroDec 2014View details →

Data from: DNA methylation combinations in adjacent normal colon tissue predict cancer recurrence: evidence from a clinical cohort study

Accumulating evidence has suggested the requirement for further stratification of patients in the same tumor stage according to molecular factors. We evaluate the combination of cancer stage and DNA methylation status as an indicator of the risk of recurrence and mortality among patients with colorectal cancer (CRC). A cohort study of 215 patients with CRC (mean age 64.32 years; 50.5% of men) from Tri-Service General Hospital in Taiwan examined the association between cancer stage and risk of CRC recurrence and mortality. A Cox proportional hazard model was used to analyze patient methylation status and clinical information at study entry, and their associations with CRC recurrence and mortality during follow-up. The advanced stage patients with p16, hMLH1, and MGMT methylation were associated with higher risk of CRC recurrence compared with the local stage patients with unmethylation status in tumor tissues, with adjusted hazard ratios (HRs) (95% confidence interval [CI]) of 9.64 (2.92–31.81), 8.29 (3.40–20.22), and 11.83 (3.49–40.12), respectively. When analyzing normal tissues, we observed similar risk of CRC recurrence with adjusted HRs (95% CI) of 10.85 (4.06–28.96), 9.04 (3.79–21.54), and 12.61 (4.90–32.44), respectively. For combined analyses, the risk of recurrence in the patients in advanced stage with DNA methylation in both normal and tumor tissues, compared with local stage with unmethylation, was increased with adjusted HR (95% CI) of 9.37 (3.36–26.09). In the advanced stage patients, methylation status and tissue subtype were associated with increased risk of 5-year cumulative CRC recurrence (p < 0.001). This study demonstrates that clustering DNA methylation status according to cancer stage and tissue subtype is critical for the assessment of risk of recurrence in CRC patients and also indicated an underlying mechanism.

opencc-zeroDec 2015View details →

Data from: Clinical and metabolic characteristics among Mexican children with different types of diabetes mellitus

Background: Current classification of diabetes mellitus (DM) is based on etiology and includes type 1 (T1DM), type 2 (T2DM), gestational, and other. Clinical and pathophysiological characteristics of T1DM and T2DM in the same patient have been designated as type 1.5 DM (T1.5DM). Objectives: The aim of this study was to classify pediatric patients with DM based on pancreatic autoimmunity and the presence or absence of overweight/obesity, and to compare the clinical, anthropometric, and biochemical characteristics between children in the different classes of DM. Methods: A sample of 185 patients, recruited (March 2008-April 2015) as part of the Cohort of Mexican Children with DM (CMC-DM); ClinicalTrials.gov, identifier: NCT02722655. The DM classification was made considering pancreatic autoimmunity (via antibodies GAD-65, IAA, and AICA) and the presence or absence of overweight/obesity. Clinical, anthropometric and biochemical variables, grouped by type of DM were compared (Kruskal-Wallis or chi-squared test). Results: The final analysis included 140 children; 18.57% T1ADM, 46.43% T1BDM, 12.14% T1.5DM, and 22.86% T2DM. Fasting C-Peptide (FCP), and hs-CRP levels were higher in T1.5DM and T2DM, and the greatest levels were observed in T1.5DM (p<0.001 and 0.024 respectively). Conclusions: We clearly identified that the etiologic mechanisms of T1DM and T2DM are not mutually exclusive, and we detailed why FCP levels are not critical for the classification system of DM in children. The findings of this study suggest that T1.5DM should be considered during the classification of pediatric DM and might facilitate more tailored approaches to treatment, clinical care and follow-up.

opencc-zeroSep 2019View details →

Data from: Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis

Objective: To assess the onset of ocrelizumab efficacy on brain magnetic resonance imaging (MRI) measures of disease activity in the Phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled Phase III studies in relapsing multiple sclerosis (RMS). Methods: Brain MRI activity was determined in the Phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the Phase III OPERA I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN β-1a (44 μg). Results: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by Week 4 vs placebo (p=0.042) and by Week 8 vs intramuscular IFN β-1a (p<0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between Weeks 4 and 8 vs both placebo and IFN β-1a (both p<0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p=0.005), and the probability of time to first protocol-defined relapse (p=0.014) vs subcutaneous IFN β-1a within the first 8 weeks. Conclusion: Epoch analysis of MRI-measured lesion activity in the Phase II study and relapse rate in the Phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively. Classification of evidence: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

Data from: Clinical spectrum and risk factors associated with asymptomatic erosive esophagitis as determined by Los Angeles classification: a cross-sectional study

Background: Gastro esophageal reflux disease (GERD) is a chronic and recurrent disease, and it varies in regions. However, to date, there are no reports available on clinical features and the risk factors for the asymptomatic reflux esophagitis in Nepalese adults. Methods: Data were gathered from 142 erosive patients who had undergone endoscopy at Bir Hospital, Kathmandu. Los Angeles classification was used to grade the severity of the disease. Patients were interviewed to find out the presence of various reflux symptoms. Results: Based on the Los Angeles classification, the severity of the disease assessed was; grade A 31.8% (31/142), grade B 39.4 % (56/142), grade C 33.8% (48/142), and grade D 4.9% (7/142). One hundred and twenty six (88.7%) subjects had reflux symptoms. Prevalence of asymptomatic esophagits was 16(11.3%). Age was independently linked to asymptomatic esophagitis (P<0.05), and the odd of being asymptomatic appeared lower in younger adults (P<0.05; OR: 0.118; CI: 0.014-.994). Conclusion: A low prevalence of asymptomatic reflux esophagits (RE) was seen. Most subjects experienced mild to moderate RE. Age remained an independent factors associated with reflux esophagitis, and the odd of being asymptomatic was lower in younger age.

opencc-zeroJun 2019View details →

Data from: Hyperandrogenism and insulin resistance-induced fetal loss: evidence for placental mitochondrial abnormalities and elevated ROS production in pregnant rats that mimic the clinical features of PCOS

Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS‐induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α‐dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin‐treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over‐production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed SOD1 and Keap1/Nrf2 antioxidant responses constitute important contributors to fetal loss in DHT+insulin‐treated pregnant rats. Many of the molecular pathways leading to placental abnormalities and fetal loss in DHT+insulin treatment were also seen in pregnant rats treated with DHT alone, whereas pregnant rats treated with insulin alone often exerted distinct effects on placental gene expression compared to insulin treatment in combination with DHT. We also found that treatment with the antioxidant N‐acetylcysteine (NAC) improved fetal survival in DHT+insulin‐treated pregnant rats, an effect related to changes in Keap1/Nrf2 and NFκB signaling. However, NAC administration resulted in fetal loss in normal pregnant rats, most likely due to PCOS‐like endocrine abnormality induced by the treatment. Our results suggest that the deleterious effects of hyperandrogenism and insulin resistance on fetal survival are related to a constellation of mitochondrial‐ROS‐SOD1/Nrf2 changes in the placenta. Our findings also suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.

opencc-zeroDec 2015View details →

Data from: Biofilm morphotypes and population structure among Staphylococcus epidermidis from commensal and clinical samples

Bacterial species comprise related genotypes that can display divergent phenotypes with important clinical implications. Staphylococcus epidermidis is a common cause of nosocomial infections and, critical to its pathogenesis, is its ability to adhere and form biofilms on surfaces, thereby moderating the effect of the host's immune response and antibiotics. Commensal S. epidermidis populations are thought to differ from those associated with disease in factors involved in adhesion and biofilm accumulation. We quantified the differences in biofilm formation in 98 S. epidermidis isolates from various sources, and investigated population structure based on ribosomal multilocus typing (rMLST) and the presence/absence of genes involved in adhesion and biofilm formation. All isolates were able to adhere and form biofilms in in vitro growth assays and confocal microscopy allowed classification into 5 biofilm morphotypes based on their thickness, biovolume and roughness. Phylogenetic reconstruction grouped isolates into three separate clades, with the isolates in the main disease associated clade displaying diversity in morphotype. Of the biofilm morphology characteristics, only biofilm thickness had a significant association with clade distribution. The distribution of some known adhesion-associated genes (aap and sesE) among isolates showed a significant association with the species clonal frame, with the exception of. These data challenge the assumption that biofilm-associated genes, such as those on the ica operon, are genetic markers for less invasive S. epidermidis isolates, and suggest that phenotypic characteristics, such as adhesion and biofilm formation, are not fixed by clonal descent but are influenced by the presence of various genes that are mobile among lineages.

Data from: Clinical reasoning: a 14-year-old girl with headache, seizures, and confusion

In this report, we characterized describe a 14-year-old girl who developed progressive cerebral venous sinus thrombosis (CVST) and, with multiple organs and systems disfunction in 7 days which are similar to Marfan Syndrome in partial clinical characteristics. Through clinical phenotype and gene detection information, During our workup we uncovered we found two novel compound heterozygous mutations of cystathionine beta-synthase (CBS) gene, c.551 T>C and c.949 A>G, leading to hyperhomocysteinemia (HHcy). This, which suggested an irreplaceable correlation in likely led to her CVST and was a well answer for the multiple organs and systems failure in the case multiorgan dysfunction. This case highlights that (1) HHcy is of great clinical significance in CVST young patients; and (2) for patients with HHcy, excluding all exogenous factors of HHcy such as dietary deficiency of vitamins, genetic factors. neurologists should recognize the potential genetic component to this disorder, especially when there is a strong family history and multisystem failure, should be paid much more attention, especially accompanied with multiple organs and systems disfunction and/or patient family history.

Data from: Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients.

Background: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation was developed. As this formulation results in improved systemic absorption, the pharmacokinetic and toxicological profile of flubendazole administered with this formulation have been assessed to ensure human safety before clinical trials could be initiated. Methods & Findings: Safety pharmacology, toxicity and genotoxicity studies have been conducted with the flubendazole ASD formulation. In animals, flubendazole has good oral bioavailability from an ASD formulation ranging from 15 % in dogs, 276 % in rats to more than 100% in jirds. In in vivo toxicity studies with the ASD formulation, high systemic exposure to flubendazole and its main metabolites was reached. Flubendazole, up to high peak plasma concentrations, does not induce Cmax related effects in the CNS or cardiovascular system. In repeated dose toxicity studies in rats and dogs, flubendazole-induced changes were observed in haematological, lymphoid and gastrointestinal systems and in testes. In dog, the liver was an additional target organ. Upon treatment cessation, at least partial recovery was observed for these changes in the dog. In rat, the low dose was the No Observed Adverse Effect Level (NOAEL) was , i.e. 5 mg (as base)/kg body weight/day (mg eq./kg/day)mg eq./kg/day in males and 2.5 mg eq./kg/day in females. In dog, the NOAEL was lower than the low dose, 20 mg eq./kg/day. Regarding genotoxicity, flubendazole was negative in the Ames test but positive in the in vivo micronucleus test. Conclusions: Based on these results, in combination with previously described genotoxicity and reproductive toxicity data and the outcome of the preclinical efficacy studies, it was concluded that no flubendazole treatment regimen can be selected that would provide efficacy in humans at safe exposure.