Controlled before-after intervention study of suburb-wide street changes to increase walking and cycling: Te Ara Mua-Future Streets study design.

BACKGROUND: Achieving a shift from car use to walking, cycling and public transport in cities is a crucial part of healthier, more environmentally sustainable human habitats. Creating supportive active travel environments is an important precursor to this shift. The longevity of urban infrastructure necessitates retrofitting existing suburban neighbourhoods. Previous studies of the effects of street changes have generally relied on natural experiments, have included few outcomes, and have seldom attempted to understand the equity impacts of such interventions. METHODS: In this paper we describe the design of Te Ara Mua - Future Streets, a mixed-methods, controlled before-after intervention study to assess the effect of retrofitting street changes at the suburb scale on multiple health, social and environmental outcomes. The study has a particular focus on identifying factors that improve walking and cycling to local destinations in low-income neighbourhoods and on reducing social and health inequities experienced by Maori (Indigenous New Zealanders) and Pacific people. Qualitative system dynamics modelling was used to develop a causal theory for the relationships between active travel, and walking and cycling infrastructure. On this basis we selected outcomes of interest. Together with the transport funder, we triangulated best evidence from the literature, transport policy makers, urban design professionals and community knowledge to develop interventions that were contextually and culturally appropriate. Using a combination of direct observation and random sample face to face surveys, we are measuring outcomes in these domains of wellbeing: road-user behaviour, changes to travel mode for short trips, physical activity, air quality, road traffic injuries, greenhouse gas emissions, and perceptions of neighbourhood social connection, safety, and walking and cycling infrastructure . DISCUSSION: While building on previous natural experiments, Te Ara Mua - Future Streets is unique in testing an intervention designed by the research team, community and transport investors together; including a wide range of objective outcome measures; and having an equity focus. When undertaking integrated intervention studies of this kind, a careful balance is needed between epidemiological imperatives, the constraints of transport funding and implementation and community priorities, while retaining the ability to contribute new evidence for healthy, equitable transport policy. The study was retrospectively registered as a clinical trial on 21 June 2018 in the ISCRTN registry: ISRCTN89845334 http://www.isrctn.com/ISRCTN89845334.

Safety of topical administration of nasal decongestants and vasoconstrictors in paediatric nasal surgery - A systematic review.

OBJECTIVES: Topical intranasal decongestants are essential in nasal surgery to improve operative field. There are concerns regarding safety in paediatric population. Data on safety and safe dosage are limited. This systematic review evaluated the literature on safety and dosage of intranasal decongestant in paediatric population. METHODS: We performed a systematic search of PubMed, EMBASE, Cochrane library for relevant articles. Quality assessment was done on included articles. RESULTS: A total of 10 articles were included: five case reports; three observational studies; and two randomised control trials. Decongestants evaluated were phenylephrine, oxymetazoline, epinephrine, xylometazoline, and cocaine. In total, 209 patients were included. Side effects reported included bradycardia, tachycardia and hypertension. These were mostly self-limiting and of no clinical compromise to the patients. A total of 4/209 (1.9%) of patients required treatment for these reported effects. No mortality was reported in the included studies. CONCLUSION: In the paediatric population, the literature suggests that when delivered in a pre-specified, controlled dosage, the haemodynamic effects of phenylephrine, oxymetazoline, xylometazoline are minimal and of no clinical significance. There is scope for further studies to establish safe dosage in the paediatric population given the paucity of current literature.

Determining levels of fecal incontinence in the community: a New Zealand cross-sectional study.

BACKGROUND: Fecal incontinence is a socially stigmatized condition, and its prevalence in the community has been problematic to quantify because of difficulty with its definition. OBJECTIVE: This study estimates the community prevalence of fecal incontinence in New Zealand by 3 scales of measurement: patient perceptions of a "problem with bowel control," their symptoms, and their quality of life. DESIGN/MAIN OUTCOME MEASURES: A postal survey of 2000 people, aged >18, randomly selected from the national electoral roll, was performed. This used a validated, reliability-tested, anonymous questionnaire, the Comprehensive Fecal Incontinence Questionnaire, incorporating the identification of a "problem with bowel control," the Fecal Incontinence Severity Index, and the Fecal Incontinence Quality of Life Scale. RESULTS: The response rate was 68.7%. A total of 14.7% (95% CI: 12.6-16.7) of participants "felt they had a problem with bowel control" and 12.4% (95% CI: 10.5-14.5) had fecal incontinence when defined using the Fecal Incontinence Severity Index table as "leakage of liquid or solid stool ≥ 1/month." In terms of quality of life, 26.8% of the population (95% CI: 24.2-29.4) noted some impairment on the Fecal Incontinence Quality of Life Scale. In total, 155 (13.2%) participants reported at least 2 of the 3 possible diagnostic measures, and this may provide a way to incorporate the 3 measures into a new definition of fecal incontinence. LIMITATIONS: This study incorporated a new "generic" question enquiring about an individual's perception of a bowel control problem and also introduced a "cutoff" value for Fecal Incontinence Quality of Life Scale to attempt to identify those with any impairment "due to accidental bowel leakage." CONCLUSIONS: This study helps to highlight some of the challenges involved with suitably identifying those who have fecal incontinence within the community. The prevalence rate of 13.2% represents a realistic measure of the burden of fecal incontinence in the general population, and further research in this area is recommended.

Penetrating paediatric thoracic injury.

Paediatric penetrating chest trauma is common in conflict, but rarely seen in peacetime. We describe the successful hospital management of a five year old female civilian casualty with life threatening penetrating thoracic trauma caused by a fragment from an explosive device.

Prophylactic total gastrectomy (PTG) for hereditary diffuse gastric cancer (HDGC): the Newfoundland experience with 23 patients.

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) results from truncating mutations of the CDH1 (E-cadherin) gene. It is an autosomal dominant cancer susceptibility syndrome with a lifetime risk of diffuse gastric cancer (DGC) of 60-80%, with a mean age of onset of 37 years. There exists no adequate screening test for DGC. Early intramucosal diffuse/signet-ring cell carcinomas have been found in prophylactic total gastrectomy (PTG) specimens following normal preoperative endoscopy. Total gastrectomy has been advocated on a prophylactic basis. The aim of this study was to report our experience with PTG in 23 patients from the Canadian province of Newfoundland and Labrador. This is the largest series worldwide. METHODS: A retrospective study of consecutive patients undergoing PTG for HDGC was performed. All patients were confirmed to have a truncating mutation of the CDH1 gene. RESULTS: Twenty-three patients underwent PTG between February 2006 and November 2008. Major complications were found in 4/23 patients (17%), with no mortality. Two of 23 patients (9%) had positive mucosal biopsies on preoperative EGD. Twenty-two of 23 patients (96%) had evidence of diffuse/signet-ring carcinoma on final standardized pathological evaluation. Therefore, 21/23 (91%) were not picked up by preoperative EGD screening. CONCLUSIONS: PTG can be performed in patients with HDGC with a low rate of serious complications. Methods of reconstruction incorporating a pouch reservoir and preservation of the postgastric branches of the vagus nerves need to be explored. More refined penetrance estimates, effective screening protocols, and long-term psychological and functional outcomes following PTG require organized multicenter collaborative efforts.

Hereditary diffuse gastric cancer: cancer risk and the personal cost of preventive surgery.

Germline CDH1 mutation carriers are at risk for early-onset diffuse gastric cancer (DGC) and female carriers have an additional risk of lobular breast cancer. The reported literature GC risk of 70% has led to the recommendation for germline mutation carriers to undergo prophylactic total gastrectomy (PTG). The objective of this research was to examine post-surgical clinical outcomes and to identify which of the domains/symptoms from the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30) were determinants of overall quality of life (QOL) in individuals undergoing PTG. Participants were recruited through multiple sources. Postsurgical clinical outcomes were obtained from hospital records. Participants completed validated questionnaires measuring generic and condition specific QOL (PROMIS, EORTC and SF 36v.II) at a single point in time. The mean QOL in this cohort was 70.6 (SD = 25.6), which is better than reference values from the general populations in USA and Canada Role and social function plus the symptoms anxiety, pain, taste, dyspnea and diarrhea were significant predictor variables for QOL (p < 0.05). Although this study reveals good overall QOL for individuals after PTG, attention should be given to managing symptoms as part of long term care to further enhance QOL. The function/symptom scores were associated with worse overall health and global health status and thus may mark a real need for more attentive post-surgical care.

Prp8 in a Reduced Spliceosome Lacks a Conserved Toggle that Correlates with Splicing Complexity across Diverse Taxa.

Conformational rearrangements are critical to regulating the assembly and activity of the spliceosome. The spliceosomal protein Prp8 undergoes multiple conformational changes during the course of spliceosome assembly, activation, and catalytic activity. Most of these rearrangements of Prp8 involve the disposition of the C-terminal Jab-MPN and RH domains with respect to the core of Prp8. Here we use x-ray structural analysis to show that a previously characterized and highly conserved ß-hairpin structure in the RH domain that acts as a toggle in the spliceosome is absent in Prp8 from the reduced spliceosome of the red alga Cyanidioschyzon merolae. Using comparative sequence analysis, we show that the presence or absence of this hairpin corresponds to the presence or absence of protein partners that interact with this hairpin as observed by x-ray and cryo-EM studies. The presence of the toggle correlates with increasing intron number suggesting a role in the regulation of splicing.

A Canadian guideline on the use of next-generation sequencing in oncology.

Rapid advancements in next-generation sequencing (ngs) technology have created an unprecedented opportunity to decipher the molecular profile of tumours to more effectively prevent, diagnose, and treat cancer. Oncologists now have the option to order molecular tests that can guide treatment decisions. However, to date, most oncologists have received limited training in genomics, and they are now faced with the challenge of understanding how such tests and their interpretation align with patient management. Guidance on how to effectively use ngs technology is therefore needed to aid oncologists in applying the results of genomic tests. The Canadian guideline presented here describes best practices and unmet needs related to ngs-based testing for somatic variants in oncology, including clinical application, assay and sample selection, bioinformatics and interpretation of reports performed by laboratories, patient communication, and clinical trials.

The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world.

Eastern Canadian Colorectal Cancer Consensus Conference 2017.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2017 was held in St. John's, Newfoundland and Labrador, 28-30 September. Experts in radiation oncology, medical oncology, surgical oncology, and cancer genetics who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of gastric, rectal, and colon cancer, including ■ identification and management of hereditary gastric and colorectal cancer (crc);■ palliative systemic therapy for metastatic gastric cancer;■ optimum duration of preoperative radiation in rectal cancer-that is, short- compared with long-course radiation;■ management options for peritoneal carcinomatosis in crc;■ implications of tumour location for treatment and prognosis in crc; and■ new molecular markers in crc.

Harmonisation of European tests for serological diagnosis of Brucella infection in bovines.

The principal methods for the serological diagnosis of bovine brucellosis are the complement fixation test (CFT), serum agglutination test (SAT), Rose-Bengal test (RBT), indirect enzyme-linked immunosorbent assay (iELISA) and more recently the competitive ELISA (cELISA) and the fluorescent polarisation assay (FPA). Guidelines set by the World Organisation for Animal Health (OIE) describe methods and diagnostic thresholds for each of these tests. Many countries have adopted these methods for the purposes of eradication of brucellosis and have legislated for the use of these tests (the CFT and SAT in particular) for the prevention of the spread of the disease through international trade. Within the European Union (EU) each member state has a National Reference Laboratory which regulates the quality of brucellosis diagnosis and works to the recommendations set by the OIE. This article describes the results from the first three EU ring trials assessing the harmonisation of diagnostic tests between each member state. The general level of harmony for SAT, CFT, and iELISA was found to be good, but issues of standardisation of the RBT, cELISA and FPA remain. The cELISA and FPA in particular need further work to create European harmony. The ring trials also proved successful at providing specific evidence of poor performance in some areas. The decision on whether or not to take action on the basis of these results rested with the individual laboratories concerned. The increase in the number of participants in these trials over time reflected the enlargement of the EU and increased the need for quality assurance.

Conserved structure of Snu13 from the highly reduced spliceosome of Cyanidioschyzon merolae.

Structural and functional analysis of proteins involved in pre-mRNA splicing is challenging because of the complexity of the splicing machinery, known as the spliceosome. Bioinformatic, proteomic, and biochemical analyses have identified a minimal spliceosome in the red alga Cyanidioschyzon merolae. This spliceosome consists of only 40 core proteins, compared to ∼ 70 in S. cerevisiae (yeast) and ∼ 150 in humans. We report the X-ray crystallographic analysis of C. merolae Snu13 (CmSnu13), a key component of the assembling spliceosome, and present evidence for conservation of Snu13 function in this algal splicing pathway. The near identity of CmSnu13's three-dimensional structure to yeast and human Snu13 suggests that C. merolae should be an excellent model system for investigating the structure and function of the conserved core of the spliceosome.

Kinetic analysis of the M1 RNA folding pathway.

The biological activity of large RNAs is dependent on the formation of complex folded structures that determine function. Typically the creation of such structures requires divalent magnesium and in many cases the folding process takes place over the course of several minutes. It has been proposed that the folding paths of large RNAs proceed through discrete intermediates but the nature of these intermediates is not known in most cases. Here, we describe our studies on the folding of the M1 RNA sub-unit of Escherichia coli RNase P. We performed kinetic footprinting studies of M1 RNA folding with the chemical footprinting reagent peroxynitrous acid to provide a detailed description of the folding pathway of RNase P RNA. Our results indicate that, in contrast to the Group I ribozyme, the M1 RNA folds into its catalytically active structure through the formation of two separately folded domains and that the folding of each proceeds through a discrete series of intermediates. Similar rates of folding were observed for regions believed to form the interface between the two domains. This observation is consistent with a kinetic trap which occurs by interaction of the domains during folding.

Evidence for helical unwinding of an RNA substrate by the RNA enzyme RNase P: use of an interstrand disulfide crosslink in substrate.

To gain an understanding of structural changes induced in substrates by Escherichia coli ribonuclease P (RNase P), we have incorporated an interstrand disulfide crosslink proximal to the cleavage site in a model substrate. RNase P is able to process the reduced, non-crosslinked form of this substrate as well as a substrate in which the free thiol molecules have been alkylated with iodoacetamide. However, the oxidized, crosslinked form is cleaved at a significantly lower rate. Therefore, helical unwinding of the analog of the aminoacyl stem of the substrate near its site of cleavage may be necessary for efficient processing by E. coli RNase P.

Validation of FPA and cELISA for the detection of antibodies to Brucella abortus in cattle sera and comparison to SAT, CFT, and iELISA.

The fluorescence polarisation assay (FPA) is a recently described test for the serological diagnosis of Brucella infection. It has many methodological advantages over older, more established tests and can be performed in a fraction of the time. To validate the FPA, serum samples from 146 confirmed (by culture) Brucella-infected cattle were tested in conjunction with serum samples from 1947 noninfected cattle. The competitive ELISA (cELISA) was validated using these positive reference samples and 1440 negative samples, while data for the indirect ELISA (iELISA) was generated from 6957 negative samples plus the positive sera. Published diagnostic specificity (DSp) data for the complement fixation test (CFT) and serum agglutination test (SAT) was used in conjunction with the test results on the positive sera to obtain diagnostic specificity plus diagnostic sensitivity (DSn). After selection of a cutoff for the FPA and cELISA, the diagnostic specificity and sensitivity total for each test were compared. The results, with 95% confidence intervals, were: FPA (195.7+/-2.79), iELISA (195.0+/-2.70), cELISA (194.9+/-3.48), CFT (191.7+/-4.45), and SAT (180.4+/-6.33). The data presented supports the use of the FPA in diagnosis of brucellosis and questions the use of the SAT and CFT for either screening or confirmatory testing.

The effect of halofenate or halofenate free acid on human, rat and guinea pig platelet aggregation.

Halofenate free acid (HFA), the major metabolite of the hypolipemic agent halofenate, blocked the secondary phase of human platelet aggregation induced by ADP, epinephrine, or thrombin; higher concentrations of clofibrate free acid (CFA) were required to produce similar inhibitory effects on platelet aggregation. HFA and CFA inhibited collagen-induced aggregation of human, rat, or guinea pig platelets. Halofenate orally administered to rats caused inhibition of collagen-induced aggregation when plasma levels of HFA exceeded 300 mug/ml, a clinically achievable human plasma concentration. The platelet inhibitory effects of clofibrate administration were less than those observed with halofenate administration.

Minoxidil overdose.

A 52-year-old man ingested 60 ml of 2 percent topical minoxidil solution resulting in severe hypotension and tachycardia. He was resuscitated with intravenously administered crystalloid solution and treated with intravenously administered dopamine, resulting in a partial hemodynamic improvement. Further treatment with intravenously administered phenylephrine infusion resulted in resolution of hypotension. The patient suffered a non-Q-wave myocardial infarction as a result of the ingestion. The toxicity of this increasingly common preparation is profound.