Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for ß-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. METHODS: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. DISCUSSION: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Activated ClpP kills persisters and eradicates a chronic biofilm infection.

Chronic infections are difficult to treat with antibiotics but are caused primarily by drug-sensitive pathogens. Dormant persister cells that are tolerant to killing by antibiotics are responsible for this apparent paradox. Persisters are phenotypic variants of normal cells and pathways leading to dormancy are redundant, making it challenging to develop anti-persister compounds. Biofilms shield persisters from the immune system, suggesting that an antibiotic for treating a chronic infection should be able to eradicate the infection on its own. We reasoned that a compound capable of corrupting a target in dormant cells will kill persisters. The acyldepsipeptide antibiotic (ADEP4) has been shown to activate the ClpP protease, resulting in death of growing cells. Here we show that ADEP4-activated ClpP becomes a fairly nonspecific protease and kills persisters by degrading over 400 proteins, forcing cells to self-digest. Null mutants of clpP arise with high probability, but combining ADEP4 with rifampicin produced complete eradication of Staphylococcus aureus biofilms in vitro and in a mouse model of a chronic infection. Our findings indicate a general principle for killing dormant cells-activation and corruption of a target, rather than conventional inhibition. Eradication of a biofilm in an animal model by activating a protease suggests a realistic path towards developing therapies to treat chronic infections.

Modelling the effect of spatially variable soil properties on the distribution of weeds.

The patch spraying of weeds is an area of precision agriculture that has had limited uptake. This is in part due to the perceived risks associated with not controlling individual weeds. Nevertheless, the inherent patchiness of weeds makes them ideal targets for site-specific management. We propose using a mechanistic model to identify areas of a field vulnerable to invasion by weeds, allowing the creation of treatment maps that are risk averse. We developed a spatially-explicit mechanistic model of the life-cycle of Alopecurus myosuroides, a particularly problematic weed of cereal crops in the UK. In the model, soil conditions which vary across the field, affect the life-cycle of A. myosuroides. The model was validated using data on the within-field distribution of A. myosuroides on commercial farms and its co-location with soil properties. We demonstrate the important role played by soil properties in determining the within-field distribution of A. myosuroides. We also show that scale-dependent correlations between A. myosuroides and soil properties observed in the field are an emergent property of the modelled dynamics of the A. myosuroides life-cycle. Our model could therefore support effective site-specific management of A. myosuroides within fields by predicting areas that are vulnerable to A. myosuroides. The usefulness of this model in its ability to predict patch locations for A. myosuroides highlights the possibility of using similar models for other species where data are available on the response of the species to various soil properties.

Exploring the Interface of Oncology and Palliative Care in Ireland

Aims To explore the integration and delivery of oncology led referrals to palliative care (PC) by examining physician attitudes and referral practices. Methods An online survey was circulated to oncologists and PC physicians in Ireland. Results The study (N = 100) comprised sixty-nine oncologists (69%) and thirty-one PC physicians (31%). Ninety-two(92%) believe patients with advanced cancer should receive concurrent treatment, however only 53% of oncologists(N = 37) routinely refer. Regarding end-of-life (EOL) care: 81% of oncologists (N = 55) are directly involved in its administration, despite 84% (N = 53) agreeing patients benefit when PC specialists coordinate EOL care. Conclusion The gulf between positive attitudes and limited implementation suggests the need for interdisciplinary changes to facilitate integration of PC in clinical practice in Ireland.

Rash management and treatment persistence of cancer patients treated with epidermal growth factor receptor inhibitors in the Truven MarketScan® research database.

PURPOSE: Rash toxicity is a common, expected class effect of epidermal growth factor receptor (EGFR) inhibitors. Although rash management is practiced, it is not well characterized in the real-world setting. We describe the management of rash that developed while receiving EGFR-inhibitor therapy and how rash affects treatment duration, using Truven MarketScan® Research Database, a US medical claims database. METHODS: Adult patients who received EGFR-inhibitor treatment between 2004 and 2015 after a diagnosis of colon, head and neck, lung, breast, or thyroid cancer were identified. Descriptive analyses were conducted to describe occurrence of rash during the EGFR-inhibitor treatment period, EGFR-inhibitor treatment persistence and management of rash, including treatment and cost. RESULTS: Of 44,533 eligible patients, 4649 (10.4%) had records of rash during the EGFR-inhibitor treatment period, and of patients experiencing rash, 2891 (62.2%) received prescription drugs for rash treatment. Treatment persistence with an EGFR inhibitor was longer among patients experiencing rash compared with no rash (median 178 vs. 80 days for EGFR-TKIs, 85 vs. 57 days for EGFR-monoclonal antibodies), especially among patients with rash who were treated for rash (208 days for EGFR-tyrosine kinase inhibitors, 104 days for EGFR- monoclonal antibodies). Annualized cost during EGFR-inhibitor treatment was lowest among patients not experiencing rash (US$185,619), followed by rash patients receiving drugs for rash management (US$215,561), and highest among rash patients not treated for rash (US$267,105). CONCLUSION: Our findings suggest that management of EGFR inhibitor-associated rash could be important for EGFR-inhibitor treatment persistence.

Changes in soil organic matter over 70 years in continuous arable and ley-arable rotations on a sandy loam soil in England.

The sequestration in soil of organic carbon (SOC) derived from atmospheric carbon dioxide (CO2) by replacing arable crops with leys, has been measured over 70 years on a sandy loam soil. The experiment was designed initially to test the effect of leys on the yields of arable crops. A 3-year grazed grass with clover (grass + clover) ley in a 5-year rotation with arable crops increased percentage organic carbon (%OC) in the top 25 cm of the soil from 0.98 to 1.23 in 28 years, but with little further increase during the next 40 years with all-grass leys given fertilizer nitrogen (N). In this second period, OC inputs were balanced by losses, suggesting that about 1.3% OC might be near the equilibrium content for this rotation. Including 3-year lucerne (Medicago sativa) leys had little effect on %OC over 28 years, but after changing to grass + clover leys, %OC increased to 1.24 during the next 40 years. Eight-year leys (all grass with N or grass + clover) in 10-year rotations with arable crops were started in the 1970s, and after three rotations %OC had increased to ca. 1.40 in 2000-2009. Over 70 years, %OC declined from 0.98 to 0.94 in an all-arable rotation with mainly cereals and to 0.82 with more root crops. Applications of 38 t ha-1 farmyard manure (FYM) every fifth year increased %OC by 0.13% by the mid-1960s when applications ceased. Soil treated with FYM still contained 0.10% more OC in 2000-2009. Changes in the amount of OC have been modelled with RothC-26.3 and estimated inputs of C for selected rotations. Little of the OC input during the 70 years has been retained; most was retained in the grazed ley rotation, but 9 t ha-1 only of a total input of 189 t ha-1. In other rotations more than 98% of the total OC input was lost. Despite large losses of C, annual increases in OC of 4‰ are possible on this soil type with the inclusion of grass or grass + clover leys or the application of FYM, but only for a limited period. Such increases in SOC might help to limit increases in atmospheric CO2. HIGHLIGHTS: Can leys sequester significant amounts of atmospheric CO 2 in SOM and contribute to the 4‰ initiative?Changes in the percentage and amount of OC were measured and modelled over 70 years and OC losses estimated.Three-year grass or grass + clover leys increased %OC, but only to an equilibrium level that was then maintained.Despite large losses, sequestering CO 2-C at 4‰ year-1 by growing grass or grass + clover leys is possible.

Antenatal Pertussis Vaccination: Why are General Practitioners Reluctant? A Mixed Methods StudySetting.

Pertussis has a disproportionately higher morbidity and mortality in infants less than 3 months of age. International and national guidelines recommend pertussis vaccination during pregnancy, as a safe and effective way to protect these infants. Antenatal pertussis vaccination uptake rates remain suboptimal, with many health care professionals (HCPs) still not recommending it. The reasons underlying this reluctance on behalf of HCPs have not been fully established. This study aims to evaluate the current practice and attitudes of General Practitioners (GPs) with regard to antenatal pertussis vaccination. An embedded mixed method design was used. The response rate was 41% (n=109). 54% of GPs who responded (n=59) routinely recommend antenatal pertussis vaccination. Safety concerns and a sense of isolation emerged as the major qualitative themes. More safety data, adequate funding from the Health Service Executive (HSE) and support from secondary care may help to increase the GP recommendation rate and enhance vaccination uptake in pregnancy.

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen.

BACKGROUND: Cetuximab, in combination with platinum chemotherapy plus 5-fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations. METHODS: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment-emergent adverse events (TEAEs). RESULTS: The majority of patients experienced ≥ 1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4%; Arm B: 68/71 patients, 95.8%). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95% confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95% CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms. CONCLUSIONS: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01081041 ; date of registration: March 3, 2010).

Pressure ulcer healing with an intensive nutrition intervention in an acute setting: a pilot randomised controlled trial.

OBJECTIVE: To investigate the feasibility of recruitment, retention, intervention delivery and outcome measurement in a nutritional intervention to promote pressure ulcer healing in an acute setting. METHOD: Some 50 tertiary hospital patients with stage II or greater pressure ulcer were randomised to receive either individualised nutritional care by a dietitian, including prescription of wound healing supplements; or standard nutritional care. Relevant nutritional and pressure ulcer (PU) parameters were collected at day 5, 10, 15, 22 and then weekly or until discharge. RESULTS: The median length of hospital stay was 14 days (1-70) with 29 patients discharged by day 15. There were 24 patients discharged before their PU fully healed. Per cent change in valid PU area and score measures from baseline to day 15 were chosen for outcome data analysis to account for varying initial size and severity of the wound and length of stay. There was a larger percentage reduction in PU measures in the intervention group, but this was not statistically significant. Little difference was found in nutritional intake between the control and intervention groups indicating a requirement to focus on effective delivery of the intervention in future studies. Future studies in the acute setting need to account for length of stay and ideally follow patients until full healing. CONCLUSION: Results indicate a positive association with nutrition intervention and PU healing and that a rigorously designed and adequately powered study is feasible. DECLARATION OF INTEREST: This research was supported by a grant from the Queensland Health, Health Practitioner Research Scheme. The authors have no conflicts of interest to declare.

The effect of pulsing movements on the physiological response to common exercises.

AIM: There is a paucity of research on responses to exercises using pulsatile movements (PM) compared to using a full range of motion (FM). The purpose of the present study was to compare the physiological responses to PM vs. FM exercises. METHODS: Eight participants completed two separate exercise sessions, comprised of three sets of 20 repetitions for five different exercises. During the FM trial, all repetitions were performed using a full range of motion. In the PM trial, half of the repetitions were performed using pulsing movements. Average VO2, total VO2, HR and RPE were compared using paired t-tests. Blood lactate [La-] responses were compared using repeated measures analysis of variance. RESULTS: Average VO2 in the PM trial (1.52±0.38 L min-1) was similar to the FM trial (1.57±0.43 L min-1). However, total VO2 (PM=23.1±6.6 L, FM=27.2±6.9 L), average HR (PM=134.4 ± 10.9, FM=146.2±14.6 beats per min) and RPE (PM=12.2±0.9, FM=13.3±0.9) were significantly (P<0.05) lower for the PM trial. There were no significant differences in blood [La-] response (PM pre=1.7±0.8, post=6.1±0.8 mmol L-1; FM pre=1.6±0.4, post=6.8±0.5 mmol L-1). CONCLUSION: FM exercises elicit higher HR and RPE responses compared to PM exercises; without corresponding increases in metabolic rate.

Changes in motor activity level in individuals with frontotemporal dementia.

Changes in motor activity are common in individuals with Frontotemporal dementia (FTD). Yet, it remains unclear why some individuals become motorically hyperactive, while others hypoactive even in early stages of the disease. This study aimed to examine the relationship between motor activity level and (1) FTD clinical subtype, and (2) cortical thickness and subcortical volumes. Eighty-two charts were retrospectively reviewed from patients meeting consensus criteria for one of the three main clinical subtypes of FTD: probable bvFTD, semantic variant Primary Progressive Aphasia (PPA), or non-fluent variant PPA. Participants were assigned to one of three groups: (1) hyperactive, (2) hypoactive, or (3) no record of change. Hyperactivity was prevalent among bvFTD (58.5%) and semantic PPA (68.8%) subtypes while hypoactivity was less common in both subtypes (29.3% and 18.8%, respectively). The majority of patients with non-fluent PPA showed no record of change in motor activity (66.7%). The analysis of cortical thickness and subcortical volumes did not identify significant associations with motor activity levels. In conclusion, increased motor activity is highly prevalent among individuals with FTD, especially bvFTD and svPPA subtypes. These findings may inform prognosis and prediction of changes in motor activity, and allow planning for appropriate environmental and behavioural interventions. Future studies with prospective, standardized longitudinal collection of information regarding the type and level of change in motor activity, including wearable measures of actigraphy, may help to further delineate the onset and progression of abnormal motor behaviours and determine neuroanatomic associations in FTD.

Pathophysiology of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease leading to dementia worldwide. While neuritic plaques consisting of aggregated amyloid-beta proteins and neurofibrillary tangles of accumulated tau proteins represent the pathophysiologic hallmarks of AD, numerous processes likely interact with risk and protective factors and one's culture to produce the cognitive loss, neuropsychiatric symptoms, and functional impairments that characterize AD dementia. Recent biomarker and neuroimaging research has revealed how the pathophysiology of AD may lead to symptoms, and as the pathophysiology of AD gains clarity, more potential treatments are emerging that aim to modify the disease and relieve its burden.

Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study.

PURPOSE: Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCß and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. METHODS: Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg p.o. daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m(2) i.v. Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. RESULTS: Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3-4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3ß trended toward greater OS with GE treatment. CONCLUSIONS: OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer.

OBJECTIVE: The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). METHODS: Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1,000 mg/m(2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m(2) plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m(2) every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. RESULTS: Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P=.199). Despite high censoring rates (>52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P=.013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR=1.22; 95% CI=0.99-1.52; P=.067). CONCLUSIONS: GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

Pre-validation of SENS-IS assay for in vitro skin sensitization of medical devices.

According to ISO 10993-1:2018, the skin sensitization potential of all medical devices must be evaluated, and for this endpoint ISO 10993-10:2010 recommends the use of in vivo assays. The goal of the present study was to determine if the in vitro SENS-IS assay could be a suitable alternative to the current in vivo assays. The SENS-IS assay uses the Episkin Large and SkinEthic RHE reconstructed human epidermis models to evaluate marker genes. In our study, the SENS-IS assay correctly identified 13 sensitizers spiked in a non-polar solvent. In a subsequent analysis six medical device silicone samples previously impregnated with sensitizers were extracted with polar and non-polar solvents. The SENS-IS assay correctly identified five of these extracts, while a sixth extract, which contained the weak sensitizer phenyl benzoate, was classified as negative. However, when this extract was concentrated, or a longer exposure time was used, the assay was able to detect phenyl benzoate. The SENS-IS assay was transferred to a naïve laboratory which correctly identified sensitizers in six blinded silicone samples, including the one containing phenyl benzoate. In light of these results, we conclude that the SENS-IS assay is able to correctly identify the presence of sensitizers in medical devices extracts.

Measles transmission in immunized and partially immunized air travellers.

Most cases of measles in Australia are associated with travel or acquired from travellers from overseas. This study presents a series of three secondary cases of measles acquired through contact with a case of infectious measles acquired in China. Two of the cases were fully immunized siblings sitting eight rows behind the index case on a 4(1/2)-h flight from Singapore. The third case was acquired in the airport where the index case was in transit. The report highlights the travel-associated risk of measles and discusses the heredity of vaccine-induced measles immunity.

A review of general surgery resident experience in common bile duct exploration in the ERCP era.

BACKGROUND: Use of minimally invasive techniques for management of common bile duct (CBD) stones has led to declining number of CBD explorations (CBDE) performed at teaching and non-teaching institutions. We evaluate the impact of this decline on surgery training in bile duct procedures. STUDY DESIGN: National operative data for general surgery residents (GSR) were examined from 2000 to 2018. Biliary operations including, cholecystectomy open and laparoscopic, and CBDE open and laparoscopic were evaluated for mean number of cases per graduating GSR. RESULTS: Despite increases in number of GSR, case numbers for laparoscopic cholecystectomy increased 39% from 84 to 117, p < .00001, per GSR. Mean number of cases for open CBDE, however, decreased 74% from 2.7 to 0.7, p < .00001, per GSR and laparoscopic CBDE declined 22% from 0.9 to 0.7 per resident. CONCLUSION: GSR operative case volume in CBDE has declined significantly creating a training deficiency for this complex skill. Novel simulation, including fresh cadavers, may offer the best option with high-fidelity, dynamic training to mitigate the loss of low volume, high acuity procedures.

Reverse genetic approaches for the development of Zika vaccines and therapeutics.

In 2015-2016, the little known Zika virus (ZIKV) caused an epidemic, in which it became recognized as a unique human pathogen associated with a range of devastating congenital abnormalities collectively categorized as congenital Zika syndrome (CZS). In adults, the virus can trigger the autoimmune disorder Guillain-Barré syndrome (GBS), characterized by ascending paralysis. In February 2016, the World Health Organization (WHO) declared ZIKV to be a Public Health Emergency of International Concern. The global public health problem prompted academia, industry, and governments worldwide to initiate development of an effective vaccine to prevent another ZIKV epidemic that would put millions at risk. The development of reverse genetic systems for the study and manipulation of RNA viral genomes has revolutionized the field of virology, providing platforms for vaccine and antiviral development. In this review, we discuss the impact of reverse genetic systems on the rapid progress of ZIKV vaccines and antiviral therapeutics.

Sources of viral respiratory infections in Canadian acute care hospital healthcare personnel.

BACKGROUND: Viral respiratory illnesses are common causes of outbreaks and can be fatal to some patients. AIM: To investigate the association between laboratory-confirmed viral respiratory infections and potential sources of exposure during the previous 7 days. METHODS: In this nested case-control analysis, healthcare personnel from nine Canadian hospitals who developed acute respiratory illnesses during the winters of 2010/11-2013/14 submitted swabs that were tested for viral pathogens. Associated illness diaries and the weekly diaries of non-ill participants provided information on contact with people displaying symptoms of acute respiratory illness in the previous week. Conditional logistic regression assessed the association between cases, who were matched by study week and site with controls with no respiratory symptoms. FINDINGS: There were 814 laboratory-confirmed viral respiratory illnesses. The adjusted odds ratio (aOR) of a viral illness was higher for healthcare personnel reporting exposures to ill household members [7.0, 95% confidence interval (CI) 5.4-9.1], co-workers (3.4, 95% CI 2.4-4.7) or other social contacts (5.1, 95% CI 3.6-7.1). Exposures to patients with respiratory illness were not associated with infection (aOR 0.9, 95% CI 0.7-1.2); however, healthcare personnel with direct patient contact did have higher odds (aOR 1.3, 95% CI 1.1-1.6). The aORs for exposure and for direct patient contact were similar for illnesses caused by influenza. CONCLUSION: Community and co-worker contacts are important sources of viral respiratory illness in healthcare personnel, while exposure to patients with recognized respiratory infections is not associated. The comparatively low risk associated with direct patient contact may reflect transmission related to asymptomatic patients or unrecognized infections.

Cloned fragment A of diphtheria toxin is expressed and secreted into the periplasmic space of Escherichia coli K12.

An 831-base pair segment of the corynebacteriophage beta tox-45 genome encoding fragment A of diphtheria toxin was cloned into plasmid pUC8 in Escherichia coli K12. Strains containing recombinant plasmids expressed the adenosine diphosphate ribosyl transferase activity characteristic of fragment A; this activity could be inhibited by polyvalent antiserum to fragment A as well as by the appropriate monoclonal antibodies to diphtheria toxin. The transferase activity was secreted into the periplasmic space of E. coli. These findings have implications for the future construction of genetically engineered chimeric toxins.