Electrical Impedance Spectroscopy Quantifies Skin Barrier Function in Organotypic In Vitro Epidermis Models.

3 D human epidermal equivalents (HEEs) are a state-of-the-art organotypic culture model in pre-clinical investigative dermatology and regulatory toxicology. Here, we investigated the utility of electrical impedance spectroscopy (EIS) for non-invasive measurement of HEE epidermal barrier function. Our setup comprised a custom-made lid fit with 12 electrode pairs aligned on the standard 24-transwell cell culture system. Serial EIS measurements for seven consecutive days did not impact epidermal morphology and readouts showed comparable trends to HEEs measured only once. We determined two frequency ranges in the resulting impedance spectra: a lower frequency range termed EISdiff correlated with keratinocyte terminal differentiation independent of epidermal thickness and a higher frequency range termed EISSC correlated with stratum corneum thickness. HEEs generated from CRISPR/Cas9 engineered keratinocytes that lack key differentiation genes FLG, TFAP2A, AHR or CLDN1 confirmed that keratinocyte terminal differentiation is the major parameter defining EISdiff. Exposure to pro-inflammatory psoriasis- or atopic dermatitis-associated cytokine cocktails lowered the expression of keratinocyte differentiation markers and reduced EISdiff. This cytokine-associated decrease in EISdiff was normalized after stimulation with therapeutic molecules. In conclusion, EIS provides a non-invasive system to consecutively and quantitatively assess HEE barrier function and to sensitively and objectively measure barrier development, defects and repair.

Electrical Impedance Spectroscopy Quantifies Skin Barrier Function in Organotypic In Vitro Epidermis Models.

3 D human epidermal equivalents (HEEs) are a state-of-the-art organotypic culture model in pre-clinical investigative dermatology and regulatory toxicology. Here, we investigated the utility of electrical impedance spectroscopy (EIS) for non-invasive measurement of HEE epidermal barrier function. Our setup comprised a custom-made lid fit with 12 electrode pairs aligned on the standard 24-transwell cell culture system. Serial EIS measurements for seven consecutive days did not impact epidermal morphology and readouts showed comparable trends to HEEs measured only once. We determined two frequency ranges in the resulting impedance spectra: a lower frequency range termed EISdiff correlated with keratinocyte terminal differentiation independent of epidermal thickness and a higher frequency range termed EISSC correlated with stratum corneum thickness. HEEs generated from CRISPR/Cas9 engineered keratinocytes that lack key differentiation genes FLG, TFAP2A, AHR or CLDN1 confirmed that keratinocyte terminal differentiation is the major parameter defining EISdiff. Exposure to pro-inflammatory psoriasis- or atopic dermatitis-associated cytokine cocktails lowered the expression of keratinocyte differentiation markers and reduced EISdiff. This cytokine-associated decrease in EISdiff was normalized after stimulation with therapeutic molecules. In conclusion, EIS provides a non-invasive system to consecutively and quantitatively assess HEE barrier function and to sensitively and objectively measure barrier development, defects and repair.

A partly stage-structured model for the abundance of salmon lice in salmonid farms.

The parasitic salmon louse constrains growth in the Norwegian salmon farming industry through density dependent host-parasite interaction. Hence, there is a need for insight into how increases in salmon production, varying spatial organisation of the production and pest control strategies affect salmon louse population dynamics. Here we present a new salmon louse model for exploring effects of varying salmon farming conditions on spatio-temporal abundances of the parasite. The salmon louse model is partly stage-structured, comprising of (i) adult female lice and (ii) other mobile stages of lice. The abundance of adult females depend on survival of females from previous weeks and recruitment from the other mobile group of lice. The other mobiles also depend on survival of other mobiles from previous weeks, as well as recruitment from the previous generation of reproducing adult females from the same farm or from farms in the neighbourhood. In addition, expected abundances of the two stage-groups are modelled as functions of biological and physical covariates. The model is fitted to weekly salmon farm data covering all marine farms producing salmonids along the Norwegian cost over the years 2012-2016. Among novel results from fitting the model are estimates of the time-lag structure representing recruitment of other mobile lice from the previous generation adult females for different temperatures. Furthermore, the model estimates how various factors affect the susceptibility of fish on farms to louse infection and effects of treatments to control infection. Finally, the model estimates density dependent effects of increasing the number of fish in farms and of increasing the numbers of farms, on the rate of recruitment of other mobile lice. Analytically, the parameters representing density dependencies suggest that few farms with many fish and large between farm distances is effective in terms of minimising the overall output of salmon lice infection.

Sensitivity of Caligus rogercresseyi (Boxshall and Bravo 2000) to pyrethroids and azamethiphos measured using bioassay tests-A large scale spatial study.

The variety of antiparasitics that can be used against caligid copepods is limited and efforts are needed to maintain their efficacies. The objective of this study was to monitor the sensitivity of Caligus rogercresseyi, populations towards antiparasitics based on deltamethrin, cypermethrin and azamethiphos within and across geographic regions. The bioassay design consisted of exposing parasites collected from 23 farms to the different chemotherapeutants at the concentration and exposure times recommended for field treatment, under laboratory conditions, and evaluating the number of dead and live parasites 48h after exposure. Parasites were collected from 23 farms distributed in four macrozones in the Los Lagos region and three macrozones in the Aysén region. Parasite sensitivity was evaluated using a Generalized Linear Mixed Model of the Binomial family (Logit) fit by the maximum likelihood, using the lme4 package in R. Parasite gender, macrozone, and antiparasitics were used as fixed factors and farm was the random factor. The model including all the factors proved to be a useful tool for predicting parasite sensitivity. This approach identified (i) those macrozones with a greater likelihood of finding parasite populations which are more or less sensitive to the three antiparasitics, (ii) cases in which parasite sensitivity to the different antiparasitics varied within a given macrozone, (iii) differences in sensitivity between females and males and (iv) an important random effect associated with farm. The results indicate a spatial variability of parasite sensitivity to antiparasitics which, added to the continuous treatments applied on farms, suggest it is necessary to regularly update the sensitivity status in the macrozones. This would allow managers to improve their decision making processes regarding the type of antiparasitic to be used in a given situation. The one-concentration type bioassay performed in this study allowed us to perform a large spatial study with replicated tests of the sensitivity of C. rogercresseyi to pyrethroids and azamethiphos. Further studies should focus on the farm effects, the relationship between the sensitivity of parasites and field efficacy, as well as parasite population structure and connectivity with regard to parasite transmission between farms.

Space-time modelling of the spread of pancreas disease (PD) within and between Norwegian marine salmonid farms.

Infectious diseases are a constant threat to industrialised farming, which is characterised by high densities of farms and farm animals. Several mathematical and statistical models on spatio-temporal dynamics of infectious diseases in various farmed host populations have been developed during the last decades. Here we present a spatio-temporal stochastic model for the spread of a disease between and within aquaculture farms. The spread between farms is divided into several transmission pathways, including (i) distance related spread and (ii) other types of contagious contacts. The within-farm infection dynamics is modelled by a susceptible-infected-recovered (SIR) model. We apply this framework to model the spread of pancreas disease (PD) in salmon farming, using data covering all farms producing salmonids over 9 years in Norway. The motivation for the study was partly to unravel the spatio-temporal dynamics of PD in salmon farming and partly to use the model for scenario simulation of PD control strategies. We find, for example, that within-farm infection dynamics vary with season and we provide estimates of the timing from unobserved infection events to disease outbreaks on farms are detected. The simulations suggest that if a strategy involving culling of infectious cohorts is implemented, the number of detected disease outbreaks per year may be reduced by 57% after the full effect has been reached. We argue that the high detail and coverage of data on salmonid production and disease occurrence should encourage the use of simulation modelling as a means of testing effects of extensive control measures before they are implemented in the salmon farming industry.

Task analysis of information technology-mediated medication management in outpatient care.

AIMS: Educating physicians in the procedural as well as cognitive skills of information technology (IT)-mediated medication management could be one of the missing links for the improvement of patient safety. We aimed to compose a framework of tasks that need to be addressed to optimize medication management in outpatient care. METHODS: Formal task analysis: decomposition of a complex task into a set of subtasks. First, we obtained a general description of the medication management process from exploratory interviews. Secondly, we interviewed experts in-depth to further define tasks and subtasks. SETTING: Outpatient care in different fields of medicine in six teaching and academic medical centres in the Netherlands and the United States. PARTICIPANTS: 20 experts. Tasks were divided up into procedural, cognitive and macrocognitive tasks and categorized into the three components of dynamic decision making. RESULTS: The medication management process consists of three components: (i) reviewing the medication situation; (ii) composing a treatment plan; and (iii) accomplishing and communicating a treatment and surveillance plan. Subtasks include multiple cognitive tasks such as composing a list of current medications and evaluating the reliability of sources, and procedural tasks such as documenting current medication. The identified macrocognitive tasks were: planning, integration of IT in workflow, managing uncertainties and responsibilities, and problem detection. CONCLUSIONS: All identified procedural, cognitive and macrocognitive skills should be included when designing education for IT-mediated medication management. The resulting framework supports the design of educational interventions to improve IT-mediated medication management in outpatient care.

Within-farm spread of infectious salmon anemia virus (ISAV) in Atlantic salmon Salmo salar farms in Chile.

Spread of infectious salmon anemia virus (ISAV) at the cage level was quantified using a subset of data from 23 Atlantic salmon Salmo salar farms located in southern Chile. Data collected from official surveillance activities were systematically organized to obtain detailed information on infectious salmon anemia (ISA) outbreaks. Descriptive statistics for outbreak duration, proportion of infected fish, and time to secondary infection were calculated to quantify the magnitude of ISAV incursions. Linear and multiple failure time (MFT) regression models were used to determine factors associated with the cage-level reproduction number (Rc) and hazard rate (HR) for recurrent events, respectively. In addition, the Knox test was used to assess if cage-to-cage transmissions were clustered in space and time. Findings suggest that within farms, ISA outbreaks, on average, lasted 30 wk (median = 26 wk, 95% CI = 24 to 37 wk) and affected 57.3% (95% CI = 47.7 to 67.0%) of susceptible cages. The median time to secondarily diagnosed cages was 23 d. Occurrence of clinical ISAV outbreaks was significantly associated with increased Rc, whereas increased HR was significantly associated with clinical outbreaks and with a large number of fish. Spatio-temporal analysis failed to identify clustering of cage cases, suggesting that within-farm ISAV spread is independent of the spatial location of the cages. Results presented here will help to better understand ISAV transmission, to improve the design of surveillance programs in Chile and other regions in which salmon are intensively farmed, and to examine the economic impact of ISAV and related management strategies on various cost and demand shifting factors.

Prolonged outpatient vitamin K antagonist use and risk of venous thromboembolism in patients undergoing total hip or knee replacement.

BACKGROUND: Long-term risk of venous thromboembolism (VTE) following total hip or knee replacement (THR/TKR) compared with controls has not been studied extensively, and the long-term influence of outpatient anticoagulant use on VTE risk remains unknown. The objectives were to evaluate long-term VTE risk following THR/TKR compared with matched controls, and to investigate effect modification by prolonged outpatient vitamin K antagonist use. METHODS: A Danish retrospective nationwide cohort study was conducted. All patients undergoing primary THR/TKR (n = 95,227) between 1998 and 2007 were selected, each matched by age, sex and region with three controls (no THR/TKR). Patients were stratified by prolonged outpatient vitamin K antagonist use in the previous 3 months (in a time-dependent manner). All subjects were followed for VTE, and Cox models were used to calculate disease and medication history adjusted hazard ratios (HRs). RESULTS: Within 6 weeks following surgery, a 13-fold increased risk of VTE was found for THR (adj. HR 12.9; 95% CI 11.2-14.7), and a 14-fold elevated risk for TKR (adj. HR 13.6; 95% CI 11.0-16.7), compared with matched controls. The risk remained substantially increased for at least 4 months following THR/TKR. Within this period, prolonged outpatient vitamin K antagonist use reduced the increase in VTE risk by 69% for THR and 54% for TKR. CONCLUSION: The risk of VTE remains substantially elevated for at least 4 months following THR/TKR; this is well beyond the recommended duration of anticoagulant use. The increase in VTE risk is less pronounced in prolonged outpatient vitamin K antagonist users.

Ustekinumab improves psoriasis-related gene expression in noninvolved psoriatic skin without inhibition of the antimicrobial response.

BACKGROUND: Ustekinumab is a fully human anti-p40 monoclonal antibody which neutralizes interleukin (IL)-12 and IL-23, thereby interfering with T-helper (Th)1/Th17 pathways and keratinocyte activation, and is highly effective in the treatment of psoriasis. During ustekinumab treatment, some of our patients noticed reduced koebnerization of noninvolved skin and less new plaque formation. OBJECTIVES: To determine whether ustekinumab improves psoriasis-related gene expression and tape-strip responses in noninvolved skin. METHODS: Before and 4 weeks after ustekinumab treatment, noninvolved skin was tape-stripped. After 5 h, biopsies were taken from untouched and tape-stripped skin. The mRNA expression of psoriasis-related markers such as NGF, GATA3 and IL-22RA1, and several antimicrobial peptides (AMP) was quantified. Leucocyte counts and a broad range of inflammatory serum proteins were analysed to gain insight into the systemic alterations. RESULTS: Four weeks following a single ustekinumab injection, NGF showed a significant decrease, whereas GATA3 and IL-22RA1 expression increased, indicative of reduced responsiveness to epidermal triggering. This was accompanied by an increase of the inflammation-related serum proteins GPNMB, MST1 and TRADD. The baseline and tape-strip-induced mRNA expression of the AMP human ß-defensin-2 (hBD-2), S100A7 and LL-37 remained unaltered. Clinically, after 4 weeks, eight out of 11 patients showed a 50% psoriasis area and severity index (PASI) improvement, which was accompanied by a significant reduction in serum hBD-2 levels. No changes were noted in total leucocytes, C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: These findings indicate that ustekinumab reduces psoriasis-related gene expression in noninvolved psoriatic skin, making it more resistant to exogenous triggering, without disturbing its antimicrobial response. In parallel, ustekinumab modulates important circulating inflammation-related proteins.

Mortality related to pancreas disease in Norwegian farmed salmonid fish, Salmo salar L. and Oncorhynchus mykiss (Walbaum).

High mortality during the salmonid seawater phase is a continuous problem for the salmonid aquaculture industry, although the mortality levels show a large variation both in farms with a disease history and those without. We wanted to examine the mortality patterns in farms with pancreas disease (PD) and compare it to farms without this diagnosis. Further, we wished to investigate the factors influencing the maximum mortality in both groups. We examined data from all salmonid farms in Norway stocked after January 2003 and slaughtered before December 2007. In total, 1884 cohorts were included, and 150 of these were diagnosed with PD. We found that season accounted for more of the variation in mortality than water temperature in PD-positive cohorts and that infection pressure influenced the mortality in non-PD cohorts, suggesting outbreaks of disease that are not diagnosed. We also found that the mortality in PD cohorts decreased significantly from 2003 to 2007, suggesting that increased knowledge about PD and targeted actions have been effective. Our study further suggests that crude mortality figures may be of limited use when wanting to examine a particular disease and risk factors for increased mortality. We suggest farmers and legislation should turn to a more modern approach with cause-specific mortality records.

Development of a scalable image formation pipeline for multiscale gigapixel photography.

We report on the image formation pipeline developed to efficiently form gigapixel-scale imagery generated by the AWARE-2 multiscale camera. The AWARE-2 camera consists of 98 "microcameras" imaging through a shared spherical objective, covering a 120° x 50° field of view with approximately 40 microradian instantaneous field of view (the angular extent of a pixel). The pipeline is scalable, capable of producing imagery ranging in scope from "live" one megapixel views to full resolution gigapixel images. Architectural choices that enable trivially parallelizable algorithms for rapid image formation and on-the-fly microcamera alignment compensation are discussed.

Use of molecular epidemiology to trace transmission pathways for infectious salmon anaemia virus (ISAV) in Norwegian salmon farming.

BACKGROUND: Infectious Salmon Anaemia (ISA) is a disease affecting farmed Atlantic salmon, and most salmon producing countries have experienced ISA outbreaks. The aim of the present study was to use epidemiological and viral sequence information to trace transmission pathways for ISA virus (ISAV) in Norwegian salmon farming. METHODS: The study covers a period from January 2007 to July 2009 with a relatively high rate of ISA outbreaks, including a large cluster of outbreaks that emerged in Northern Norway (the North-cluster). Farms with ISA outbreaks and neighbouring salmon farms (At-risk-sites) were tested for the presence of ISAV, and epidemiological information was collected. ISAV hemagglutinin-esterase (HE) and fusion (F) protein genes were sequenced and phylogenetic analyses were performed. Associations between sequence similarities and salmon population data were analysed to substantiate possible transmission pathways. RESULTS: There was a high degree of genetic similarity between ISAV isolates within the North-cluster. ISAV was detected in 12 of 28 At-risk-sites, and a high proportion of the viruses were identified as putative low virulent genotypes harbouring the full length highly polymorphic region (HPR); HPR0 of the HE protein and the amino acid glutamine (Q) in the F protein at position 266. The sequences from HPR0/F (Q(266)) genotypes revealed larger genetic variation, lower viral loads and lower prevalence of infection than HPR-deleted genotypes. Seaway distance between salmon farms was the only robust explanatory variable to explain genetic similarity between ISAV isolates. DISCUSSION: We suggest that a single HPR-deleted genotype of ISAV has spread between salmon farms in the North-cluster. Furthermore, we find that HPR0/F (Q(266)) genotypes are frequently present in farmed populations of Atlantic salmon. From this, we anticipate a population dynamics of ISAV portrayed by low virulent genotypes occasionally transitioning into virulent genotypes, causing solitary outbreaks or local epidemics through local transmission.

Modelling the spread of infectious salmon anaemia among salmon farms based on seaway distances between farms and genetic relationships between infectious salmon anaemia virus isolates.

Infectious salmon anaemia (ISA) is an important infectious disease in Atlantic salmon farming causing recurrent epidemic outbreaks worldwide. The focus of this paper is on tracing the spread of ISA among Norwegian salmon farms. To trace transmission pathways for the ISA virus (ISAV), we use phylogenetic relationships between virus isolates in combination with space-time data on disease occurrences. The rate of ISA infection of salmon farms is modelled stochastically, where seaway distances between farms and genetic distances between ISAV isolates from infected farms play prominent roles. The model was fitted to data covering all cohorts of farmed salmon and the history of all farms with ISA between 2003 and summer 2009. Both seaway and genetic distances were significantly associated with the rate of ISA infection. The fitted model predicts that the risk of infection from a neighbourhood infectious farm decreases with increasing seaway distance between the two farms. Furthermore, for a given infected farm with a given ISAV genotype, the source of infection is significantly more likely to be ISAV of a small genetic distance than of moderate or large genetic distances. Nearly half of the farms with ISA in the investigated period are predicted to have been infected by an infectious farm in their neighbourhood, whereas the remaining half of the infected farms had unknown sources. For many of the neighbourhood infected farms, it was possible to point out one or a few infectious farms as the most probable sources of infection. This makes it possible to map probable infection pathways.

[Hallucinations and vivid dreams by use of metoprolol]. / Hallucinaties en levendige dromen bij metoprololgebruik.

A 71-year-old man had had visual hallucinations and vivid dreams for two years after starting to take metoprolol. When metoprolol was replaced by atenolol the patient's symptoms disappeared within five days. Side-effects of beta-blockers on the central nervous system are relatively uncommon. The mechanisms underlying these side-effects are not fully understood. Lipophilic beta-blockers can cross the blood-brain barrier, whereas hydrophilic beta-blockers cannot. Doctors need to be alerted to the varying side-effects of specific beta-blockers.

Molecular diagnostics of psoriasis, atopic dermatitis, allergic contact dermatitis and irritant contact dermatitis.

BACKGROUND: Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. OBJECTIVES: To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. METHODS: We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. RESULTS: Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, beta-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. CONCLUSIONS: These observations contribute to molecular diagnostic criteria for inflammatory skin conditions.

The course of behavioral problems in elderly nursing home patients with dementia when treated with antipsychotics.

BACKGROUND: Although antipsychotic treatment of behavioral problems in dementia is common, studies investigating the course of these symptoms in nursing homes are scarce. Our primary objective is therefore to describe the course of behavioral problems during antipsychotic treatment in a large sample of elderly nursing home patients with dementia. METHODS: The course of behavioral problems during antipsychotic treatment was studied by comparing the characteristics of patients before, during and after antipsychotic treatment. The study was conducted using the VURAIDB, a database with over 40,000 assessments of over 10,000 nursing home residents in the Netherlands. We used the Challenging Behavior Profile (CBP) to measure an overall behavior score. RESULTS: In total, 556 patients starting with antipsychotics were studied. Of these, 101 (18.2%) improved and 260 (46.8%) deteriorated at three months on the behavior score, compared with their scores before therapy (z = -7.955; P<0.0001). Patients with severe challenging behavior showed improvement more often than patients with mild disturbances. The course of behavioral symptoms after withdrawal was evaluated in 520 patients. Of these patients, 352 (68%) remained stable or improved at 3 months compared with their scores before withdrawal (z = -0.697; p = 0.486), this figure was 58% at 6 months after withdrawal (z = -2.77; p = 0.006). CONCLUSIONS: During treatment of nursing home residents with dementia with antipsychotics the severity of most behavioral problems continues to increase in most patients, with only one out of six patients showing improvement. After withdrawal of antipsychotics, behavioral problems remained stable or improved in 58% of patients.

[Cardiac effects of cholinesterase inhibitors: a reason for restraint?]. / Cardiale neveneffecten van cholinesteraseremmers: een reden tot terughoudendheid in voorschrijven?

Cholinesterase inhibitors are prescribed in the treatment of mild to moderate Alzheimer's dementia. Little is known about the cardiac safety of these drugs. We present two different cases in which cardiac events occurred during the use of a cholinesterase inhibitor. The pathophysiology, the effects of these drugs on the heart, information about the reports of side effects in pharmacovigilance databases and known literature are discussed. Although cardiac risks of cholinesterase inhibitors seem small, we advise to monitor cardiac effects of cholinesterase inhibitors carefully in patients with existing cardiac disease, especially in those using concomitant drugs known to interact with the cardiac risks of cholinesterase inhibitors.

Risk factors for pancreas disease (PD) outbreaks in farmed Atlantic salmon and rainbow trout in Norway during 2003-2007.

Pancreas disease (PD) is an emerging infectious disease in farmed Atlantic salmon (Salmo salar L.) and rainbow trout (Oncorhynchus mykiss Walbaum) caused by salmonid alphavirus (SAV). The present study is a large scale study aiming at quantifying the probability of contracting PD in farmed salmonid cohorts in Norway due to exposure to risk factors that may be associated with specific transmission pathways for SAV, or may increase a cohort's susceptibility to PD. Monthly reports of numbers of fish and mean fish weight from all marine salmonid farm sites in Norway were used to identify cohorts of farmed salmonids. Only cohorts that were initiated and terminated during 2003-2007 were assembled for the study. Records of clinical diagnosis of PD on marine farm sites were used to identify PD case cohorts. In PD case cohorts, PD-outbreaks were defined to start the month the diagnosis was recorded and last until the cohort was terminated. All cohorts in which PD was not recorded were assigned to the control-class. In total 143 PD case cohorts and 1079 control cohorts were assembled. Risk factors were assigned to the cohorts and analysed using logistic regression by generalized additive models (GAM). We find that infection pressure, a variable designed to capture the potential for local disease spread, has a strong effect on the probability of recording a PD-outbreak in a cohort. The function describing the effect of infection pressure increased steeply as infection pressure increased from 0 to moderate values corresponding to having a mean sized neighbouring fish stock with PD at a distance of 2 km, after which the function levelled off. The study emphasises horizontal transmission pathways as important for the spread of PD in Norwegian salmon farming, and accordingly that bio-security measures aimed at controlling horizontal transmission are necessary in order to reduce the number of outbreaks of PD.

Risk of cerebrovascular events in elderly users of antipsychotics.

It has been shown that elderly patients with dementia treated with atypical and conventional antipsychotics have a twofold increased risk of cerebrovascular adverse events (CVAEs). To investigate the temporal relationship between exposure to antipsychotics and the risk of CVAE, a case-control analysis nested within a cohort of 26,157 community-dwelling patients (mean age 76 +/- 9.7) with at least one antipsychotic prescription was conducted. Data were used from Dutch community pharmacies and hospital discharge records. Five hundred and eighteen cases of hospital admission for CVAE were identified. For each case, four randomly selected controls matched by sex and age were sampled from the cohort. To evaluate the temporal relationship between antipsychotic use and the occurrence of CVAE, two measures were used: the first being a current, recent or past user, and the second for the current users, the duration of use up to the index date. In addition, the cumulative exposure was assessed. Current and recent exposure to antipsychotics were associated with an increased risk of CVAE compared with non-users (odds ratio [OR] 1.7, CI 1.4-2.2). A strong temporal relationship was found; the OR for a history of use less than a week is 9.9 (5.7-17.2). The risk decreases in time and is comparable to non-users after 3 months of use (OR 1.0, CI 0.7-1.3). Cumulative exposure was not associated with an increase in risk. The risk of CVAE in elderly patients associated with antipsychotics is elevated especially during the first weeks of treatment. This risk decreases over time and is back on base level after 3 months of treatment. Chronic use is not associated with CVAE.

Integration of hydrodynamics into a statistical model on the spread of pancreas disease (PD) in salmon farming.

Pancreas disease (PD) is an emerging disease in salmon farming caused by the salmonid alphavirus (SAV). SAV is evidently spread horizontally between neighbouring salmon farms, but whether such transmission occurs by passive drift in the water current or via fomites is not known. We tested whether hydrodynamic modelling contributes to explain the spread of PD, in which case SAV is likely to spread by passive drift. We present a simple logistic regression model that accounts for the effect of PD in the neighbourhood on the probability of acquiring PD in cohorts of farmed salmonids from an area on the west coast of Norway between 2005 and 2008. For a given cohort, we calculated infection pressure (IP) based on Euclidean distance, seaway distance or estimated water contact to sites with PD, and compared the amount of variance explained in the regression model by the different variants of IP. Water contact between a discharging farm site and a receiving site was calculated by simulating particle discharge using a hydrodynamic model. IP estimated by water contact was the best predictor of PD cases and controls in the model, which performed significantly better than IP estimated by seaway distance or Euclidean distance. Since the spread of PD in the study area was best explained by modelled water velocity, we conclude that PD is likely to be spread by passive drift of SAV in the water current.