Conceptualising migraine attacks from a biopsychosocial model using qualitative and functional behavioural analysis.

OBJECTIVE: The aim of this study was to explore patients' experiences and management of pain in connection with a migraine attack in episodic migraine. DESIGN, SETTING AND SUBJECTS: This qualitative study used a semi-structured interview format based on functional behavioural analysis as commonly used in cognitive behavioural therapy. We interviewed eight participants and analysed their responses using systematic text condensation. RESULTS: Participants' descriptions of their experiences and management of pain from episodic migraine were sorted into three description First physical sensations, Automatic reactions and Acts according to the interpretation. CONCLUSION: From a biopsychosocial perspective, a migraine attack is much more complex than just an experience of pain. The purely biological pain prompts a number of automatic reactions leading to strategies for pain management.

Functional behavioural analysis can increase our understanding of experiences during a migraine attack from a biopsychosocial pain perspective.Several pain mechanisms appear to be relevant during the experience of a migraine attack than are described in the diagnostic criteria for migraine.Pain management consists of a chain of behaviours, approaches to the migraine attack and medication and the consequences of pain management.Knowledge and understanding of patients' experiences of pain and pain management during a migraine attack is an important tool in the biopsychosocial model.

Legacy and emerging organohalogenated compounds in feathers of Eurasian eagle-owls (Bubo bubo) in Norway: Spatiotemporal variations and associations with dietary proxies (δ13C and δ15N).

The occurrence of organohalogenated compounds (OHCs) in wildlife has received considerable attention over the last decades. Among the matrices used for OHCs biomonitoring, feathers are particularly useful as they can be collected in a minimally or non-invasive manner. In this study, concentrations of various legacy OHCs -polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs)-, as well as emerging OHCs -per- and polyfluoroalkyl substances (PFAS) and organophosphate ester flame retardants (OPEs)- were determined in feathers of 72 Eurasian eagle-owls (Bubo bubo) from Norway, with the goal of studying spatiotemporal variation using a non-invasive approach. Molted feathers were collected at nest sites from northern, central and southern Norway across four summers (2013-2016). Additionally, two museum-archived feathers from 1979 to 1989 were included. Stable carbon (δ13C) and nitrogen isotopes (δ15N) were used as dietary proxies. In total, 11 PFAS (sum range 8.25-215.90 ng g-1), 15 PCBs (4.19-430.01 ng g-1), 6 OCPs (1.48-220.94 ng g-1), 5 PBDEs (0.21-5.32 ng g-1) and 3 OPEs (4.49-222.21 ng g-1) were quantified. While we observed large variation in the values of both stable isotopes, suggesting a diverse diet of the eagle-owls, only δ13C seemed to explain variation in PFAS concentrations. Geographic area and year were influential factors for δ15N and δ13C. Considerable spatial variation was observed in PFAS levels, with the southern area showing higher levels compared to northern and central Norway. For the rest of OHCs, we observed between-year variations; sum concentrations of PCBs, OCPs, PBDEs and OPEs reached a maximum in 2015 and 2016. Concentrations from 1979 to 1989 were within the ranges observed between 2013 and 2016. Overall, our data indicate high levels of legacy and emerging OHCs in a top predator in Norway, further highlighting the risk posed by OHCs to wildlife.

Effects of patient-driven iCBT for anxiety in routine primary care and the relation between increased experience of empowerment and outcome: A randomized controlled trial.

BACKGROUND: The World Health Organization has declared that primary care should be organized to empower individuals, families, and communities to optimize health. Internet cognitive behavioral therapy (iCBT) tailored by psychologists' initial assessments to meet patients' specific needs have shown promising effects. However, few studies have evaluated patient involvement in decisions during iCBT. AIM: This study aimed to explore the effect of patient-driven iCBT compared to standard iCBT on perceived control over treatment, adherence, and level of anxiety symptoms. A secondary aim was to assess the relationship between changes in empowerment and changes in anxiety symptoms. METHOD: Participants were patients recruited form primary care and assessed as meeting the criterion for an anxiety disorder. Participants were randomized to patient-driven iCBT (n = 27) or standard iCBT (n = 28). Patient-driven iCBT was adapted to participants' preferences regarding for example focus of treatment program and order of modules. Participants randomized to the control condition received the standard iCBT program for anxiety disorders at the participating unit. The outcome measures were patients' perceived control over treatment, adherence to treatment, symptoms of anxiety, depression and general disability as well as the experience of empowerment. RESULTS: Participants in patient-driven iCBT had statistically higher perceived control over treatment (t(43) = 2.13, p = .04). Symptoms were significantly reduced in both arms with regards to anxiety, depression, and general disability. A significant time per condition interaction effect for anxiety symptoms was observed (df = 45.0; F = 3.055; p = .038), where the patient-driven condition had a significantly larger reduction in anxiety. For both groups a significant correlation of r = -0.47 was found between changes in empowerment and changes in anxiety. CONCLUSION: Results indicate that iCBT that is patient-driven, may have a greater effect on anxiety, than standard iCBT. The effect on perceived control over treatment might also be larger in patient-driven treatments than in standard iCBT. Internet-based therapies inherently promote as active agents of their own care and might be well suited for promoting perceived control and empowerment. Findings need to be replicated given the small sample size and the explorative nature of the study. CLINICAL TRIALS REGISTRATION: NCT04688567.

Primary Human Hepatocyte Spheroid Model as a 3D In Vitro Platform for Metabolism Studies.

3D cultures of primary human hepatocytes (PHH) are emerging as a more in vivo-like culture system than previously available hepatic models. This work describes the characterisation of drug metabolism in 3D PHH spheroids. Spheroids were formed from three different donors of PHH and the expression and activities of important cytochrome P450 enzymes (CYP1A2, 2B6, 2C9, 2D6, and 3A4) were maintained for up to 21 days after seeding. The activity of CYP2B6 and 3A4 decreased, while the activity of CYP2C9 and 2D6 increased over time (P < 0.05). For six test compounds, that are metabolised by multiple enzymes, intrinsic clearance (CLint) values were comparable to standard in vitro hepatic models and successfully predicted in vivo CLint within 3-fold from observed values for low clearance compounds. Remarkably, the metabolic turnover of these low clearance compounds was reproducibly measured using only 1-3 spheroids, each composed of 2000 cells. Importantly, metabolites identified in the spheroid cultures reproduced the major metabolites observed in vivo, both primary and secondary metabolites were captured. In summary, the 3D PHH spheroid model shows promise to be used in drug discovery projects to study drug metabolism, including unknown mechanisms, over an extended period of time.

Forecasting drug utilization and expenditure: ten years of experience in Stockholm.

BACKGROUND: Operating under constrained budgets, payers and providers globally face challenges in enabling appropriate and sustainable access to new medicines. Among payer initiatives aiming to improve preparedness of healthcare systems for the introduction of new medicines, drug utilization and expenditure forecasting has played an increasingly important role. This study aims to describe the forecasting model used in Region Stockholm and to evaluate the accuracy of the forecasts produced over the past decade. METHODS: In this repeated cross-sectional study, we compared the predicted pharmaceutical expenditure with actual expenditure during the entire available follow-up period (2007-2018) both for overall drug utilization and for individual therapeutic groups. All analyses were based on pharmaceutical expenditure data that include medicines used in hospitals and dispensed prescription medicines for all residents of the region. RESULTS: According to the forecasts, the total pharmaceutical expenditure was estimated to increase between 2 and 8% annually. Our analyses showed that the accuracy of these forecasts varied over the years with a mean absolute error of 1.9 percentage points. Forecasts for the same year were more accurate than forecasts for the next year. The accuracy of forecasts also differed across the therapeutic areas. Factors influencing the accuracy of forecasting included the timing of the introduction of both new medicines and generics, the rate of uptake of new medicines, and sudden changes in reimbursement policies. CONCLUSIONS: Based on the analyses of all forecasting reports produced since the model was established in Stockholm in the late 2000s, we demonstrated that it is feasible to forecast pharmaceutical expenditure with a reasonable accuracy. A number of factors influencing the accuracy of forecasting were also identified. If forecasting is used to provide data for decisions on budget allocation and agreements between payers and providers, we advise to update the forecast as close as possible prior to the decision date.

Health care use, drug treatment and comorbidity in patients with schizophrenia or non-affective psychosis in Sweden: a cross-sectional study.

BACKGROUND: This study investigated the prevalence of schizophrenia (ICD-10 F 20) and of other non-affective psychosis (NAP, ICD-10 F 21 - F 29) in Sweden. It further assessed health care use, comorbidity and medication for these patient groups. Most studies either have a study population of patients with strictly defined schizophrenia or a psychosis population of which strict schizophrenia cases form a smaller set. The present study permits comparison of the two mutually exclusive patient groups using data at the individual level in the diagnosis of non-affective psychosis, use of health care, medical treatment and comorbidity by diagnosis or medical treatment. METHODS: In 2012, data were extracted from a regional registry containing patient-level data on consultations, hospitalisations, diagnoses and dispensed drugs for the total population in the region of Stockholm (2.1 million inhabitants). The size of the total psychosis population was 18,769, of which 7284 had a diagnosis of schizophrenia. Crude prevalence rates and risk rates with 95% confidence intervals were calculated. RESULTS: In 2012, the prevalence of schizophrenia and NAP was 3.5/1000 and 5.5/1000, respectively. Schizophrenia was most common among patients aged 50-59 years and NAP most common among patients aged 40-49 years. Schizophrenia patients used psychiatric health care more often than the NAP patients but less overall inpatient care (78.6 vs. 60.0%). The most prevalent comorbidities were substance abuse/dependence (7.9% in the schizophrenia group vs. 11.7% in the NAP group), hypertension (7.9 vs. 9.7%) and diabetes (6.9 vs. 4.8%). The parenteral form of long-acting injectable antipsychotics was more often dispensed to patients with schizophrenia (10 vs. 2%). CONCLUSIONS: This study, analysing all diagnoses recorded in a large health region, confirmed prevalence rates found in previous studies. Schizophrenia patients use more psychiatric and less overall inpatient health care than NAP patients. Differences between the two patient groups in comorbidity and drug treatment were found. The registered rates of a substance abuse/dependence diagnosis were the most common comorbidity observed among the patients investigated. The observed differences between the schizophrenia and the NAP patients in health care consumption, comorbidity and drug treatment are relevant and warrant further studies.

The Early Awareness and Alert System in Sweden: History and Current Status.

Introduction: Over the past decades, early awareness and alert (EAA) activities and systems have gained importance and become a key early health technology assessment (HTA) tool. While a pioneer in HTA, Sweden had no national level EAA activities until 2010. We describe the evolution and current status of the Swedish EAA System. Methods: This was a historical analysis based on the knowledge and experience of the authors supplemented by a targeted review of published and gray literature as well as documents relating to EAA activities in Sweden. Key milestones and a description of the current state of the Swedish EAA System is presented. Results: Initiatives to establish a system for the identification and assessment of emerging health technologies in Sweden date back to the 1980s. In the 1990s, the Swedish Agency for HTA and Assessment of Social Services (SBU) supported the development of EuroScan as one of its founder members. In the mid-2000s, an independent regional initiative, driven by the Stockholm County Drug and Therapeutics Committee, resulted in the establishment of a regional horizon scanning function. By 2009, this work had expanded to a collaboration between the four biggest counties in Sweden. The following year it was further expanded to the national level and since then the Swedish EAA System has been carrying out identification, filtration and prioritization of new medicines, early assessment of the prioritized medicines, and dissemination of information. In 2015, the EAA System was incorporated into the Swedish national process for managed introduction and follow-up of new medicines. Outputs from the EAA System are now used to select new medicines for inclusion in this process. Conclusions: The Swedish EAA System started as a regional initiative and rapidly grew to become a national level activity. An important feature of the system today is its complete integration into the national process for managed introduction and follow-up of new medicines. The system will continue to evolve as a response both to the changing landscape of health innovations and to new policy initiatives at the regional, national and international level.

Operational strategies to manage non-elective orthopaedic surgical flows: a simulation modelling study.

OBJECTIVES: To explore the value of simulation modelling in evaluating the effects of strategies to plan and schedule operating room (OR) resources aimed at reducing time to surgery for non-elective orthopaedic inpatients at a Swedish hospital. METHODS: We applied discrete-event simulation modelling. The model was populated with real world data from a university hospital with a strong focus on reducing waiting time to surgery for patients with hip fracture. The system modelled concerned two patient groups that share the same OR resources: hip-fracture and other non-elective orthopaedic patients in need of surgical treatment. We simulated three scenarios based on the literature and interaction with staff and managers: (1) baseline; (2) reduced turnover time between surgeries by 20 min and (3) one extra OR during the day, Monday to Friday. The outcome variables were waiting time to surgery and the percentage of patients who waited longer than 24 hours for surgery. RESULTS: The mean waiting time in hours was significantly reduced from 16.2 hours in scenario 1 (baseline) to 13.3 hours in scenario 2 and 13.6 hours in scenario 3 for hip-fracture surgery and from 26.0 hours in baseline to 18.9 hours in scenario 2 and 18.5 hours in scenario 3 for other non-elective patients. The percentage of patients who were treated within 24 hours significantly increased from 86.4% (baseline) to 96.1% (scenario 2) and 95.1% (scenario 3) for hip-fracture patients and from 60.2% (baseline) to 79.8% (scenario 2) and 79.8% (scenario 3) for patients with other non-elective patients. CONCLUSIONS: Healthcare managers who strive to improve the timelines of non-elective orthopaedic surgeries may benefit from using simulation modelling to analyse different strategies to support their decisions. In this specific case, the simulation results showed that the reduction of surgery turnover times could yield the same results as an extra OR.

Influence of pre-existing inflammation on the outcome of acute coronary syndrome: a cross-sectional study.

OBJECTIVES: Inflammation is a well-established risk factor for the development of coronary artery disease (CAD) and acute coronary syndrome (ACS). However, less is known about its influence on the outcome of ACS. The aim of this study was to determine if blood biomarkers of inflammation were associated specifically with acute myocardial infarction (MI) or unstable angina (UA) in patients with ACS. DESIGN: Cross-sectional study. SETTING: Patients admitted to the coronary care unit, via the emergency room, at a central county hospital over a 4-year period (1992-1996). PARTICIPANTS: In a substudy of Carlscrona Heart Attack Prognosis Study (CHAPS) of 5292 patients admitted to the coronary care unit, we identified 908 patients aged 30-74 years, who at discharge had received the diagnosis of either MI (527) or UA (381). MAIN OUTCOME MEASURES: MI or UA, based on the diagnosis set at discharge from hospital. RESULTS: When adjusted for smoking, age, sex and duration of chest pain, concentrations of plasma biomarkers of inflammation (high-sensitivity C reactive protein>2 mg/L (OR=1.40 (1.00 to 1.96) and fibrinogen (p for trend=0.035)) analysed at admission were found to be associated with MI over UA, in an event of ACS. A strong significant association with MI over UA was found for blood cell markers of inflammation, that is, counts of neutrophils (p for trend<0.001), monocytes (p for trend<0.001) and thrombocytes (p for trend=0.021), while lymphocyte count showed no association. Interestingly, eosinophil count (p for trend=0.003) was found to be significantly lower in patients with MI compared to those with UA. CONCLUSIONS: Our results show that, in patients with ACS, the blood cell profile and degree of inflammation at admission was associated with the outcome. Furthermore, our data suggest that a pre-existing low-grade inflammation may dispose towards MI over UA.

The influence of smoking and impaired glucose homoeostasis on the outcome in patients presenting with an acute coronary syndrome: a cross-sectional study.

OBJECTIVES: Smoking, diabetes, male sex, hypercholesterolaemia and hypertension are well-established risk factors for the development of coronary artery disease (CAD). However, less is known about their role in influencing the outcome in the event of an acute coronary syndrome (ACS). The aim of this study was to determine if these risk factors are associated specifically with acute myocardial infarction (MI) or unstable angina (UA) in patients with suspected ACS. DESIGN: Cross-sectional study. SETTING: Patients admitted to the coronary care unit, via the emergency room, at a central county hospital over a 4-year period (1992-1996). PARTICIPANTS: From 5292 patients admitted to the coronary care unit, 908 patients aged 30-74 years were selected, who at discharge had received the diagnosis of either MI (527) or UA (381). A control group consisted of 948 patients aged 30-74 years in whom a diagnosis of ACS was excluded. MAIN OUTCOME MEASURES: MI or UA. RESULTS: Current smoking (OR 2.42 (1.61 to 3.62)), impaired glucose homoeostasis defined as glycated haemoglobin ≥5.5% + blood glucose ≥7.5 mM (OR 1.78 (1.19 to 2.67)) and male sex (OR 1.71 (1.21 to 2.40)) were significant factors predisposing to MI over UA, in the event of an ACS. Compared with the non-ACS group, impaired glucose homoeostasis, male sex, cholesterol level and age were significantly associated with development of an ACS (MI and UA). Interestingly, smoking was significantly associated with MI (OR 2.00 (1.32 to 3.02)), but not UA. CONCLUSIONS: Smoking or impaired glucose homoeostasis is an acquired risk factor for a severe ACS outcome in patients with CAD. Importantly, smoking was not associated with UA, suggesting that it is not a risk factor for all clinical manifestations of CAD, but its influence is important mainly in the acute stages of ACS. Thus, on a diagnosis of CAD, the cessation of smoking and management of glucose homoeostasis are of upmost importance to avoid severe subsequent ACS consequences.

Can authorities appreciably enhance the prescribing of oral generic risperidone to conserve resources? Findings from across Europe and their implications.

BACKGROUND: Generic atypical antipsychotic drugs offer health authorities opportunities for considerable savings. However, schizophrenia and bipolar disorders are complex diseases that require tailored treatments. Consequently, generally there have been limited demand-side measures by health authorities to encourage the preferential prescribing of generics. This is unlike the situation with hypertension, hypercholaesterolaemia or acid-related stomach disorders.The objectives of this study were to compare the effect of the limited demand-side measures in Western European countries and regions on the subsequent prescribing of risperidone following generics; to utilise the findings to provide future guidance to health authorities; and where possible, to investigate the utilisation of generic versus originator risperidone and the prices for generic risperidone. METHODS: Principally, this was a segmented regression analysis of retrospective time-series data of the effect of the various initiatives in Belgium, Ireland, Scotland and Sweden following the introduction of generic risperidone. The study included patients prescribed at least one atypical antipsychotic drug up to 20 months before and up to 20 months after generic risperidone. In addition, retrospective observational studies were carried out in Austria and Spain (Catalonia) from 2005 to 2011 as well as one English primary care organisation (Bury Primary Care Trust (PCT)). RESULTS: There was a consistent steady reduction in risperidone as a percentage of total selected atypical antipsychotic utilisation following generics. A similar pattern was seen in Austria and Spain, with stable utilisation in one English PCT. However, there was considerable variation in the utilisation of generic risperidone, ranging from 98% of total risperidone in Scotland to only 14% in Ireland. Similarly, the price of generic risperidone varied considerably. In Scotland, generic risperidone was only 16% of pre-patent loss prices versus 72% in Ireland. CONCLUSION: Consistent findings of no increased prescribing of risperidone post generics with limited specific demand-side measures suggests no 'spillover' effect from one class to another encouraging the preferential prescribing of generic atypical antipsychotic drugs. This is exacerbated by the complexity of the disease area and differences in the side-effects between treatments. There appeared to be no clinical issues with generic risperidone, and prices inversely reflected measures to enhance their utilisation.

Changes in the utilization of venlafaxine after the introduction of generics in Sweden.

BACKGROUND: There has been an appreciable increase in the prescribing efficiency of proton pump inhibitors, statins, and renin-angiotensin inhibitor drugs in Sweden in recent years. This has been achieved through multiple reforms encouraging the prescription of generics at low prices versus patented drugs in the same class. Generic venlafaxine also presents an opportunity to save costs given the prevalence of depression. However, depression is more complex to treat, with physicians reluctant to change prescriptions if patients are responding to a particular antidepressant. OBJECTIVES: We assessed (a) changes in the utilization pattern of venlafaxine versus other newer antidepressants before and after the availability of generic venlafaxine and before and after the initiation of prescription restrictions for duloxetine limiting its prescription to refractory patients, (b) utilization of generic versus original venlafaxine after its availability, and (c) price reductions for generic venlafaxine and the subsequent influence on total expenditure on newer antidepressants over time. METHODOLOGY: We performed interrupted time series analysis of changes in monthly reimbursed prescriptions using defined daily doses (DDDs) of patients dispensed at least one newer antidepressant from January 2007 to August 2011. DDDs was defined as the average maintenance dose of a drug when used in its major indication in adults. This included 19 months after the availability of generic venlafaxine and before initiation of prescription restrictions for duloxetine to 13 months after prescription restrictions. Total expenditure and expenditure/DDD for venlafaxine were measured over time. RESULTS: No appreciable change in the utilization pattern for venlafaxine was observed after generic availability when no appreciable demand-side activities by the regions (counties) were implemented to encourage its use. The utilization of venlafaxine significantly increased after prescription restrictions for duloxetine. Generic venlafaxine was dispensed once available, reaching 99.6 % of total venlafaxine (DDD basis) by August 2011. There was an appreciable fall in expenditure for newer antidepressants in Sweden after generic venlafaxine despite increased utilization, helped by a 90 % reduction in expenditure/DDD for venlafaxine by the end of the study versus prepatent loss prices. CONCLUSION: Multiple demand-side measures are needed to change physician prescribing habits. Authorities should not rely on a spillover effect between drug classes to effect change. Limited influence of prescription restrictions on the subsequent utilization of duloxetine reflects the complexity of this disease area. This is exacerbated by heterogeneous indications for duloxetine.

Priority setting in kidney transplantation: a qualitative study evaluating Swedish practices.

BACKGROUND: Transplantation is the treatment of choice for end-stage renal disease; it increases survival and quality of life, while being more cost-effective than dialysis. It is, however, limited by the scarcity of kidneys. The aim of this paper is to investigate the fairness of the priority setting process underpinning Swedish kidney transplantation in reference to the Accountability for Reasonableness (A4R) framework. METHODS: Fifteen semi-structured interviews were carried out with transplant surgeons (7), nephrologists (6) and coordinators (2) representing centers nationwide. Collected data was analysed using thematic analysis. To assess fairness in the priority setting process, identified factors were assessed in the reference to the four conditions (publicity, relevance, revision and appeal, enforcement) forming the accountability for reasonableness framework. RESULTS: Decision-making in assessment and allocation is based on clusters of factors. The factors appeal to various values, which are balanced against each other throughout the kidney allocation process: maximizing benefit, priority to the worst off and equality. The factors described by subjects and the values on which they rest satisfy the relevance condition of the accountability for reasonableness framework. However, two potential sources for unfair inequalities in access to treatment are identified: clinical judgment and institutional policies. CONCLUSIONS: The development of national guidelines both for assessing transplant candidacy, and for the allocation of kidneys from deceased donors, would contribute to standardize practices across centres; it will also help to better meet the conditions of fairness in reference to Accountability for Reasonableness. The benefits of this policy proposal in Swedish kidney transplantation merits consideration.

Immunological status in patients undergoing in vitro fertilisation: responses to hormone treatment and relationship to outcome.

We aimed to prospectively investigate the paternal antigen-induced cytokine secretion by peripheral blood mononuclear cells (PBMCs) in response to hormone treatment in women undergoing in vitro fertilisation (IVF) and to examine the predictive value of the cytokine secretion profile in the outcome of IVF treatment, in a pilot study. Twenty-five women were included and IVF treatment was successful for six and unsuccessful for 19 women. Blood samples were collected before IVF treatment, on four occasions during IVF and four weeks after embryo transfer. The numbers of Th1-, Th2- and Th17-associated cytokine-secreting cells and cytokine levels in cell supernatants were analysed by enzyme-linked immunospot-forming (ELISpot), enzyme-linked immune-sorbent (ELISA) or Luminex assay. None of the cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17, TNF and GM-CSF) had any predictive value regarding IVF outcome. The majority of the cytokines reached their peak levels at ovum pick-up, suggesting an enhancing influence of the hormonal stimulation. Pregnancy was associated with a high number of IL-4-, IL-5- and IL-13-secreting cells four weeks after ET. In conclusion, the results do not support our hypothesis of a more pronounced peripheral Th1 and Th17 deviation towards paternal antigens in infertile women with an unsuccessful IVF outcome, although this is based on a small number of observations. A larger study is required to confirm this conclusion. Higher numbers of Th2-associated cytokine-secreting cells in pregnant women four weeks after ET do corroborate the hypothesis of a Th2 deviation during pregnancy.

Reduced IFN-γ and IL-10 responses to paternal antigens during and after pregnancy in allergic women.

Normal pregnancy and allergy are both characterized by a T helper (Th) 2 deviation. In the current study, we hypothesized that paternal antigen-induced cytokine responses during pregnancy would be deviated toward Th2 and an anti-inflammatory profile, and that the Th2 deviation would be more pronounced in allergic pregnant women. Blood samples were collected longitudinally on three occasions during pregnancy and two occasions post partum (pp). Of the 86 women initially included, 54 women had a normal pregnancy and completed the sampling procedures. Twelve women fulfilled the criteria for allergy (allergic symptoms and circulating immunoglobulin [Ig] E antibodies to inhalant allergens) and 20 were non-allergic (nonsensitized without symptoms). The levels of Th1- and Th2-associated cytokines and chemokines, the Th17 cytokine IL-17 and the anti-inflammatory cytokine IL-10 of the groups were compared. Paternal antigen-induced IL-4 and IL-10 responses increased between the first and the third trimester. Allergy was associated with decreased paternal antigen-induced IFN-γ and CXCL10 secretion in the nonpregnant state (one year pp) and also decreased IFN-γ/IL-4 and IFN-γ/IL-13 ratios during pregnancy. We also observed a decreased paternal antigen-induced IL-10 response in allergic compared with non-allergic women during pregnancy, along with a decreased IL-10/IL-13 ratio. In conclusion, our findings support the hypothesis of lower Th1 responses toward paternal antigens in allergic than in non-allergic women, but also indicate that allergy is associated with a lower capacity to induce anti-inflammatory IL-10 responses after paternal antigen stimulation during pregnancy.

Analysing management policies for operating room planning using simulation.

In this paper we analyse the operating room planning at a department of orthopaedic surgery in Sweden. We focus on the problem of meeting the uncertainty in demand of patient arrival and surgery duration and at the same time maximizing the utilization of operating room (OR) time. With a discrete-event model we simulate how different management polices affect different performance metrics such as patient waiting time, cancellations and the utilization of OR time. The experiments show that the performance of the operating room department can be improved significantly by applying a different policy in reserving OR-capacity for emergency cases together with a policy to increase staff in stand-by. Moreover, the developed simulation model provides estimates for a what-if situation related to the prognosis of an increasing number of hip-joint replacements.

Forecasting drug utilization and expenditure in a metropolitan health region.

BACKGROUND: New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011. METHODS: Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee. RESULTS: The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs. CONCLUSIONS: The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice.

Total and allergen-specific IgE levels during and after pregnancy in relation to maternal allergy.

Type 2 T-helper cell (Th2)-skewed immunity is associated with successful pregnancy and the ability to easily direct immune responses to a Th2-polarised profile may be an evolutionary benefit. The Th2-like immunity associated with allergic disease might generate favourable effects for the maintenance of pregnancy, but could also promote development of Th2-like immune responses and allergic disease in the offspring. The aim of this study was to explore, by using IgE as a stable proxy for Th2, the Th1/Th2 balance in allergic and non-allergic women by measuring allergen-specific and total IgE antibody levels in plasma during pregnancy and after delivery. Specific and total IgE antibody levels were determined by ImmunoCAP technology at five occasions during pregnancy (gestational weeks 10-12, 15-16, 25, 35 and 39), as well as at 2 and 12 months after delivery. Thirty-six women without and 20 women with allergic symptoms were included, of whom 13 were sensitised with allergic symptoms and 30 were non-sensitised without allergic symptoms. The levels of total IgE, but not allergen-specific IgE, were increased during early pregnancy when compared to 12 months after delivery in the sensitised women with allergic symptoms, but not in the non-sensitised women without allergic symptoms (p<0.01). This increase in total IgE levels during early pregnancy only in the sensitised women with allergic symptoms indicates that allergy is associated with an enhanced Th2 deviation during pregnancy.