Long-term clinical and economic outcomes in previously untreated paediatric patients with severe haemophilia A: A nationwide real-world study with 700 person-years.

AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. RESULTS: All 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1 years. The mean (SD) annual treatment costs (€ per kg) were 4391€ (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383 448€ (259 085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. CONCLUSIONS: Early high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2 years.

Economic evaluation of exercise-based cardiac rehabilitation in patients with a recent acute coronary syndrome.

Health care decision-making requires evidence of the cost-effectiveness of medical therapies. We evaluated the cost-effectiveness of exercise-based cardiac rehabilitation (ECR) implemented according to guidelines. All the patients (n = 204) had experienced a recent acute coronary syndrome and were randomized to a 1-year ECR (n = 109) or usual care (UC) group (n = 95). The patients' health-related quality of life was followed using the 15D instrument and health care costs were collected from electronic health registries. The cost-effectiveness of ECR was estimated based on intervention and health care costs and quality-adjusted life years (QALYs) gained. The total average cost per patient was lower in ECR than in UC. The incremental cost was divided by the baseline-adjusted incremental QALYs (0.045), yielding an incremental cost-effectiveness ratio of -€24511/QALYs. A combined endpoint of mortality, recurrent coronary event, or hospitalization for a heart failure occurred for five patients in ECR and 16 patients in UC (HR 3.9, 95% CI 1.4-10.6, P = 0.004, relative risk reduction 73%, number needed to treat eight). ECR is a dominant treatment option and decreases the occurrence of adverse cardiac events. These results are useful for decision-making when planning optimal utilization of resources in Finnish health care.

Plasmonic surface lattice resonances at the strong coupling regime.

We show strong coupling involving three different types of resonances in plasmonic nanoarrays: surface lattice resonances (SLRs), localized surface plasmon resonances on single nanoparticles, and excitations of organic dye molecules. The measured transmission spectra show splittings that depend on the molecule concentration. The results are analyzed using finite-difference time-domain simulations, a coupled-dipole approximation, coupled-modes models, and Fano theory. The delocalized nature of the collective SLR modes suggests that in the strong coupling regime molecules near distant nanoparticles are coherently coupled.

Spatial coherence properties of organic molecules coupled to plasmonic surface lattice resonances in the weak and strong coupling regimes.

We study spatial coherence properties of a system composed of periodic silver nanoparticle arrays covered with a fluorescent organic molecule (DiD) film. The evolution of spatial coherence of this composite structure from the weak to the strong coupling regime is investigated by systematically varying the coupling strength between the localized DiD excitons and the collective, delocalized modes of the nanoparticle array known as surface lattice resonances. A gradual evolution of coherence from the weak to the strong coupling regime is observed, with the strong coupling features clearly visible in interference fringes. A high degree of spatial coherence is demonstrated in the strong coupling regime, even when the mode is very excitonlike (80%), in contrast to the purely localized nature of molecular excitons. We show that coherence appears in proportion to the weight of the plasmonic component of the mode throughout the weak-to-strong coupling crossover, providing evidence for the hybrid nature of the normal modes.

Treatment of follicular non-Hodgkin's lymphoma with or without rituximab: cost-effectiveness and value of information based on a 5-year follow-up.

BACKGROUND: Rituximab induction together with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab maintenance (RCHOP-R) resulted to significant progression-free survival (PFS) benefit in comparison to RCHOP in the EORTC20981 trial of relapsed/refractory follicular non-Hodgkin's lymphoma (FL). However, the overall survival (OS) difference between RCHOP-R and RCHOP was insignificant. This study evaluated the cost-effectiveness of RCHOP, RCHOP-R, and CHOP in the treatment of relapsed/refractory FL. DESIGN: A lifetime Markov modeling based on the 5-year EORTC20981 survivals (Weibull regressions) was carried out from the public health care payer perspective. Finnish costs (drug, routine, adverse event, and relapse management) were employed. The main outcomes were incremental cost (€2008) per quality-adjusted life-year (QALY), progression-free year (PFY), and life-years gained (LYG). Analyses included cost-effectiveness acceptability frontier and multinomial expected value of perfect information (mEVPI). RESULTS: RCHOP-R resulted to OS (PFS) benefit compared with RCHOP and CHOP: 6 (10) and 17 (25) months, respectively. The incremental costs per QALY gained/LYG/PFY gained were €18 147/€16 380/€10 416 for RCHOP-R versus RCHOP (mEVPI €5196); €14 360/€13 041/€8976 for RCHOP-R versus CHOP (mEVPI €1986); and €12 123/€11 049/€8004 for RCHOP versus CHOP (mEVPI €1,240). RCHOP-R was the optimal option when the willingness to pay per QALY gained exceeded €18 399. CONCLUSION: RCHOP-R is a potentially cost-effective treatment option for the FL.

Exotic superfluid states of lattice fermions in elongated traps.

We present real-space dynamical mean-field theory calculations for attractively interacting fermions in three-dimensional lattices with elongated traps. The critical polarization is found to be 0.8, regardless of the trap elongation. Below the critical polarization, we find unconventional superfluid structures where the polarized superfluid and Fulde-Ferrell-Larkin-Ovchinnikov-type states emerge across the entire core region.

Use of ADHD drugs in the Nordic countries: a population-based comparison study.

OBJECTIVE: To compare national use of attention-deficit/hyperactivity disorder (ADHD) drugs between five Nordic countries. METHOD: A population-based drug utilisation study based on nationwide prescription databases, covering in total 24 919 145 individuals in 2007. ADHD drugs defined according to the World Health Organization Anatomic Therapeutic Chemical classification system as centrally acting sympathomimetics (N06BA). RESULTS: The 2007 prevalence of ADHD drug use among the total Nordic population was 2.76 per 1000 inhabitants, varying from 1.23 per 1000 in Finland to 12.46 per 1000 in Iceland. Adjusting for age, Icelanders were nearly five times more likely than Swedes to have used ADHD drugs (Prev.Ratio = 4.53, 95% CI: 4.38-4.69). Prevalence among boys (age 7-15) was fourfold the prevalence among girls (Prev.Ratio = 4.28, 95% CI: 3.70-4.96). The gender ratio was diminished among adults (age 21 +) (Prev.Ratio = 1.24, CI: 1.21-1.27). CONCLUSION: A considerable national variation in use of ADHD drugs exists between the Nordic countries.

Induced interactions and the superfluid transition temperature in a three-component Fermi gas.

We study many-body contributions to the effective interaction between fermions in a three-component Fermi mixture. We find that effective interactions induced by the third component can lead to a phase diagram different from that predicted if interactions with the third component are neglected. As a result, in a confining potential a superfluid shell structure can arise even for equal populations of the components. We also find a critical temperature for the BCS transition in a 6Li mixture which can deviate strongly from the one in a weakly interacting two-component system.

Coupled dipole approximation across the Γ-point in a finite-sized nanoparticle array.

We study the response of a finite-sized nanoparticle array to an incident field in the vicinity of the Γ-point of the lattice. Using the coupled dipole approximation, we find that the dipole distributions can be strongly inhomogeneous and that strong modulations appear as the energy is above the Γ-point. We highlight how this is reflected in real-space extinction efficiencies as well as in radiation patterns from the finite-sized array.This article is part of the themed issue 'New horizons for nanophotonics'.

Lasing in dark and bright modes of a finite-sized plasmonic lattice.

Lasing at the nanometre scale promises strong light-matter interactions and ultrafast operation. Plasmonic resonances supported by metallic nanoparticles have extremely small mode volumes and high field enhancements, making them an ideal platform for studying nanoscale lasing. At visible frequencies, however, the applicability of plasmon resonances is limited due to strong ohmic and radiative losses. Intriguingly, plasmonic nanoparticle arrays support non-radiative dark modes that offer longer life-times but are inaccessible to far-field radiation. Here, we show lasing both in dark and bright modes of an array of silver nanoparticles combined with optically pumped dye molecules. Linewidths of 0.2 nm at visible wavelengths and room temperature are observed. Access to the dark modes is provided by a coherent out-coupling mechanism based on the finite size of the array. The results open a route to utilize all modes of plasmonic lattices, also the high-Q ones, for studies of strong light-matter interactions, condensation and photon fluids.

Direct costs of warfarin treatment among patients with atrial fibrillation in a Finnish health care setting.

OBJECTIVE: The main objective was to estimate the mean direct costs of warfarin treatment for atrial fibrillation (AF) patients. Secondly, the costs of initiating warfarin treatment during a 60-day period and the impact of International Normalized Ratio (INR) and co-morbidities on costs were estimated. DESIGN AND DATA: The study was performed as a retrospective cohort study over a 12-month period in a Finnish communal health care setting. All AF patients aged 65 years or older (n = 250) with warfarin treatment were identified from the database of the health service district of an urban area. Patient specific information related to comorbidities, INR-control, complications and health care resource use were collected. Cost information was obtained from the Finnish national health care unit cost list. METHODS: The effect of treatment balance and other background variables on treatment costs were evaluated using ordinary least squares regression (OLS), log-transformed OLS and generalized linear model (GLM). The mean costs were calculated on the basis of the different models and bias corrected and accelerated (BCa) bootstrap confidence intervals (CIs) were calculated for the mean costs. RESULTS: The best fitting cost model was log-transformed OLS. The costs of warfarin treatment on the basis of the log-transformed model were 589.82 Euros (BCa 95% CI: 586.68-591.99) per patient compared to 616.00 Euros (BCa 95% CI: 579.98-652.96) obtained with the OLS-model. For the treatment initiation period, the mean costs were 263 Euros (BCa 95% CI: 218.90-314.71). Depending on the way that INR-control was defined, the mean costs were 95.27 Euros or 166.92 Euros higher for patients who were not in the defined INR-balance. CONCLUSIONS: The INR-control has a significant impact on the warfarin treatment costs. The choice of model influences the estimated mean costs. In addition, different models identify statistically significant effects between different background variables and costs.

Nationwide survey of comorbidity, use, and costs of all medications in Finnish diabetic individuals.

OBJECTIVE: To investigate comorbidity and overall use and costs of medication for all Finnish individuals with diabetes treated with drugs compared with sex- and age-matched control subjects. RESEARCH DESIGN AND METHODS: According to a cross-sectional population study using national registries, 116,224 individuals purchased antidiabetic medications in Finland in 1995. The same number of nondiabetic individuals matched for sex, age, and area of residence were chosen as control subjects. Age at onset of diabetes was used as a criterion for distinguishing between type 1 and type 2 diabetes. The criterion could be applied in 74% of cases. A total of 16,955 individuals were defined as having type 1 diabetes, and 68,517 were defined as having type 2 diabetes. Comorbidity was determined by linkage with a national register including all individuals entitled to special reimbursement for drug treatment for a range of chronic diseases. Data on use and costs of all medications prescribed were obtained from drug purchase records. RESULTS: Cardiovascular diseases and uremia were, as expected, the chronic diseases most closely associated with diabetes. Use of almost all kinds of medication was significantly greater in individuals with type 1 and type 2 diabetes than in control subjects. The greatest differences were observed in relation to cardiovascular drugs and antibiotics. Unexpectedly low use of antiasthmatics was observed in individuals with both types of diabetes, low use of neuroleptics was observed in type 1 diabetic individuals, and low use of hormone replacement therapy was observed in women with type 2 diabetes. Total costs of medications for individuals with diabetes were 3.5 times greater than those for nondiabetic control subjects. The higher costs were mostly attributable to insulin therapy for individuals with type 1 diabetes. The higher costs for individuals with type 2 diabetes were related to the cost of medications other than antidiabetic medication. The possible selection bias in omitting diabetic individuals treated with diet only and individuals in whom diabetes type could not be determined must be considered in interpreting the results. CONCLUSIONS: Greater use by and costs of medications for individuals with diabetes than for nondiabetic individuals is related not only to antidiabetic treatment but also to all other kinds of medications. Although drug treatment and the prevalence of several chronic conditions were overall greater in individuals with diabetes versus other individuals, some exceptions merit further study

Production of basement membrane laminin and type IV collagen by tumors of striated muscle: an immunohistochemical study of rhabdomyosarcomas of different histologic types and a benign vaginal rhabdomyoma.

Immunohistochemical methods were used to demonstrate the distribution of basement membrane laminin and type IV collagen in eight tumors derived from striated muscle (three botryoid, two alveolar, and two adult-type rhabdomyosarcomas; one benign vaginal rhabdomyoma). All of the tumors produced significant amounts of both basement membrane components. Stainings clearly revealed the alveolar nature of the rhabdomyosarcomas, with the alveolar spaces surrounded by distinct basement membranes. Different stages of cellular development were identified in the botryoid sarcomas, with the most immature cells of the cambium layer devoid of external basement membrane around the tumor cells, although the stroma contained finely dispersed basement membrane material and some cells contained intracytoplasmic laminin or type IV collagen, indicative of the synthesis of these proteins. The more mature cells, which had abundant granular cytoplasm, were enveloped by distinct basement membranes and seemed to have coalesced, forming structures resembling myotubes. The adult-type rhabdomyosarcomas were composed of large pleomorphic cells that were surrounded by basement membranes, either individually or in small groups. Some giant cells contained intracytoplasmic laminin. The vaginal rhabdomyoma was composed of round rhabdoblastic cells or elongated strap cells with cross-striations. Cells of both of these types were surrounded by thin but distinct basement membranes. The results suggest that demonstration of basement membranes would be helpful in the diagnosis of tumors derived from striated muscle. The findings concerning different stages of maturation of tumor cells are in accordance with previous in vitro observations of myoblastic cells.

Why has the utilization of antiasthmatics increased in Finland?

The sales of antiasthmatics have increased rapidly in the Nordic countries during the 1980s. The causes for this growth in Finland were studied. Four nationwide population surveys show that the prevalence of self-reported asthma has risen, a larger proportion of asthmatic patients are under medication, the number of antiasthmatics per patient has increased, and the dosage recommendations of inhalation glucocorticoids and beta-agonists have grown. The average cost of medical treatment of an asthmatic patient was FIM 1848 (approximately U.S. $510.00) in 1990. The highest average expenses in the 21 districts studied were FIM 2171 and the lowest FIM 1535. To identify the consequences of these variations, the frequency of symptomatic periods as well as the quality of life of the asthmatic patients should be studied.

Recent trends in the consumption of lipid-lowering drugs in Finland.

The consumption of lipid-lowering drugs in Finland and in other Nordic countries increased almost steadily in 1988-1993. The exceptions were the year 1992 in Finland and 1993 in Iceland, when consumption was lower than in the previous year. In both cases the temporary decline in consumption was associated with a reduction in reimbursement for the costs of lipid-lowering drugs. In 1993, the consumption level was 2.7 defined daily doses/1000 inhabitants/day in Finland and ranged from 2.3 to 4.0 in other Nordic countries. According to the Finnish nationwide prescription register, 0.5% of men and 0.6% of women purchased lipid-lowering drugs in the period from January to September, 1994. The rate of use was highest among people of middle age. In the early 1990s, statins took the lead in the consumption of lipid-lowering drugs, accounting for 70% of prescriptions in 1993; the percentages of fibrates, resins, and nicotinic acid derivatives declined in the same period. In 1994 the prevalence of familial hypercholesterolemia (FH) according to strictly predetermined criteria was 0.8 per 1000 among Finns, and the proportion of FH patients among all users of lipid-lowering drugs was 11%. The use of lipid-lowering drugs is not particularly high in Finland and seems to be reasonably targeted.

[Immunohistochemical detection of acid cysteine proteinase inhibitors in lymphatic infiltrates of the thyroid gland]. / Immunhistochemischer Nachweis eines sauren Cysteinproteinaseinhibitors (ACPI) in lymphatischen Infiltraten der Schilddrüse.

Thyroid tissues containing lymphoid secondary follicles were studied immunohistochemically for the presence of acid cysteine proteinase inhibitor (ACPI). Reticulum cells in the lymphoid secondary follicles, mainly dendritic reticulum cells, exhibited a positive reaction. In addition, in 2 cases a positive reaction could be detected in some of the thyroid epithelial cells, adjacent to the lymphoid secondary follicles. The possible function of ACPI generally and its role in the function of those cells containing it, is discussed.

Health economic consequences of reducing salt intake and replacing saturated fat with polyunsaturated fat in the adult Finnish population: estimates based on the FINRISK and FINDIET studies.

BACKGROUND/OBJECTIVES: To predict the health economic consequences of modest reductions in the daily intake of salt (-1.0 g per day) and replacement of saturated fat (SFA, -1.0 energy percent (E%)) with polyunsaturated fat (PUFA, +1.0 E%) in the Finnish population aged 30-74 years. SUBJECTS/METHODS: A Markov model with dynamic population structure was constructed to present the natural history of cardiovascular diseases (CVDs) based on the most current information about the age- and sex-specific cardiovascular risk factors, dietary habits and nutrient intake. To predict the undiscounted future health economic consequences of the reduction of dietary salt and SFA, the model results were extrapolated for the years 2010-2030 by replacing the baseline population in the year 2007 with the extrapolated populations from the official Finnish statistics. Finnish costs (€2009, societal perspective) and EQ-5D utilities were obtained from published references. RESULTS: During the next 20 years, a population-wide intervention directed at salt intake and dietary fat quality could potentially lead to 8000-13,000 prevented CVD cases among the Finnish adults compared the situation in year 2007. In addition, the reduced incidence of CVDs could gain 26,000-45,000 quality-adjusted life years and save €150-225 million over the same time period. CONCLUSION: A modest reduction of salt and replacement of SFA with PUFA in food products can significantly reduce the burden of CVD in the adult Finnish population. This impact may be even larger in the near future due to the ageing of Finnish population.