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Soili Törmälehto,1 Tanja Svirskis,2 Timo Partonen,3 Erkki Isometsä,2 Sami Pirkola,4 Marianna Virtanen,1,5 Reijo Sund6 1School of Educational Sciences and Psychology, University of Eastern Finland, Joensuu, Finland; 2Department of Psychiatry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 3Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland; 4Faculty of Social Sciences, University of Tampere and Pirkanmaa Hospital District, Tampere, Finland; 5Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 6Institute of Clinical Medicine, University of Eastern Finland, Kuopio, FinlandCorrespondence: Soili Törmälehto, School of Educational Sciences and Psychology C/O Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, Kuopio, FI-70211, Finland, Email soili.tormalehto@uef.fiPurpose: To examine seasonal patterns of hospital admissions due to mood and psychotic disorders and to investigate whether the admission rates show variation according to the seasonal daylength (photoperiods).Patients and Methods: A retrospective nationwide register-based cohort of all psychiatric admissions (N=978,079) during 1987– 2017 in Finland was utilized. The smoothed time-series of adjusted ratio of observed and expected (O/E) daily counts were estimated to examine seasonal variation. The mean O/E with 95% confidence intervals (CI) was used to study the admission rates by photoperiods. The calendar days were classified into the 71-day photoperiods based on the daylength (long/summer, short/winter, equal/spring, equal/fall) and the pace of change in daylength (slowly/rapidly increasing/decreasing daylength).Results: Manic episodes peaked in summer during the long (mean O/E=1.10, 95% CI=1.06– 1.13) and slowly decreasing (1.09, 1.06– 1.13) photoperiods and had a nadir in winter during the slowly increasing (0.93, 0.89– 0.98) photoperiod. Admissions for unipolar depressive (UPD) episodes peaked in autumn and in spring at the end of the rapidly decreasing (1.03, 1.02– 1.04) and increasing (1.03, 1.01– 1.04) photoperiod, and dropped in summer during the long and slowly decreasing (0.95, 0.94– 0.96) photoperiods. Bipolar depressive (BPD) and mixed episodes signaled excess admissions in autumn and in spring. Admissions for schizophrenia were higher than expected from summer to early-autumn, during the long and slowly decreasing photoperiods (1.02, 1.02– 1.03), and lower than expected in other seasons, especially in mid-spring during the rapidly increasing photoperiod (0.98, 0.98– 0.99).Conclusion: The study indicates the seasonality and photoperiodicity of mental disorders, especially for manic episodes. The seasonal pattern is similar between schizophrenia and manic episodes, and between UPD, BPD, and mixed episodes.Keywords: seasonal variation, photoperiod, hospital admission, mood disorders, bipolar disorder, schizophrenia

Obstructive sleep apnea (OSA) is a common disease associated with a high prevalence of costly comorbidities and accidents that add to the disease's economic impact. Although more attention has been focused on OSA in recent years, no previous systematic reviews have synthesized findings from existing studies that provide estimates of the economic cost of OSA. This study aims to summarize the findings of existing studies that provide estimates of the cost of OSA. Two bibliographic databases, PubMed and Scopus, were used to identify articles on the costs of OSA. The systematic literature review identified 5,938 publications, of which 31 met the inclusion criteria. According to the results, adjusted for inflation and converted to euros, the annual cost per patient ranged from €236 (the incremental cost of OSA) for New Zealand to €28,267 for the United States. The total annual cost per patient in Europe ranged from €1,669 to €5,186. OSA causes a significant burden on society, and OSA-related costs increase many years before the diagnosis and remain elevated for a long time after the diagnosis. Despite some well-conducted studies, the cost estimates for OSA are uncertain and specific to the context in which the study was conducted., Competing Interests: Declaration of competing interest The authors state that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Life satisfaction is an essential construct of well-being that is tied to behavioral, emotional, social and psychological outcomes. This study aimed to examine changes in total and domain-specific life satisfaction during the retirement transition and additionally examine whether those changes differ by gender, occupation, health and spousal working status. Aging public sector employees ( n  = 3543) from the Finnish Retirement and Aging Study cohort study were followed up annually before and after retirement. Total life satisfaction score (range 4-20) was computed by summing up the responses in four domains (interestingness, happiness, easiness and togetherness). The mean and mean change estimates and their 95% CI were calculated by using the linear regression models with generalized estimating equations, adjusted for age, gender, occupation, health and marital status. Total life satisfaction score improved among the entire study population during the retirement transition and remained stable thereafter. The improvement was greater among women versus men (gender * time interaction p  = 0.004), among those with suboptimal health before retirement vs. those who had good (health * time p  < 0.0001) and those who had no spouse vs. those who had a retired or working spouse (spousal-status * time p  < 0.0001). In case of domain-specific life satisfaction scores, the greatest improvement was observed in the easiness domain. Life satisfaction improves during the retirement transition period, especially among women, those with suboptimal health and those living without a spouse. The improvement was considerably greater in the easiness domain than any other domains. Life satisfaction remained improved and stable during the post-retirement period., Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00745-8., Competing Interests: Conflict of interestNone (All the authors declare that they have no conflict of interest)., (© The Author(s) 2022.)

Background: Season of birth is a risk factor of schizophrenia, and it is possible that cumulative exposure to climatic factors during childhood affects the risk of schizophrenia. We conducted a cohort study among 365,482 persons born in Finland in 1990-1995 to examine associations of 10-year cumulative exposure to global solar radiation and ambient temperature in childhood with schizophrenia., Methods: Data on schizophrenia diagnoses and sociodemographic factors from the Finnish population register and health care register were linked to daily meteorological data using residential information. The study population was followed from age 10 until the first schizophrenia diagnosis, death, emigration or December 31, 2017, whichever came first. Hazard ratios (HR) for the risk of schizophrenia were estimated using Cox proportional hazards model., Results: Compared to the lowest quintile of global solar radiation or ambient temperature, growing up in the second highest quintile (Q4) was associated with greater risk of schizophrenia. These hazard ratios were attenuated after adjustment for parental mental disorder, parental education, parental income, area-level socioeconomic characteristics and urbanicity (HR = 1.29, 95 % CI 1.06-1.58 for radiation; HR = 1.24, 95 % CI, 1.02-1.52 for temperature). Continuous linear terms evaluated in secondary models suggested a greater risk of schizophrenia at greater childhood exposure to global radiation and ambient temperature, but these associations did not remain in fully adjusted models., Conclusions: We found no consistent evidence that cumulative exposure to sunlight and ambient temperature in childhood is associated with the risk of developing schizophrenia. Studies in other populations residing in different latitudes are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Knee osteoarthritis (OA) worsens health-related quality of life (HRQoL) but the symptom pathway varies from person to person. We aimed to identify groups of people with knee OA or at its increased risk whose HRQoL changed similarly. Our secondary aim was to evaluate if patient-related characteristics, incidence of knee replacement (KR) and prevalence of pain medication use differed between the identified HRQoL trajectory groups., Methods: Eight-year follow-up data of 3053 persons with mild knee OA or at increased risk were obtained from the public Osteoarthritis Initiative (OAI) database. Group-based trajectory modeling was used to identify patterns of experiencing a decrease of ≥10 points (Minimal Important Change, MIC) in the Quality of Life subscale of the Knee injury and Osteoarthritis Outcome Score compared to baseline. Multinomial logistic regression, Cox regression and generalized estimating equation models were used to study secondary aims., Results: Four HRQoL trajectory groups were identified. Persons in the 'no change' group (62.9%) experienced no worsening in HRQoL. 'Rapidly' (9.5%) and 'slowly' worsening (17.1%) groups displayed an increasing probability of experiencing the MIC in HRQoL. The fourth group (10.4%) had 'improving' HRQoL. Female gender, higher body mass index, smoking, knee pain, and lower income at baseline were associated with belonging to the 'rapidly worsening' group. People in 'rapidly' (hazard ratio (HR) 6.2, 95% confidence interval (CI) 3.6-10.7) and 'slowly' worsening (HR 3.4, 95% CI 2.0-5.9) groups had an increased risk of requiring knee replacement. Pain medication was more rarely used in the 'no change' than in the other groups., Conclusions: HRQoL worsening was associated with several risk factors; surgical and pharmacological interventions were more common in the poorer HRQoL trajectory groups indicating that HRQoL does reflect the need for OA treatment. These findings may have implications for targeting interventions to specific knee OA patient groups., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: ST has been a paid employee of Medfiles Ltd and is the founder of MediSoili Oy. JAM is a founding partner of ESiOR Oy. These companies were not involved in carrying out this research. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have declared that no competing interests exist.

Background: Biologic treatments have enhanced the treatment outcomes of patients with active ankylosing spondylitis (AS). Until recently, TNF-alpha-inhibitors have been the only biologics approved for the treatment of active AS. The objective of this study was to assess the potential financial impact of the first non-TNF-alpha biologic secukinumab (fully human IL-17A-inhibitor) vs adalimumab (TNF-alpha-inhibitor) in the treatment of AS in Finland., Materials and Methods: In this model-based budget impact analysis, patients were treated either with secukinumab (150 mg) or adalimumab (40 mg). The number of patients and market share of different biologics were based on national reimbursement registry data. Adalimumab was the most commonly used biologic treatment for AS, and in the base case analysis all adalimumab patients are assumed to switch to secukinumab. Response rates were based on a matching-adjusted indirect comparison between secukinumab and adalimumab. Patients not achieving response were switched to another biologic treatment., Results: Treating AS patients with secukinumab instead of adalimumab leads to potential savings of 18.2 million euros within a 5-year time period. The total costs within the follow-up time were 59.5 million euros and 77.7 million euros with and without secukinumab, respectively. According to sensitivity analyses, a higher adoption rate of secukinumab corresponds to higher potential savings., Conclusions: Secukinumab is a cost-saving treatment option compared with adalimumab in the treatment of AS in Finland. More patients could be treated with a biologic by allocating resources more efficiently.

Background: The purpose was to quantify the decrement in health utility (referred as disutility) associated with knee osteoarthritis (OA) and different symptomatic and radiographic uni- and bilateral definitions of knee OA in a repeated measures design of persons with knee OA or at increased risk of developing knee OA., Methods: Data were obtained from the Osteoarthritis Initiative database. SF-12 health-related quality of life was converted into SF-6D utilities, and were then handled as the health utility loss by subtracting 1.000 from the utility score, yielding a negative value (disutility). Symptomatic OA was defined by radiographic findings (Kellgren-Lawrence, K-L, grade ≥ 2) and frequent knee pain in the same knee. Radiographic OA was defined by five different definitions (K-L ≥ 2 unilaterally / bilaterally, or the highest / mean / combination of K-L grades of both knees). Repeated measures generalized estimating equation (GEE) models were used to investigate disutility in relation to these different definitions., Results: Utility decreased with worsening of symptomatic or radiographic status of knee OA. The participants with bilateral and unilateral symptomatic knee OA had 0.03 (p < 0.001) and 0.02 (p < 0.001) points lower utility scores, respectively, compared with the reference group. The radiographic K-L grade 4 defined as the mean or the highest grade of both knees was related to a decrease of 0.04 (p < 0.001) and 0.03 (p < 0.001) points in utility scores, respectively, compared to the reference group., Conclusions: Knee OA is associated with diminished health-related quality of life. Health utility can be quantified in relation to both symptomatic and radiographic uni- and bilateral definitions of knee OA, and these definitions are associated with differing disutilities. The performance of symptomatic definition was better, indicating that pain experience is an important factor in knee OA related quality of life.

Objective: To examine the association between neuropsychiatric symptoms (NPS) with self- and caregiver-rated Quality of Life (QoL) for patients with Alzheimer's disease (AD) during a 5-year follow-up., Methods: The ALSOVA 5-year follow-up study included, at baseline, 236 patients with either very mild (Clinical Dementia Rating Scale (CDR) 0.5), or mild (CDR 1) AD, together with their caregivers from three Finnish hospital districts. QoL was evaluated using patient self-reported, and caregiver-rated, QoL in AD (QoL-AD) scores. NPS were assessed using the Neuropsychiatric Inventory (NPI), and AD severity was evaluated using the CDR, with cognition tested by the mini-mental state examination. The performance of daily activities was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory., Results: Over the 5-year follow-up period, patient self-reported QoL-AD scores did not change significantly (p = 0.245), despite increases in their NPS. However, caregiver-rated patient QoL-AD scores declined significantly (p ≤ 0.001), as total NPI scores increased during follow-up. No NPS at baseline, and only apathy at follow-up, correlated significantly (p = 0.007) with patient self-rated QoL-AD scores. Caregiver-rated patient QoL-AD scores correlated significantly with most NPS, especially (p ≤ 0.001) apathy, agitation, anxiety, irritability, depression, and delusions at baseline, and delusions, hallucinations, apathy, appetite disturbances, and anxiety during follow-up., Conclusions: Patient rated QoL-AD scores are an unreliable tool with which to evaluate the success of therapy for NPS. Instead, caregiver-rated scores for patients correlated well with NPI scores, and health care professionals in the clinic should preferentially use these. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Psychotropic medications are widely prescribed to manage neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD). Our objective was to investigate the longitudinal associations between psychotropic medication use and NPS, cognition, and functional performance in persons with very mild or mild AD at baseline., Methods: Data were collected as part of the prospective three-year study of home-dwelling persons with AD and their caregivers (n = 236 dyads). The associations between psychotropic medication use and clinical measures were analyzed using repeated measures Generalized Estimating Equation (GEE) models. NPS, cognition, daily functioning, and disease severity were assessed with NPI, CERAD-NB, or MMSE, ADCS-ADL, and CDR-SOB, respectively. All analyses were adjusted for age, gender, education, and co-morbidities., Results: The prevalence of benzodiazepines and related medications increased from 16% to 24% (p = 0.031), antidepressants from 11% to 18% (p = 0.057), and antipsychotics from 4% to 16% (p = 0.011) in the three years following AD diagnosis. In adjusted multivariable analyses, a one-point increase in NPI increased the odds of using any psychotropic medication class by 4% (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.07). ADCS-ADL (1/OR 1.04, 95% CI 1.02-1.06) and CDR-SOB (OR 1.27, 95% CI 1.13-1.42) were associated with use of antipsychotics. CERAD-NB and MMSE were not associated with any psychotropic medication class use in the models., Conclusions: Psychotropic medication use increased significantly in relation to increasing dependency in AD, especially with NPS. Furthermore, the use of antipsychotics increased with disease severity, and with decline in daily functioning. Cognitive performance was not associated with psychotropic medication use.

The treatments of lung cancer have progressed significantly during the past ten years through the enhanced understanding of the underlying biological processes. Treatment outcomes have become better in the era of targeted treatments, but these new treatments are more expensive than their predecessors. Cost-effectiveness of the new treatments has been widely evaluated internationally. Nevertheless, the results from these analyses have been contradictory. Based on the published evaluations it is neither possible to rank the new treatments nor is it possible to unambiguously claim the cost-effectiveness of the new treatments compared with traditional treatments. National cost-effectiveness analyses of lung cancer treatments have not been published in Finland.

Background: Hip fractures require operation within 36-48 h, and they are most common in the elderly. A high International Normalized Ratio should be corrected before surgery. In the current study, we analyzed the budget impact of various warfarin reversal approaches., Methods: Four reversal strategies were chosen for the budget impact analysis: the temporary withholding of warfarin, administration of vitamin K, fresh frozen plasma (FFP), and a four-factor prothrombin complex concentrate (PCC)., Results: We estimated that, annually, 410 hip fracture patients potentially require warfarin reversal in Finland. The least costly treatment was vitamin K, which accounted for €289,000 in direct healthcare costs, and the most costly treatment option was warfarin cessation, which accounted for €1,157,000. In the budget impact analysis, vitamin K, PCC and FFP would be cost-saving to healthcare compared with the current treatment mix., Conclusion: The various warfarin reversal strategies have different onset times, which may substantially impact the subsequent healthcare costs.

Neuropsychiatric symptoms of Alzheimer's disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti-inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions.

The major disadvantage concerning clinical use of bishosphonate drugs, like clodronate, is their poor and variable absorption after oral administration. The objective of this study was to assess the effects of four different absorption enhancers-palmitoyl carnitine chloride (PCC), N-trimethyl chitosan chloride (TMC), sodium caprate (C10), and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)-on the transport of clodronate using Caco-2 cell culture model. The transport experiments were performed in a normal (1.3mM) and in a minimum-calcium concentration (apically calcium-free medium and basolaterally 100 microM calcium concentration). In the normal calcium concentration, a strong enhancement in clodronate permeation was observed with the enhancers: EGTA (2.5mM), TMC (1.5% w/v), and PCC (0.2mM) increased the transport of 1mM clodronate 190-, 20-, and 10-fold, respectively, and the transport of 10mM clodronate 130-, 70-, and 35-fold. In the minimum-calcium concentration, the effects of the absorption enhancers on the transport of clodronate were not so potent: TMC, PCC, and EGTA caused 2- to 20-fold enhancement in clodronate permeation whereas C10 (10mM) was without any effect. According to the results, the permeation of clodronate through Caco-2 cells could be significantly promoted by the absorption enhancers, which cause widening of the tight junctions and, thus, increase the permeability of the paracellular route.

Purpose: To investigate possible reasons for the low frequency of GI side-effects of clodronate, even though clodronate is known to be metabolised into a cytotoxic nucleotide analogue (AppCCl(2)p) by many cell types. The effects of some lipophilic prodrugs of clodronate were also studied., Methods: The effects of clodronate and its lipophilic derivatives on the proliferation and viability of Caco-2 cells were examined using an MTT assay. The intracellular uptake of 14C-clodronate and the accumulation of a clodronate metabolite (AppCCl(2)p) in Caco-2 cells were evaluated using ion-pairing HPLC-ESI-MS., Results: Clodronate had little effect on growth of proliferating, or the viability of confluent, Caco-2 cells. The uptake of clodronate by Caco-2 cells was only about 0.04% of total clodronate. The potentially cytotoxic clodronate metabolite, AppCCl(2)p, was detected in Caco-2 cell extracts after 3 h of exposure. Dianhydride- and triPOM-clodronate were metabolised to AppCCl(2)p more efficiently and also affected the viability of Caco-2 cells more than clodronate., Conclusions: Clodronate appears to be metabolised into a cytotoxic ATP-analogue (AppCCl(2)p) by any cell type capable of internalising the drug. However, the cytotoxicity depends on the degree of uptake of clodronate. Due to the very low initial uptake of clodronate by epithelial Caco-2 cells, they do not accumulate sufficient intracellular concentrations of AppCCl(2)p to affect cell function. This explains the low frequency of gastrointestinal side-effects caused by oral clodronate therapy.

This work was aimed at improving the absorption of bisphosphonates by targeting carrier systems in the intestine and the intestinal peptide carrier system (hPEPT1), in particular. (14)C-Labeled pamidronate and alendronate as well as radiolabeled and "cold" peptidyl-bisphosphonates, Pro-[(3)H]Phe-[(14)C]pamidronate, and Pro-[(3)H]Phe-[(14)C]alendronate were synthesized. In situ single-pass perfusion studies revealed competitive inhibition of transport by Pro-Phe, suggesting peptide carrier-mediated transport. Prodrug transport in the Caco-2 cell line was significantly better than that of the parent drugs, and the prodrugs exhibited high affinity to the intestinal tissue. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration in rats, and the bioavailability of Pro-Phe-alendronate was 3.3 (F(TIBIA)) and 1.9 (F(URINE)) times higher than that of the parent drug. The results indicate that the oral absorption of bisphosphonates can be improved by peptidyl prodrugs via the hPEPT1; however, other transporters may also be involved.