Profiling amyloid-ß peptides as biomarkers for cerebral amyloid angiopathy.

Brain amyloid-ß (Aß) deposits are key pathological hallmarks of both cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). Microvascular deposits in CAA mainly consist of the Aß40 peptide, whereas Aß42 is the predominant variant in parenchymal plaques in AD. The relevance in pathogenesis and diagnostic accuracy of various other Aß isoforms in CAA remain understudied. We aimed to investigate the biomarker potential of various Aß isoforms in cerebrospinal fluid (CSF) to differentiate CAA from AD pathology. We included 25 patients with probable CAA, 50 subjects with a CSF profile indicative of AD pathology (AD-like), and 23 age- and sex-matched controls. CSF levels of Aß1-34 , Aß1-37 , Aß1-38 , Aß1-39 , Aß1-40 , and Aß1-42 were quantified by liquid chromatography mass spectrometry. Lower CSF levels of all six Aß peptides were observed in CAA patients compared with controls (p = 0.0005-0.03). Except for Aß1-42 (p = 1.0), all peptides were decreased in CAA compared with AD-like subjects (p = 0.007-0.03). Besides Aß1-42 , none of the Aß peptides were decreased in AD-like subjects compared with controls. All Aß peptides combined differentiated CAA from AD-like subjects better (area under the curve [AUC] 0.84) than individual peptide levels (AUC 0.51-0.75). Without Aß1-42 in the model (since decreased Aß1-42 served as AD-like selection criterion), the AUC was 0.78 for distinguishing CAA from AD-like subjects. CAA patients and AD-like subjects showed distinct disease-specific CSF Aß profiles. Peptides shorter than Aß1-42 were decreased in CAA patients, but not AD-like subjects, which could suggest different pathological mechanisms between vascular and parenchymal Aß accumulation. This study supports the potential use of this panel of CSF Aß peptides to indicate presence of CAA pathology with high accuracy.

Financial hardship associated with catastrophic out-of-pocket spending tied to primary care services in low- and lower-middle-income countries: findings from a modeling study.

BACKGROUND: Financial risk protection (FRP) is a key component of universal health coverage (UHC): all individuals must be able to obtain the health services they need without experiencing financial hardship. In many low-income and lower-middle-income countries, however, the health system fails to provide sufficient protection against high out-of-pocket (OOP) spending on health services. In 2018, OOP health spending comprised approximately 40% of current health expenditures in low-income and lower-middle-income countries. METHODS: We model the household risk of catastrophic health expenditures (CHE), conditional on having a given disease or condition-defined as OOP health spending that exceeds a threshold percentage (10, 25, or 40%) of annual income-for 29 health services across 13 disease categories (e.g., diarrheal diseases, cardiovascular diseases) in 34 low-income and lower-middle-income countries. Health services were included in the analysis if delivered at the primary care level and part of the Disease Control Priorities, 3rd edition "highest priority package." Data were compiled from several publicly available sources, including national health accounts, household surveys, and the published literature. A risk of CHE, conditional on having disease, was modeled as depending on usage, captured through utilization indicators; affordability, captured via the level of public financing and OOP health service unit costs; and income. RESULTS: Across all countries, diseases, and health services, the risk of CHE (conditional on having a disease) would be concentrated among poorer quintiles (6.8% risk in quintile 1 vs. 1.3% in quintile 5 using a 10% CHE threshold). The risk of CHE would be higher for a few disease areas, including cardiovascular disease and mental/behavioral disorders (7.8% and 9.8% using a 10% CHE threshold), while lower risks of CHE were observed for lower cost services. CONCLUSIONS: Insufficient FRP stands as a major barrier to achieving UHC, and risk of CHE is a major problem for health systems in low-income and lower-middle-income countries. Beyond its threat to the financial stability of households, CHE may also lead to worse health outcomes, especially among the poorest for whom both ill health and financial risk are most severe. Modeling the risk of CHE associated with specific disease areas and services can help policymakers set progressive health sector priorities. Decision-makers could explicitly include FRP as a criterion for consideration when assessing the health interventions for inclusion in national essential benefit packages.

Attention-deficit/hyperactivity disorder (ADHD) symptoms and their relation to diagnosed ADHD, sociodemographic characteristics, and substance use among patients receiving opioid agonist therapy: a Norwegian cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) symptoms may challenge sufficient treatment of substance use and mental disorders. The literature on the extent of such symptoms among patients receiving opioid agonist therapy (OAT) is scarce. This study examined ADHD symptoms using the ADHD self-report scale (ASRS) and the association between the 'ASRS-memory' and 'ASRS-attention' scores and substance use and sociodemographic characteristics among patients receiving OAT. METHODS: We used data from assessment visits of a cohort of patients in Norway. In total, 701 patients were included from May 2017 to March 2022. All patients responded at least once to two ASRS questions assessing memory and attention, respectively. Ordinal regression analyses were performed to investigate whether the two obtained scores were associated with age, sex, frequent substance use, injecting use, housing status, and educational attainment at baseline, i.e., the first assessment, and over time. The results are presented as odds ratios (OR) with 95% confidence intervals (CI). Additionally, a subsample of 225 patients completed an extended interview, including the ASRS-screener and collection of registered mental disorder diagnoses from the medical records. Standard cutoffs were used to define the presence of each ASRS symptom or a positive ASRS-screener ('ASRS-positive'). RESULTS: At baseline, 428 (61%) and 307 (53%) patients scored over the cutoffs on the 'ASRS-memory' and 'ASRS-attention,' respectively. Frequent cannabis use was associated with higher 'ASRS-memory' (OR: 1.7, 95% CI: 1.1-2.6) and 'ASRS-attention' (1.7, 1.1-2.5) scores compared with less or no use at baseline, though reduced score on the 'ASRS-memory' over time (0.7, 0.6-1.0). At baseline, frequent stimulant use (1.8, 1.0-3.2) and low educational attainment (0.1, 0.0-0.8) were associated with higher 'ASRS-memory' scores. In the subsample fulfilling the ASRS-screener, 45% of the patients were 'ASRS-positive,' of whom 13% with a registered ADHD diagnosis. CONCLUSIONS: Our findings illustrate a relationship between the ASRS-memory and -attention scores and frequent cannabis and stimulant use. Furthermore, nearly half of the subsample was 'ASRS-positive.' Patients receiving OAT might benefit from being further assessed for ADHD, but improved diagnostic methods are required.

Association between oral and general health related quality of life among Norwegian patients with substance use disorders in opioid agonist therapy.

OBJECTIVE: Assess the association between oral and general health related quality of life using oral impacts on daily performances (OIDP) and the quality of life tool EQ-5D-5L from EuroQoL among patients with substance use disorder (SUD) who receive opioid agonist therapy. METHOD: 609 patients with SUD completed the EQ-5D-5L. A dental sub-study of 167 patients completed OIDP and an oral examination when attending outpatient clinics in Western Norway for their opioid agonist therapy. The merged analytical sample consisted of 165 patients. The association between OIDP and EQ-5D-5L was assessed by Spearman's rho and a linear multiple variable regression analysis. A line graph and a Pen's parade displayed the distributions of OIDP sum scores and EQ-5D-5L index values. RESULTS: Overall mean summary- and index EQ-5D-5L scores were 9.97 (sd 3.25) and 0.69 (sd 0.22). Mean score for OIDP was 9.75 (sd 9.59). Spearman's rho was 0.34 (p < .01) between OIDP and EQ-5D-5L summary scores. Linear regression revealed an association adjusted for sex and age of 0.12 (95% CI 0.07-0.17) and a coefficient of determination of 0.1460. CONCLUSION: This study reveals a strong association between OIDP and EQ-5D-5L reflecting the importance of oral health to general health for patients with SUD. Health care professionals should pay attention to oral health. Effective interventions might improve patients' oral and health related quality of life.

Microglia in Cultured Porcine Retina: Qualitative Immunohistochemical Analyses of Reactive Microglia in the Outer Retina.

A late stage of several retinal disorders is retinal detachment, a complication that results in rapid photoreceptor degeneration and synaptic damages. Experimental retinal detachment in vivo is an invasive and complicated method performed on anesthetized animals. As retinal detachment may result in visual impairment and blindness, research is of fundamental importance for understanding degenerative processes. Both morphological and ethical issues make the porcine retina a favorable organotypic model for studies of the degenerative processes that follow retinal detachment. In the cultured retina, photoreceptor degeneration and synaptic injuries develop rapidly and correlate with resident microglial cells' transition into a reactive phenotype. In this immunohistochemical study, we have begun to analyze the transition of subsets of reactive microglia which are known to localize close to the outer plexiform layer (OPL) in degenerating in vivo and in vitro retina. Biomarkers for reactive microglia included P2Ry12, CD63 and CD68 and the general microglial markers were CD11b, Iba1 and isolectin B4 (IB4). The reactive microglia markers labeled microglia subpopulations, suggesting that protective or harmful reactive microglia may be present simultaneously in the injured retina. Our findings support the usage of porcine retina cultures for studies of photoreceptor injuries related to retinal detachment.

Estimating impact of food choices on life expectancy: A modeling study.

BACKGROUND: Interpreting and utilizing the findings of nutritional research can be challenging to clinicians, policy makers, and even researchers. To make better decisions about diet, innovative methods that integrate best evidence are needed. We have developed a decision support model that predicts how dietary choices affect life expectancy (LE). METHODS AND FINDINGS: Based on meta-analyses and data from the Global Burden of Disease study (2019), we used life table methodology to estimate how LE changes with sustained changes in the intake of fruits, vegetables, whole grains, refined grains, nuts, legumes, fish, eggs, milk/dairy, red meat, processed meat, and sugar-sweetened beverages. We present estimates (with 95% uncertainty intervals [95% UIs]) for an optimized diet and a feasibility approach diet. An optimal diet had substantially higher intake than a typical diet of whole grains, legumes, fish, fruits, vegetables, and included a handful of nuts, while reducing red and processed meats, sugar-sweetened beverages, and refined grains. A feasibility approach diet was a midpoint between an optimal and a typical Western diet. A sustained change from a typical Western diet to the optimal diet from age 20 years would increase LE by more than a decade for women from the United States (10.7 [95% UI 8.4 to 12.3] years) and men (13.0 [95% UI 9.4 to 14.3] years). The largest gains would be made by eating more legumes (females: 2.2 [95% UI 1.1 to 3.4]; males: 2.5 [95% UI 1.1 to 3.9]), whole grains (females: 2.0 [95% UI 1.3 to 2.7]; males: 2.3 [95% UI 1.6 to 3.0]), and nuts (females: 1.7 [95% UI 1.5 to 2.0]; males: 2.0 [95% UI 1.7 to 2.3]), and less red meat (females: 1.6 [95% UI 1.5 to 1.8]; males: 1.9 [95% UI 1.7 to 2.1]) and processed meat (females: 1.6 [95% UI 1.5 to 1.8]; males: 1.9 [95% UI 1.7 to 2.1]). Changing from a typical diet to the optimized diet at age 60 years would increase LE by 8.0 (95% UI 6.2 to 9.3) years for women and 8.8 (95% UI 6.8 to 10.0) years for men, and 80-year-olds would gain 3.4 years (95% UI females: 2.6 to 3.8/males: 2.7 to 3.9). Change from typical to feasibility approach diet would increase LE by 6.2 (95% UI 3.5 to 8.1) years for 20-year-old women from the United States and 7.3 (95% UI 4.7 to 9.5) years for men. Using NutriGrade, the overall quality of evidence was assessed as moderate. The methodology provides population estimates under given assumptions and is not meant as individualized forecasting, with study limitations that include uncertainty for time to achieve full effects, the effect of eggs, white meat, and oils, individual variation in protective and risk factors, uncertainties for future development of medical treatments; and changes in lifestyle. CONCLUSIONS: A sustained dietary change may give substantial health gains for people of all ages both for optimized and feasible changes. Gains are predicted to be larger the earlier the dietary changes are initiated in life. The Food4HealthyLife calculator that we provide online could be useful for clinicians, policy makers, and laypeople to understand the health impact of dietary choices.

Correction: Estimating impact of food choices on life expectancy: A modeling study.

[This corrects the article DOI: 10.1371/journal.pmed.1003889.].

Prevalence and correlates of suicide attempts in high-risk populations: a cross-sectional study among patients receiving opioid agonist therapy in Norway.

BACKGROUND: Death by suicide in patients enrolled in opioid agonist therapy (OAT) is a major clinical concern. However, little knowledge exists regarding suicide attempts in this patient group. This study presents the lifetime prevalence of suicide attempts and the associations between suicide attempts and clinical and sociodemographic variables such as education, sex, early onset of substance use (< 13 years of age), substance use patterns, and injecting substance use among patients receiving OAT. METHODS: We used data from a cohort of OAT patients in Norway obtained from a health assessment of self-reported suicide attempts and sociodemographic and clinical factors. A total of 595 patients receiving OAT were assessed from 2016 to 2020. A binary logistic regression analysis was performed and reported with an unadjusted odds ratio and 95% confidence intervals (OR). The purpose of this assessment was to analyze associations between suicide attempts and substance use patterns as well as the injection of substances during the 30 days leading up to the health assessment. A negative binomial regression analysis with an incidence rate ratio and 95% confidence intervals (IRR) was performed to investigate sex, education, early onset of substance use, and the number of suicide attempts. RESULTS: Forty-one percent of the OAT patients had attempted to die by suicide at least once during their lifetime. An early onset of substance use was strongly associated with the suicide attempts (IRR: 1.7, 1.3-2.2). No significant association was found between suicide attempts and sex (IRR: 1.2, 0.9-1.6) or education (IRR: 0.6, 0.2-2.1). Likewise, no association was identified between suicide attempts and injecting substance use (OR: 0.9, 0.6-1.3), nor using alcohol (OR: 0.9, 0.7-1.3), amphetamines (OR: 1.0, 0.7-1.3), benzodiazepines (OR: 1.0, 0.7-1.4), cannabis (OR: 1.2, 0.9-1.7), cocaine (OR: 1.3, 0.6-3.0), or opioids (OR: 1.4, 0.9-2.0). CONCLUSION: The lifetime prevalence of suicide attempts was alarmingly high in the OAT population. An early onset of substance use seemed to be an important risk factor for suicide attempts. There was a non-significant association to more current use of opioids among OAT patients with previous suicide attempts.

Effectiveness and Safety of Low-Threshold Opioid-Agonist Treatment in Hard-To-Reach Populations with Opioid Dependence.

OBJECTIVES: Opioid-use disorder is related to premature death worldwide. Opioid-agonist treatment (OAT) is an effective treatment for opioid dependence. OAT delivery platforms may influence treatment access and outcomes, especially for the most vulnerable groups. The aim of this study was to determine the effectiveness and safety of low-threshold OAT compared to the standard treatment. METHODS: Patients with diagnosed opioid dependence undergoing low-threshold OAT at the Bergen delivery platform in Norway were enrolled in a cohort study in 2014-2019. A national OAT cohort was the reference group. The main outcomes were treatment retention, the use of illicit opioids, non-fatal overdose, overdose death, and all-cause mortality during the first year following treatment initiation and the full treatment period. Additionally, healthcare utilization in the periods before and during OAT was investigated. RESULTS: Compared to the reference cohort, the low-threshold cohort (n = 128, mean age: 38 years, women: 28%) showed treatment retention rates of 95% versus 92%, illicit opioid use of 7% versus 10%, non-fatal overdose of 7% versus 6%, and death at 1.0% versus 1.3%, respectively. The incident rate ratios (IRRs) for healthcare utilization increased substantially during the OAT period compared to the period before; the IRR increased by 3.3 (95% confidence interval (CI): 2.8, 3.9) and 3.4 (95% CI: 3.1, 3.9) for all in- and outpatient healthcare, respectively. CONCLUSIONS: Low-threshold OAT was at least as effective and safe as the standard OAT in terms of treatment retention, the use of illicit opioids, non-fatal overdose, and death. Healthcare utilization increased during the OAT compared to the period before. Lowering the threshold for OAT entrance within proper delivery platforms should be broadly considered to reduce harm and improve healthcare access among patients with opioid dependence.

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

BACKGROUND: The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID. METHODS AND FINDINGS: INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment. CONCLUSIONS: Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov.no NCT03155906.

Health equity impact of community-initiated kangaroo mother care: a randomized controlled trial.

BACKGROUND: Kangaroo mother care (KMC) can substantially enhance overall survival of low birthweight babies. In a large randomized controlled trial, we recently showed that supporting mothers to provide community initiated KMC (ciKMC) can reduce mortality among infants up to 180 days of life by 25% (hazard ratio (HR) 0.75). With the current analysis, we aimed to explore if ciKMC promotion leads to increased inequity in survival. METHODS: In the trial we randomized 8402 low birthweight babies to a ciKMC (4480 babies) and a control (3922 babies) arm, between 2015 and 2018 in Haryana, India. We estimated the difference in concentration indices, which measure inequality, between babies in the ciKMC and control arms for survival until 180 days of life. Further, we compared the effect of ciKMC promotion across subgroups defined by socioeconomic status, caste, maternal literacy, infant's sex, and religion. RESULTS: Our intervention did not increase survival inequity, as the concentration index in the ciKMC arm of the trial was 0.05 (95% CI -0.07 to 0.17) lower than in the control arm. Survival impact was higher among those belonging to the lower two wealth quintiles, those born to illiterate mothers and those belonging to religions other than Hindu. CONCLUSIONS: We found that ciKMC promotion did not increase inequity in survival associated with wealth. The beneficial impact of ciKMC tended to be larger among vulnerable groups. Supporting mothers to provide KMC at home to low birthweight babies will not increase and could indeed reduce inequities in infant survival. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02653534 . Registered January 12, 2016-Retrospectively registered.

Generalised cost-effectiveness analysis of 159 health interventions for the Ethiopian essential health service package.

BACKGROUND: Cost effectiveness was a criterion used to revise Ethiopia's essential health service package (EHSP) in 2019. However, there are few cost-effectiveness studies from Ethiopia or directly transferable evidence from other low-income countries to inform a comprehensive revision of the Ethiopian EHSP. Therefore, this paper reports average cost-effectiveness ratios (ACERs) of 159 health interventions used in the revision of Ethiopia's EHSP. METHODS: In this study, we estimate ACERs for 77 interventions on reproductive maternal neonatal and child health (RMNCH), infectious diseases and water sanitation and hygiene as well as for 82 interventions on non-communicable diseases. We used the standardised World Health Organization (WHO) CHOosing Interventions that are cost effective methodology (CHOICE) for generalised cost-effectiveness analysis. The health benefits of interventions were determined using a population state-transition model, which simulates the Ethiopian population, accounting for births, deaths and disease epidemiology. Healthy life years (HLYs) gained was employed as a measure of health benefits. We estimated the economic costs of interventions from the health system perspective, including programme overhead and training costs. We used the Spectrum generalised cost-effectiveness analysis tool for data analysis. We did not explicitly apply cost-effectiveness thresholds, but we used US$100 and $1000 as references to summarise and present the ACER results. RESULTS: We found ACERs ranging from less than US$1 per HLY gained (for family planning) to about US$48,000 per HLY gained (for treatment of stage 4 colorectal cancer). In general, 75% of the interventions evaluated had ACERs of less than US$1000 per HLY gained. The vast majority (95%) of RMNCH and infectious disease interventions had an ACER of less than US$1000 per HLY while almost half (44%) of non-communicable disease interventions had an ACER greater than US$1000 per HLY. CONCLUSION: The present study shows that several potential cost-effective interventions are available that could substantially reduce Ethiopia's disease burden if scaled up. The use of the World Health Organization's generalised cost-effectiveness analysis tool allowed us to rapidly calculate country-specific cost-effectiveness analysis values for 159 health interventions under consideration for Ethiopia's EHSP.

Contextualization of cost-effectiveness evidence from literature for 382 health interventions for the Ethiopian essential health services package revision.

BACKGROUND: Cost-effectiveness of interventions was a criterion decided to guide priority setting in the latest revision of Ethiopia's essential health services package (EHSP) in 2019. However, conducting an economic evaluation study for a broad set of health interventions simultaneously is challenging in terms of cost, timeliness, input data demanded, and analytic competency. Therefore, this study aimed to synthesize and contextualize cost-effectiveness evidence for the Ethiopian EHSP interventions from the literature. METHODS: The evidence synthesis was conducted in five key steps: search, screen, evaluate, extract, and contextualize. We searched MEDLINE and EMBASE research databases for peer-reviewed published articles to identify average cost-effectiveness ratios (ACERs). Only studies reporting cost per disability-adjusted life year (DALY), quality-adjusted life year (QALY), or life years gained (LYG) were included. All the articles were evaluated using the Drummond checklist for quality, and those with a score of at least 7 out of 10 were included. Information on cost, effectiveness, and ACER was extracted. All the ACERs were converted into 2019 US dollars using appropriate exchange rates and the GDP deflator. RESULTS: In this study, we synthesized ACERs for 382 interventions from seven major program areas, ranging from US$3 per DALY averted (for the provision of hepatitis B vaccination at birth) to US$242,880 per DALY averted (for late-stage liver cancer treatment). Overall, 56% of the interventions have an ACER of less than US$1000 per DALY, and 80% of the interventions have an ACER of less than US$10,000 per DALY. CONCLUSION: We conclude that it is possible to identify relevant economic evaluations using evidence from the literature, even if transferability remains a challenge. The present study identified several cost-effective candidate interventions that could, if scaled up, substantially reduce Ethiopia's disease burden.

Validation of a three-item Fatigue Severity Scale for patients with substance use disorder: a cohort study from Norway for the period 2016-2020.

BACKGROUND: Little attention has been paid to customising fatigue questionnaires for patients with Substance Use Disorders (SUDs). The present study aims to validate and shorten the nine-item Fatigue Severity Scale (FSS-9) and Visual Analogue Fatigue Scale (VAFS) for use with this population. METHODS: We used data from a nested cohort with annual health assessments with responses on the FSS-9 and VAFS. During the period 2016-2020, 917 health assessments were collected from 655 patients with SUD in Bergen and Stavanger, Norway. A total of 225 patients answered the health assessment at least twice. We defined baseline as the first annual health assessment when the health assessments were sorted chronologically per patient. We checked for internal consistency, and we used longitudinal confirmatory factor analysis (CFA) and linear mixed model (LMM) analysis to validate and shorten the FSS-9 and VAFS. RESULTS: The internal consistency of the FSS-9 was excellent with a Cronbach's α of 0.94 at baseline and 0.93 at the second annual health assessment. When shortening the FSS-9 to a three-item FSS (FSS-3, items 5-7), the Cronbach's α was 0.87 at baseline and 0.84 at the second health assessment. The internal consistency was not affected when the VAFS was added to the FSS-3 and the FSS-9. The longitudinal CFA model showed a well-fitting model for the FSS-3 (χ2 = 13.33, degree of freedom = 8, P = 0.101). The LMM analysis showed equal linear changes at the individual level for the FSS-3 (slope: 0.00, P > 0.05) and FSS-9 (slope: 0.01, P > 0.05) between the health assessments. CONCLUSION: The FSS-9 could be shortened to the FSS-3 with high validity and reliability for patients with SUDs and the addition of VAFS did not provide much added variability.

Morphological analyzes of microglia heterogeneity and dynamics during photoreceptor degeneration in vitro: Presumptive dark microglia in porcine retina.

In the adult retina, ramifying microglia interact with the outer plexiform layer (OPL) monitoring the synaptic integrity between photoreceptors and post-synaptic target cells. Microglia are reactive during photoreceptor diseases, but their disease-related function(s) are not fully understood. Retinal explant cultures are model systems used to study degenerative events including photoreceptor degeneration and gliosis. Our culture paradigm, with adult porcine retinas subjected to coculture with human A-retinal pigment epithelia-19 (ARPE) cells, is an experimental approach resulting in improved photoreceptor survival and reduced gliosis. Under the in vitro pathological conditions with photoreceptor degeneration, reactive Iba1-and CD11b-immunoreactive microglia and their processes positioned in proximity with the OPL and among photoreceptor outer segments. Coculture for 3 days with ARPE-cells resulted in a significantly increased density of microglia at the OPL. After 5 days of culture, the density of microglia at the OPL was similar between coculture and control specimens. Electron microscopy revealed the presence of two subtypes of microglia: one exhibiting a dark nucleus and cytosol with dilated endoplasmic reticulum, vacuoles, endosomes and mitochondrial variations. This subtype localized close to synaptic structures in the OPL. The other subtype appeared as pale phagocytic microglia localized among degenerating outer segments. The Iba1-and CD11b-immunoreactive microglia in degenerating retina may be of two separate subtypes, which differ in localization, subcellular morphology and perhaps function.

Health gains and financial risk protection afforded by public financing of selected malaria interventions in Ethiopia: an extended cost-effectiveness analysis.

BACKGROUND: Malaria is a public health burden and a major cause for morbidity and mortality in Ethiopia. Malaria also places a substantial financial burden on families and Ethiopia's national economy. Economic evaluations, with evidence on equity and financial risk protection (FRP), are therefore essential to support decision-making for policymakers to identify best buys amongst possible malaria interventions. The aim of this study is to estimate the expected health and FRP benefits of universal public financing of key malaria interventions in Ethiopia. METHODS: Using extended cost-effectiveness analysis (ECEA), the potential health and FRP benefits were estimated, and their distributions across socio-economic groups, of publicly financing a 10% coverage increase in artemisinin-based combination therapy (ACT), long-lasting insecticide-treated bed nets (LLIN), indoor residual spraying (IRS), and malaria vaccine (hypothetical). RESULTS: ACT, LLIN, IRS, and vaccine would avert 358, 188, 107 and 38 deaths, respectively, each year at a net government cost of $5.7, 16.5, 32.6, and 5.1 million, respectively. The annual cost of implementing IRS would be two times higher than that of the LLIN interventions, and would be the main driver of the total costs. The averted deaths would be mainly concentrated in the poorest two income quintiles. The four interventions would eliminate about $4,627,800 of private health expenditures, and the poorest income quintiles would see the greatest FRP benefits. ACT and LLINs would have the largest impact on malaria-related deaths averted and FRP benefits. CONCLUSIONS: ACT, LLIN, IRS, and vaccine interventions would bring large health and financial benefits to the poorest households in Ethiopia.

Financial risk of seeking maternal and neonatal healthcare in southern Ethiopia: a cohort study of rural households.

INTRODUCTION: Ethiopian households' out-of-pocket healthcare payments constitute one-third of the national healthcare budget and are higher than the global and low-income countries average, and even the global target. Such out-of-pocket payments pose severe financial risks, can be catastrophic, impoverishing, and one of the causal barriers for low utilisation of healthcare services in Ethiopia. This study aimed to assess the financial risk of seeking maternal and neonatal healthcare in southern Ethiopia. METHODS: A population-based cohort study was conducted among 794 pregnant women, 784 postpartum women, and their 772 neonates from 794 households in rural kebeles of the Wonago district, southern Ethiopia. The financial risk was estimated using the incidence of catastrophic healthcare expenditure, impoverishment, and depth of poverty. Annual catastrophic healthcare expenditure was determined if out-of-pocket payments exceeding 10% of total household or 40% of non-food expenditure. Impoverishment was analysed based on total household expenditure and the international poverty line of ≈ $1.9 per capita per day. RESULTS: Approximately 93% (735) of pregnant women, 31% (244) of postpartum women, and 48% (369) of their neonates experienced illness. However, only 56 households utilised healthcare services. The median total household expenditure was $527 per year (IQR = 390: 370,760). The median out-of-pocket healthcare payment was $46 per year (IQR = 46: 46, 92) with two episodes per household, and shared 19% of the household's budget. The poorer households paid more than did the richer for healthcare, during pregnancy-related and neonatal illness. However, the richer paid more than did the poorer during postpartum illness. Forty-six percent of households faced catastrophic healthcare expenditure at the threshold of 10% of total household expenditure, or 74% at a 40% non-food expenditure, and associated with neonatal illness (aRR: 2.56, 95%CI: 1.02, 6.44). Moreover, 92% of households were pushed further into extreme poverty and the poverty gap among households was 45 Ethiopian Birr per day. The average household size among study households was 4.7 persons per household. CONCLUSIONS: This study demonstrated that health inequity in the household's budget share of total OOP healthcare payments in southern Ethiopia was high. Besides, utilisation of maternal and neonatal healthcare services is very low and seeking such healthcare poses a substantial financial risk during illness among rural households. Therefore, the issue of health inequity should be considered when setting priorities to address the lack of fairness in maternal and neonatal health.

Dispensation of attention deficit hyperactivity disorder (ADHD) medications in patients receiving opioid agonist therapy; a national prospective cohort study in Norway from 2015 to 2017.

BACKGROUND: It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated. METHODS: Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection. RESULTS: A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2-2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016. CONCLUSION: Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.

Too much or too little opioids to patients receiving opioid agonist therapy in Norway (2013-2017): a prospective cohort study.

BACKGROUND: Dispensations of opioid analgesics to patients on opioid agonist therapy (OAT) may increase the risk of overdoses. The current study's objectives are to investigate the dispensation rates and mean daily doses of dispensed opioid analgesics among patients who received OAT opioids in Norway during 2013-2017 and evaluate whether discontinuing OAT opioids affects the dispensed dose of opioid analgesics. METHODS: Information on opioids was collected from the Norwegian Prescription Database. Dispensation rates were calculated by dividing the number of patients who were dispensed at least one opioid analgesic by the number of patients who were dispensed an OAT opioid. We calculated the mean daily dose of opioid analgesics in oral morphine equivalents. The OAT opioid dose was defined as a ratio between the dispensed doses divided by the mean recommended dose. We used logistic regression to estimate the association between the dispensation of an opioid analgesic, a dose of OAT opioids, having chronic pain, and being on palliative care. RESULTS: A total of 10,371 patients were dispensed at least one OAT opioid during the study period. In 2017, 18% were dispensed an opioid analgesic with a mean daily dose of 29 mg of oral morphine equivalents. Being dispensed an opioid analgesic was associated with having chronic pain (adjusted odds ratio (aOR): 3.6, 95% confidence interval: 3.2-4.2), being on palliative care (aOR: 6.1, 4.7-7.9), and receiving an OAT opioid dose below half of the recommended OAT dose (aOR: 1.7, 1.4-2.0). Similar results were seen in 2013-2016. The discontinuation of OAT opioids could increase the dose of dispensed opioid analgesics. CONCLUSION: Reducing the dispensation of opioid analgesics can be achieved by increasing the OAT opioid dose for patients on a low OAT dose, and by extending the period needed to taper off the OAT opioid dose at discontinuation.

Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients receiving opioid agonist therapy; a prospective cohort study in Norway from 2013 to 2017.

BACKGROUND: Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients on opioid agonist therapy (OAT) are common and have pros and cons. The objectives of the current study are to define the dispensation rates of these potentially addictive drugs, and whether the number and the mean daily doses of dispensed OAT opioids and discontinuing OAT, are associated with being dispensed benzodiazepines, z-hypnotics and gabapentinoids among patients on OAT in Norway in the period 2013 to 2017. METHODS: Information about all dispensed opioids, benzodiazepines, z-hypnotics and gabapentinoids were recorded from the Norwegian Prescription Database (NorPD). A total of 10,371 OAT patients were included in the study period. The dispensation rates were defined as the number of patients who were dispensed at least one of the potentially addictive drugs divided among the number of patients who have dispensed an OAT opioid per calendar year. Mean daily doses were calculated, and for benzodiazepines and z-hypnotics, stated in diazepam equivalents. The association between dispensed potentially addictive drugs, and the number and the type of dispensed OAT opioids were calculated by using logistic regression models. RESULTS: Half of the OAT patients received at least one dispensation of a benzodiazepine or z-hypnotic, and 11% were dispensed at least a gabapentinoid in 2017. For dispensed benzodiazepines or z-hypnotics, the mean daily dose was reduced from 21 mg (95% confidence interval (CI): 20-23) diazepam equivalents in 2013 to 17 mg (95% CI: 16-17) in 2017. The mean daily dose of pregabalin increased from 365 mg (95% CI: 309-421) in 2013 to 386 mg (95% CI: 349-423) in 2017. Being dispensed a gabapentinoid (adjusted odds ratio (aOR) = 2.5, 95% CI: 2.1-3.0) or a non-OAT opioid (aOR = 3.0, 95% CI: 2.6-3.5) was associated with being dispensed a benzodiazepine or z-hypnotic. Discontinuing OAT did not affect the number of dispensations and the doses of potentially addictive drugs. CONCLUSION: The dispensation rates of potentially addictive drugs are high in the OAT population. Treatment indications, as well as requirements for prescription authority, need to be debated and made explicit. Randomized controlled trials evaluating the benefits and risks of such co-prescription are required.