Treatment patterns in myasthenia gravis: A United States health claims analysis.

INTRODUCTION/AIMS: Limited knowledge exists on treatment patterns in clinical practice in patients with myasthenia gravis (MG). In this study we examined MG treatment patterns in the United States. METHODS: Adult patients newly diagnosed with MG were identified from the IBM MarketScan insurance claims database. Patients with ≥2 MG International Classification of Disease diagnosis codes ≥3 months apart were retrospectively followed from the date of their first MG diagnosis record or start of treatment with acetylcholinesterase inhibitors (AChEI), intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig), or plasma exchange (PLEx) therapy. Based on treatment received at any time during the follow-up period, patients were segmented into six main treatment cohorts. Exacerbations and use of IVIg, SCIg, or PLEx after the index date were identified. RESULTS: During 2010 to 2019, 7,194 patients were followed for up to 10 (median, 2.3) years. Of 6,539 treated patients, 6,462 (99%) were ever treated with AChEI and/or corticosteroids (CS); 95% were first treated with AChEI and/or CS only; 33% received ≥1 nonsteroid immunosuppressive treatment (IST) and 2% received a biologic. During treatment with first IST (n = 2,166), patients experienced 42% and 94% higher incidence rates of exacerbations and IVIg, respectively, compared with AChEI and/or CS (n = 6,242), and 33% and 23% higher, respectively, compared with a second IST (n = 353). DISCUSSION: Many patients experienced exacerbations and received rescue therapy despite treatment, suggesting current treatments may not provide adequate disease control for some patients and that additional treatment options should be explored.

Prenatal Methamphetamine Exposure and Adverse Neonatal Outcomes: A Nationwide Cohort Study.

BACKGROUND: There is limited knowledge on the adverse outcomes in newborns after maternal methamphetamine (MA) use during pregnancy. OBJECTIVES: To compare neonatal outcomes in newborns exposed to MA with the newborns of opioid-exposed mothers and of mothers from the general population (GP). METHOD: A cohort study using nationwide registries in Czechia (2000-2014). Women hospitalized with a main diagnosis of MA use disorder during pregnancy (n = 258) and their newborns were defined as MA-exposed. The comparison groups consisted of women (n = 199) diagnosed with opioid use disorder during pregnancy, defined as opioid-exposed, and women (n = 1,511,310) with no substance use disorder diagnosis (GP). The neonatal outcomes studied were growth parameters, gestational age, preterm birth, and Apgar score. To explore the associations between MA exposure and neonatal outcomes, regression coefficients (b) and odds ratios from multivariable linear and binary logistic regression were estimated. RESULTS: MA-exposed women had similar socio-economic characteristics to opioid-exposed, both of which were worse than in the GP. After adjustment, MA exposure was associated with a more favourable birthweight when compared to the opioid-exposed (adjusted mean differences [aMD] b = 122.3 g, 95% CI: 26.0-218.5) and length (aMD b = 0.6 cm, 0.0-1.1). Unadjusted results from the comparison with the GP showed that the MA group had poorer neonatal outcomes, especially in the growth parameters. Adjustment for background characteristics had a profound effect on the comparison with the GP. After adjustment, MA exposure was associated only with a slightly reduced birthweight (aMD b = -63.0 g, -123.0 to -3.1) and birth length (aMD b = -0.3 cm, -0.6 to 0.0). CONCLUSIONS: Although the observed negative outcomes were large in the MA-exposed newborns, the adjustment had a profound effect on the comparison with the GP, indicating the large influence of lifestyle and socio-economic factors in these high-risk pregnancies. MA-exposed newborns had better neonatal outcomes compared to opioids-exposed.

Cannabis Use during Pregnancy and Risk of Adverse Birth Outcomes: A Longitudinal Cohort Study.

BACKGROUND: With recent changes in legislation regulating recreational and medical cannabis use around the globe, increased use in pregnancy is to be expected. OBJECTIVES: To investigate the association between cannabis use during pregnancy and birth outcomes. METHOD: Data from the Norwegian Mother and Child Cohort Study (MoBa), a prospective pregnancy cohort, were used. Participants were recruited from all over Norway between 1999 and 2008: 9,312 women with 10,373 pregnancies who reported use of cannabis before or in pregnancy. Women reported on their illegal drug use before pregnancy and at pregnancy weeks 17/18 and 30 and at 6 months postpartum. Linear regression was used to estimate crude and adjusted effects of prenatal cannabis exposure on birth outcomes. RESULTS: In 10,101 pregnancies, women had used cannabis before pregnancy but not during pregnancy. In 272 pregnancies, women had used cannabis during pregnancy, and among these, in 63 pregnancies, women had used cannabis in at least 2 periods. In adjusted analyses for potential confounders, only cannabis use during at least 2 periods of pregnancy showed statistically significant effects on birth weight. The effect was observed in the complete cohort (B = -228 g, 95% CI = -354 to -102, p < 0.001) and for the subgroup where information about the child's father was available (B = -225 g, 95% CI = -387 to -63, p = 0.01). Our results may indicate that prolonged use causes more harm, whereas short-term use did not indicate adverse effects on birth outcomes. CONCLUSIONS: There was a statistically significant and clinically relevant association between the use of cannabis during pregnancy and reduced birth weight. Clinicians should screen not only for cannabis use but also for the length and intensity of use as part of a comprehensive substance use screening.

In utero opioid exposure and risk of infections in childhood: A multinational Nordic cohort study.

PURPOSE: There is an increasing number of children with in utero exposure to opioids. Knowledge about opioid safety in pregnancy, particularly for outcomes later in childhood is scarce. It has been suggested that opioids can modulate immune system and increase the risk of infections. Our goal was to study the impact of in utero opioid exposure on the immune system and the risk of infections in childhood. METHODS: This population-based cohort study used nationwide registers from Denmark, Norway, and Sweden. Among pregnant women we identified users of opioids for two different indications, opioids used in opioid maintenance therapy (OMT) and opioids used for treatment of pain. We followed the exposed children and studied susceptibility for infections measured as number of antibiotic prescriptions expressed as Incidence rate ratios (IRRs) and diagnoses in specialist health care expressed as hazard ratios (HRs). RESULTS: After adjustment we did not observe increased risk for filling antibiotic prescriptions in children exposed to OMT opioids compared with OMT discontinuers (IRR, 1.08; 95% CI 0.81-1.44 in Norway and Sweden, and IRR, 0.74; 95% CI 0.63-0.88 in Denmark), or for diagnosis of infection in specialist health care (HR 0.83; 95% CI 0.55-1.26 in Norway and Sweden, and 0.82; 95% CI 0.62-1.10 in Denmark). CONCLUSIONS: In this population-based cohort study, we did not observe increased risk of infections among children prenatally exposed to OMT opioids when compared to OMT discontinuers, nor long-term analgesic opioids exposed when compared to short-term analgesic opioids exposed.

Use of nasal fentanyl for cancer pain: A pharmacoepidemiological study.

BACKGROUND: Breakthrough pain affects 40%-90% of patients with cancer pain. Nasal fentanyl is one of the recommended treatments, particularly if the breakthrough pain is of rapid onset. AIM: To investigate the prevalence of use of nasal fentanyl, to study which strong opioids have been used prior to nasal fentanyl and to examine which opioids are used concomitantly with nasal fentanyl. DESIGN: Longitudinal cohort study based on death cohorts defined according to year of death. SETTING/PARTICIPANTS: The study is based on data from the complete national Norwegian Prescription Database. The study population included all persons in Norway who died in the years 2010, 2011 and 2012 and who had received nasal fentanyl with reimbursement for palliative treatment. RESULTS: Of those who died from cancer in 2010, 2011 and 2012, 611 persons (2%) received dispensed prescriptions of nasal fentanyl. Two-thirds had received other short-acting strong opioids before nasal fentanyl. One quarter did not receive a long-acting opioid concomitantly with nasal fentanyl, but 68% of these received only one dispensed prescription of nasal fentanyl. Of those who received a long-acting opioid together with nasal fentanyl, transdermal fentanyl was the most common drug (65%). One-third received another short-acting opioid concomitantly with nasal fentanyl. CONCLUSION: The use of nasal fentanyl was surprisingly low. There is a need for clinical research addressing the use of nasal fentanyl without a long-acting opioid for background pain and the use of nasal fentanyl together with another short-acting opioid.

Prevalence of use of non-prescription analgesics in the Norwegian HUNT3 population: Impact of gender, age, exercise and prescription of opioids.

BACKGROUND: There are concerns about potential increasing use of over-the-counter (OTC) analgesics. The aims of this study were to examine 1) the prevalence of self-reported use of OTC analgesics; 2) the prevalence of combining prescription analgesics drugs with OTC analgesics and 3) whether lifestyle factors such as physical activity were associated with prevalence of daily OTC analgesic use. METHODS: Questionnaire data from the Nord-Trøndelag health study (HUNT3, 2006-08), which includes data from 40,000 adult respondents. The questionnaire included questions on use of OTC analgesics, socioeconomic conditions, health related behaviour, symptoms and diseases. Data were linked to individual data from the Norwegian Prescription Database. A logistic regression was used to investigate the association between different factors and daily use of paracetamol and/or non-steroid anti-inflammatory drugs (NSAIDs) in patients with and without chronic pain. RESULTS: The prevalence of using OTC analgesics at least once per week in the last month was 47%. Prevalence of paracetamol use was almost 40%, compared to 19% and 8% for NSAIDs and acetylsalicylic acid (ASA), respectively. While the use of NSAIDs decreased and the use of ASA increased with age, paracetamol consumption was unaffected by age. Overall more women used OTC analgesics. About 3-5% of subjects using OTC analgesics appeared to combine these with the same analgesic on prescription. Among subjects reporting chronic pain the prevalence of OTC analgesic use was almost twice as high as among subjects without chronic pain. Subjects with little physical activity had 1.5-4 times greater risk of daily use of OTC compared to physically active subjects. CONCLUSIONS: Use of OTC analgesics is prevalent, related to chronic pain, female gender and physical inactivity.

Healthcare resource use in myasthenia gravis: a US health claims analysis.

Background: There are limited data on the impact of myasthenia gravis (MG) on real-world healthcare resource use (HCRU) and patient burden in the United States. Objectives: This study aims to assess HCRU in patients with MG using data from a US health claims database. Design: A retrospective, database study of adult patients newly diagnosed with MG, using the IBM® MarketScan® Commercial Claims and Encounters and Medicare supplemental health insurance claims database. Methods: Patients with ⩾2 MG International Classification of Disease diagnosis codes ⩾3 months apart were followed from the date of their first MG diagnosis record or start of treatment. HCRU and use of immunoglobulins and plasma exchange during follow-up was assessed, as well as comorbidities, hospitalizations, emergency room (ER) visits, intensive care unit (ICU) admissions, and specialist visits per year after diagnosis, and compared with age- and sex-matched non-MG controls. Results: During 2010-2019, 7194 patients were followed for up to 10 years (median = 2.3 years). During follow-up, patients with MG were 2.6-fold more likely than controls to be hospitalized, and 4.5-fold more likely to be admitted to an ICU. Risk and numbers of ER admission, hospitalization, and ICU visits were the highest in the 12 months post-diagnosis of MG and were consistently higher than controls during follow-up. MG was the main cause for most hospitalizations. Conclusion: Patients with MG have higher HCRU, compared with the age- and sex-matched non-MG controls. The early years after MG diagnosis are a period of particularly high healthcare burden, with many patients requiring hospitalization and ICU care to manage serious exacerbations.

Physician- and patient-reported perspectives on myasthenia gravis in Europe: a real-world survey.

BACKGROUND: Myasthenia gravis (MG) is a rare, chronic, debilitating, unpredictable, and potentially life-threatening neuromuscular disease. There is a lack of real-world data on disease management that could be used to further understand and address unmet patient needs and burden. We aimed to provide comprehensive real-world insights in the management of MG in five European countries. METHODS: Data were collected using the Adelphi Real World Disease Specific Programme™ in MG, a point-in-time survey of physicians and their patients with MG in France, Germany, Italy, Spain, and the United Kingdom (UK). Physician- and patient-reported clinical data were collected, including demographics, comorbidities, symptoms, disease history, treatments, healthcare resource utilization (HCRU), and quality of life outcomes. RESULTS: In total, 144 physicians completed 778 patient record forms from March to July 2020 in the UK, and from June to September 2020 in France, Germany, Italy and Spain. Mean patient age at symptom onset was 47.7 years, with a mean time from symptom onset to diagnosis of 332.4 days (10.97 months). At diagnosis, 65.3% of patients were classified as Myasthenia Gravis Foundation of America Class II or above. Mean number of symptoms reported at diagnosis per patient was five, with ocular myasthenia reported in at least 50% of patients. At time of survey completion, the mean number of symptoms reported per patient was five and ocular myasthenia and ptosis were each still present in more than 50% of patients. Acetylcholinesterase inhibitors were the most commonly prescribed chronic treatments in all countries. Of 657 patients treated with chronic treatment at the time of the survey, 62% continued to experience moderate-to-severe symptoms. On average, 3.1 healthcare professionals (HCPs) were involved in patient management, 6.2 consultations were made per patient with any HCP over the last 12 months, and 178 (22.9%) patients were hospitalized in the last 12 months. Overall, HCRU and disease management were similar across all countries. CONCLUSIONS: Our findings demonstrated the high burden of MG despite current treatment options for patients with MG.

Epidemiology and treatment of myasthenia gravis: a retrospective study using a large insurance claims dataset in Germany.

Myasthenia gravis (MG) is a rare, chronic autoimmune disease with symptoms of fluctuating muscular weakness and fatigability. The aim of this retrospective cohort study was to estimate the prevalence and incidence of MG in Germany, and to understand the burden of disease and treatment patterns, based on anonymized German claims data. Two patient samples were identified: (1) incident MG patients with newly onset disease between 2015 and 2019, and (2) prevalent MG patients in 2019. In total, 775 incident MG patients with a mean age of 66.9 years; and 1,247 prevalent MG patients with a mean age of 68.6 years were included. The prevalence for Germany was estimated to be 39.3/100,000 on 31/12/2019; the incidence in 2019 was 4.6 cases/100,000 persons. The 12-month mortality was 5.7. For 31.5% of the incident patients, no MG treatment was observed in the first year after the index date. Of all incident patients, 29.9% experienced an exacerbation, and 6.7% a myasthenic crisis during the observation. Our study indicates that a substantial proportion of MG patients remains untreated. Many MG patients still experience exacerbations / MG crises. MG seems to be associated with an excess mortality in comparison to the general non-MG population.

Prenatal opioid exposure and risk of asthma in childhood: a population-based study from Denmark, Norway, and Sweden.

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown. Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma. Methods: Cohort study using linked nationwide registers in Denmark (1996-2015), Norway (2005-2015), and Sweden (2006-2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixed-effects meta-analysis. Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust. Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions.

[Education and use of drugs in Norway]. / Utdanning og legemiddelbruk.

BACKGROUND: Many studies have demonstrated that a low socioeconomic status is associated with poor health. The aim of the study was to investigate whether use of prescription drugs, generally and within selected categories, varies with education. MATERIAL AND METHOD: Data on education from the 2001 Population and Housing Census for 645,023 men and women born in the period 1960-1969 and living in Norway in 2001 were linked to data from the Norwegian Prescription Database on drugs dispensed in the period 2004-2009. The overall frequency of drug dispensing was compared with six levels of education. The relative risk associated with limited education (≤ 10 years) compared with long education (> 10 years) of having at least one drug dispensed during the period was calculated for 42 selected drug categories. RESULTS: There was a dose-response relationship between education and the number of drug prescriptions dispensed. Subjects with lower secondary education collected prescription drugs about three times as often on average as subjects with researcher education. The average relative risk of drug dispensing for subjects with short education (≤ 10 years) compared with long (>10 years) for the 42 selected drug categories was 1.29 for men and 1.31 for women. INTERPRETATION: Given that dispensing of drugs is an expression of state of health, our findings support earlier studies that have shown that there is social inequality in the health of the adult population.

Physician-Reported Perspectives on Myasthenia Gravis in the United States: A Real-World Survey.

INTRODUCTION: Myasthenia gravis (MG) is a rare, debilitating, chronic disorder caused by the production of pathogenic immunoglobulin G autoantibodies against the neuromuscular junction. A lack of real-world studies in rare diseases reflects a relatively limited understanding of the significant unmet needs and burden of disease for patients. We aimed to provide comprehensive real-world insights into the management and burden of MG from treating physicians in the United States (US). METHODS: Data were collected using the Adelphi Real World MG Disease Specific Programme™, a point-in-time survey of physicians and their patients with MG, in the US between March and July 2020. Physician-reported clinical data, including demographics, comorbidities, symptoms, disease history, treatments, and healthcare resource utilization, were collected. RESULTS: In total, 456 patient record forms were completed by 78 physicians based in the US. At time of survey completion, patient mean age was 54.5 years. Mean time from symptom onset to diagnosis was 9.0 months (n = 357). Ocular symptoms were reported in 71.7% of patients. General fatigue affected 47.1% of patients and over half of those reported the severity as moderate or severe (59.5%, n = 128). Acetylcholinesterase inhibitors and/or steroids were the most frequently prescribed first-line treatment type among patients receiving treatment at time of survey completion and with moderate-to-severe symptoms (77.9%, n = 159/204). High-dose steroids (n = 14) and intravenous immunoglobulin (n = 13) were the most prescribed acute treatments among those receiving an acute treatment at time of survey completion (n = 36), with symptom exacerbations or myasthenic crises being the most common reasons for acute treatment. On average, 2.5 healthcare professionals were involved in patient management and 5.0 consultations were made per patient over the last 12 months. CONCLUSIONS: Our findings indicated that, despite treatment, there is a proportion of patients with MG in the US who had a significant need for improved disease management.

Prevalence, incidence and persistence of etanercept and adalimumab in Norway 2005-2009.

PURPOSE: Examining the prevalence, incidence and persistence of use of etanercept and adalimumab in Norway during 2005-2009. METHODS: We retrieved data from the nationwide Norwegian Prescription Database (NorPD) for all individuals who were dispensed etanercept or adalimumab from pharmacies during 2005-2009. The NorPD covers the total Norwegian population in ambulatory care. Key measurements were one-year prevalence, incidence rate and persistence (minimum refill). RESULTS: The one-year prevalence for etanercept and adalimumab was 1.59‰ (n = 3840) for men and 1.85‰ (n = 4483) for women in 2009, an increase from 0.76‰ (n = 1752) for men and 1.21‰ (n = 2830) for women from 2005. The prevalence increased during the entire study time in all ages, with the highest prevalence for both genders among those aged 50-69. A total of 7786 individuals started therapy with etanercept or adalimumab during 2005-2009. Annual incidence of new users increased with 23.6% from 2005 to 2009. Sixty one percent of new users redeemed etanercept as the first drug, and 39% redeemed adalimumab. Sixty seven percent of all individuals who received etanercept or adalimumab in 2005 refilled their prescription at least once each of the following 4 years. CONCLUSIONS: Both prevalence and incidence of use of etanercept and adalimumab increased in Norway during 2005-2009. A high proportion of the individuals redeemed prescriptions regularly over 5 years.

Non-steroidal anti-inflammatory drugs: use and co-treatment with potentially interacting medications in the elderly.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the elderly. NSAIDs may cause a series of adverse drug reactions, of which gastrointestinal, renovascular/cardiovascular and bleeding complications are of particular concern. Concomitant use of several other drugs may further increase the risk of these adverse effects. OBJECTIVE: To examine the extent of chronic use of NSAIDs and co-prescription of drugs which may seriously interact with NSAIDs in elderly subjects, by using data from the Norwegian Prescription Database. RESULTS: A total of 7.3% of all individuals (71,681/984,457) over 60 years of age filled at least one prescription for reimbursed NSAIDs during the 1-year study period (2006). Co-prescription of medications which may interact with NSAIDs was prevalent for drugs used for hypertension and/or heart failure (59.5%), antithrombotic drugs (35.1%), systemic glucocorticoids (12.9%) and SSRI antidepressants (8.3%). As many as 4.8 and 3.8% of NSAID users were co-prescribed warfarin or oral methotrexate respectively. CONCLUSION: The frequent co-prescription of medications which may cause detrimental interactions in elderly chronic NSAID users adds to safety concerns regarding this widely prescribed class of drugs.

Socioeconomic characteristics of women with substance use disorder during pregnancy and neonatal outcomes in their newborns: A national registry study from the Czech Republic.

BACKGROUND: Maternal substance use can pose a risk to the fetal health. We studied the background characteristics of women with substance use disorders (SUDs) and selected neonatal outcomes in their children. MATERIAL AND METHODS: A database-linkage study was performed. The sample consisted of pregnant women with a SUD during pregnancy (ICD-10 diagnosis F10-F19 except F17, n = 1710), women not diagnosed with a SUD (n = 1,511,310) in Czechia in 2000-2014, and their children. The monitored neonatal outcomes were gestational age, birth weight, preterm birth, and small-for-gestational age (SGA). Binary logistic regression adjusted for age, marital status, education, concurrent substance use, and prenatal care was performed. RESULTS: Women with illicit SUDs were younger, more often unmarried, with a lower level of education, a higher abortion rate, a higher smoking rate, and lower compliance to prenatal care than women with a SUD related to alcohol, or sedatives and hypnotics (SH). Women with a SUD had worse socioeconomic situations, poorer pregnancy care, and worse neonatal outcomes than women without a SUD. After adjustment, we found no difference in SGA between the illicit SUD groups and the alcohol and the SH groups. The newborns from all SUD groups had a higher risk of SGA when compared to women without a SUD. However after adjustment, the difference remained significant just in the alcohol group (OR = 1.9, 95 % CI = 1.4-2.6). CONCLUSION: Mother's SUD during pregnancy increased risk of fetal growth restriction as measured by SGA. The role of maternal socioeconomic and lifestyle factors for the risk of SGA was substantial.

Opioid maintenance treatment of pregnant women in the Scandinavian countries.

Background: WHO guidelines emphasise the need for descriptions of clinical practice and observational studies on risk and benefits of pharmacotherapies in pregnancy. The aims of the present study were to: (1) Describe opioid maintenance treatment (OMT) in the Scandinavian countries in general, and specifically for pregnant women, (2) Describe a project which utilises a new approach using registry-linkage data to examine associations between prenatal exposure to OMT and child outcomes: a Scandinavian cohort study of pregnant women in OMT during pregnancy (ScopeOMT). Data: Guidelines describing the treatment of persons with opioid use disorders in general, and specifically for pregnant women. Scandinavian registry-linkage data from ScopeOMT. Results: Registry data show that approximately 800 pregnant women received OMT during pregnancy in the period of the ScopeOMT study. Similarities across the Scandinavian countries include access to free healthcare and treatment; multidisciplinary teams trained to support pregnant women in OMT; buprenorphine as the recommended drug when initiating therapy; and a holistic focus on the patients' lives. An important difference is that Norwegian women who use illegal substances that may harm the foetus may be admitted - voluntarily, or against their will - for parts of, or the remainder of the pregnancy to inpatient treatment at specialised clinics. Conclusion: Many similarities in the treatment provided to opioid-dependent persons in the Scandinavian countries place this area in an excellent position to combine the efforts and carry out observational studies concerning the safety of OMT during pregnancy.

Detection of anti-NS1 antibodies after pandemic influenza exposure: Evaluation of a serological method for distinguishing H1N1pdm09 infected from vaccinated cases.

BACKGROUND: Reliable exposure information is crucial for assessing health outcomes of influenza infection and vaccination. Current serological methods are unable to distinguish between anti-hemagglutinin (HA) antibodies induced by infection or vaccination. OBJECTIVES: We aimed to explore an alternative method for differentiating influenza infection and vaccination. METHODS: Sera from animals inoculated with influenza viruses or purified H1N1pdm09 HA were obtained. Human samples were selected from a pregnancy cohort established during the 2009 H1N1 pandemic. Unvaccinated, laboratory-confirmed cases (N = 18), vaccinated cases without influenza-like-illness (N = 18) and uninfected, unvaccinated controls (N = 18) were identified based on exposure data from questionnaires, national registries and maternal hemagglutination inhibition (HI) titres at delivery. Animal and human samples were tested for antibodies against the non-structural protein 1 (NS1) and HA from H1N1pdm09, using a Luciferase Immunoprecipitation System (LIPS). RESULTS: Anti-NS1 H1N1pdm09 antibodies were detected in sera from experimentally infected, but not from vaccinated, animals. Anti-HA H1N1pdm09 antibodies were detectable after either of these exposures. In human samples, 28% of individuals with laboratory-confirmed influenza were seropositive for H1N1pdm09 NS1, whereas vaccinated cases and controls were seronegative. There was a trend for H1N1pdm09 NS1 seropositive cases reporting more severe and longer duration of symptomatic illness than seronegative cases. Anti-HA H1N1pdm09 antibodies were detected in all cases and in 61% of controls. CONCLUSIONS: The LIPS method could differentiate between sera from experimentally infected and vaccinated animals. However, in human samples obtained more than 6 months after the pandemic, LIPS was specific, but not sufficiently sensitive for ascertaining cases by exposure.

LPS-activated monocytes suppress T-cell immune responses and induce FOXP3+ T cells through a COX-2-PGE2-dependent mechanism.

Monocytes initiate innate immune responses and interact with T cells to induce antigen-specific immune responses by antigen presentation and secretion of humoral factors. We have previously shown that adaptive regulatory T cells inhibit T-cell effector functions in a cyclooxygenase (COX)-2-prostaglandin E(2) (PGE(2))-dependent manner and that PGE(2) converts resting CD4+CD25- T cells into FOXP3+ T cells with a suppressive phenotype. Here, we demonstrate that stimulation of monocytes with LPS leads to suppression of T-cell immune responses by a COX-2-PGE(2)-dependent mechanism that is reversible with COX-2 inhibitors as well as PGE(2)-neutralizing antibody and cAMP antagonist. Furthermore, we show that LPS-activated monocytes induce FOXP3 expression in resting CD4+CD25- T cells by the same pathway. These results suggest that monocytes are able to efficiently suppress T-cell immune responses in a regulatory manner and elicit an inhibitory immune profile.

Differentiation of naive CD4+ T cells into CD4+CD25+FOXP3+ regulatory T cells by continuous antigen stimulation.

Human CD4+CD25+ regulatory T (T(R)) cells express the transcription factor forkhead box p3 (FOXP3) and have potent immunosuppressive properties. While naturally occurring T(R) cells develop in the thymus, adaptive T(R) cells develop in the periphery from naive CD4+ T cells. Adaptive T(R) cells may express cyclooxygenase type 2 (COX-2) and suppress effector T cells by a PGE(2)-dependent mechanism, which is reversible with COX inhibitors. In this study we have characterized the differentiation of naive CD4+ T cells into adaptive T(R) cells in detail during 7 days of continuous antigen stimulation. After 2 days of stimulation of CD4+CD25- T cells, the cells expressed FOXP3 and COX-2 and displayed potent immunosuppressive properties. The suppressive phenotype was present at all observed time-points from Day 2, although suppression was merely present at Day 7. The adaptive T(R) cells expressed cell surface markers consistent with an activated phenotype and secreted high levels of TGF-beta, IL-10, and PGE(2). However, the suppressive phenotype was found exclusively in cells that proliferated upon activation. These data support the notion that activation of naive CD4+ T cells leads to concomitant acquisition of effector and suppressive properties.

Hospitalization of children after prenatal exposure to opioid maintenance therapy during pregnancy: a national registry study from the Czech Republic.

BACKGROUND AND AIMS: Our understanding of the long-term safety of prenatal exposure to opioid maintenance treatment (OMT) is insufficient. We compared childhood morbidity (0-3 years) between OMT-exposed and relevant comparison groups. DESIGN: Nation-wide, registry-based cohort study. Registries on reproductive health, addiction treatment, hospitalization and death were linked using identification numbers. SETTING: The Czech Republic (2000-14). PARTICIPANTS: Children with different prenatal exposure: (i) mother in OMT during pregnancy (OMT; n = 218), (ii) mother discontinued OMT before pregnancy (OMT-D; n = 55), (iii) mother with opioid use disorder, but not in OMT during pregnancy (OUD; n = 85) and (iv) mother in the general population (GP) (n = 1 238 452) MEASUREMENTS: Episodes of hospitalization were observed as outcomes. Information on in-patient contacts, length of stay and diagnoses (International Classification of Diseases version 10) were assessed. Binary logistic regressions were conducted to estimate the associations between OMT exposure and the outcomes, crude and adjusted for the socio-economic status and smoking. FINDINGS: No significant differences were found in the overall proportion of hospitalization among OMT-exposed children, children of OMT-D and children of women with OUD [54.1%, 95% confidence interval (CI) = 47.3-60.1%; 47.3%, 95% CI = 33.9-61.1%; 51.8%, 95% CI = 40.7%-62.6%], while the proportion was significantly lower (35.8%, 95% CI = 35.7-35.8%) in the GP. There were no significant differences in risk of specific diagnoses between OMT-exposed children, children of OMT-D and children of women with OUD. In the adjusted analyses, differences between OMT-exposed and children in the GP were still present for infections and parasitic diseases (OR = 2.0, 95% CI = 1.4-2.7), diseases of the digestive system (OR = 1.7, 95% CI = 1.2-2.6) and diseases of the skin and subcutaneous tissue (OR = 1.9, 95% CI = 1.2-3.2). CONCLUSION: This study did not find clear evidence for an increase in risk of morbidity during the first 3 years of life in children with prenatal opioid maintenance treatment exposure compared with children of women who discontinued such treatment before pregnancy or suffered from opioid use disorder without this treatment. Compared the general population, there appears to be an increased risk of hospitalizations for infectious, gastrointestinal and skin diseases.