Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6 days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial. METHODS: The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0 and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes. ETHICS AND DISSEMINATION: PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21/03/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: PACTR202104532026017).

Place of care and death preferences among recently bereaved family members: a cross-sectional survey.

OBJECTIVES: The aim was: (1) to investigate preferred place for end-of-life care and death for bereaved family members who had recently lost a person with advanced illness and (2) to investigate associations between bereaved family members' preferences and individual characteristics, health-related quality of life, as well as associations with their perception of the quality of care that the ill person had received, the ill person's preferred place of death and involvement in decision-making about care. METHODS: A cross-sectional survey with bereaved family members, employing descriptive statistics and multinominal logistic regression analyses. RESULTS: Of the 485 participants, 70.7% were women, 36.1% were ≥70 years old, 34.5% were partners and 51.8% were children of the deceased. Of the bereaved family members, 52% preferred home for place of end-of-life care and 43% for place of death. A higher likelihood of preferring inpatient palliative care was associated with being female and having higher education, whereas a lower likelihood of preferring a nursing home for the place of care and death was associated with higher secondary or higher education. Partners were more likely to prefer hospital for place of care and nursing home for place of death. CONCLUSIONS: Home was the most preferred place for end-of-life care and death. Bereaved people's experiences of end-of-life care may impact their preferences, especially if they had a close relationship, such as a partner who had a higher preference for nursing home and hospital care. Conversations about preferences for the place of care and death considering previous experience are encouraged.

Discordance between mean glucose and time in range in relation to HbA1c in individuals with type 1 diabetes: results from the GOLD and SILVER trials.

AIMS/HYPOTHESIS: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. METHODS: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. RESULTS: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA1c, MG explained 63% of the variation in HbA1c (r=0.79, p<0.001). The variation in HbA1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA1c based on the overall association between MG and TIR with HbA1c. TBR and TAR level 2 significantly influenced the association between TIR and HbA1c. At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA1c when accounting for MG. CONCLUSIONS/INTERPRETATION: Inter-individual variations exist between MG and HbA1c, as well as between TIR and HbA1c, with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions.

Effects, Safety, and Treatment Experience of Advanced Hybrid Closed-Loop Systems in Clinical Practice Among Adults Living With Type 1 Diabetes.

BACKGROUND: There are few studies providing a more comprehensive picture of advanced hybrid closed-loop (AHCL) systems in clinical practice. The aim was to evaluate the effects of the AHCL systems, Tandem® t: slim X2™ with Control IQ™, and MiniMed™ 780G, on glucose control, safety, treatment satisfaction, and practical barriers for individuals with type 1 diabetes. METHOD: One hundred forty-two randomly selected adults with type 1 diabetes at six diabetes outpatient clinics in Sweden at any time treated with either the Tandem Control IQ (TCIQ) or the MiniMed 780G system were included. Glycated hemoglobin A1c (HbA1c) and glucose metrics were evaluated. Treatment satisfaction and practical barriers were examined via questionnaires. RESULTS: Mean age was 42 years, median follow-up was 1.7 years, 58 (40.8%) were females, 65% used the TCIQ system. Glycated hemoglobin A1c was reduced by 0.6% (6.8 mmol/mol; 95% confidence interval [CI] = 0.5-0.8% [5.3-8.2 mmol/mol]; P < .001), from 7.3% to 6.7% (57-50 mmol/mol). Time in range (TIR) increased with 14.5% from 57.0% to 71.5% (95% CI = 12.2%-16.9%; P < .001). Time below range (TBR) (<70 mg/dL, <3.9 mmol/L) decreased from 3.8% to 1.6% (P < .001). The standard deviation of glucose values was reduced from 61 to 51 mg/dL (3.4-2.9 mmol/L, P < .001) and the coefficient of variation from 35% to 33% (P < .001). Treatment satisfaction increased, score 14.8 on the Diabetes Treatment Satisfaction Questionnaire (DTSQ) (change version ranging from -18 to 18, P < .001). Four severe hypoglycemia events were detected and no cases of ketoacidosis. Skin problems were experienced by 32.4% of the study population. CONCLUSIONS: Advanced hybrid closed-loop systems improve glucose control with a reasonable safety profile and high treatment satisfaction. Skin problems are common adverse events.

The effect of carbohydrate intake on glycaemic control in individuals with type 1 diabetes: a randomised, open-label, crossover trial.

Background: Few studies have examined the effects of lower carbohydrate diets on glucose control in persons with type 1 diabetes (T1D). The objective of the study was to investigate whether a moderate carbohydrate diet improves glucose control in persons with T1D. Methods: A randomised, multicentre, open-label, crossover trial over 12 weeks. There were 69 individuals assessed for eligibility, 54 adults with T1D and HbA1c ≥ 58 mmol/mol (7.5%) were randomised. Interventions were moderate carbohydrate diet versus traditional diet (30 vs 50% of total energy from carbohydrates) over four weeks, with a four-week wash-out period between treatments. Masked continuous glucose monitoring was used to evaluate effects on glucose control. The primary endpoint was the difference in mean glucose levels between the last 14 days of each diet phase. Findings: 50 individuals were included in the full analysis set with a mean baseline HbA1c of 69 mmol/mol (8.4%), BMI 29 kg/m2, age of 48 years, and 50% were female. The difference in mean glucose levels between moderate carbohydrate and traditional diet was -0.6 mmol/L, 95% CI -0.9 to -0.3, p < 0.001. Time in range increased during moderate carbohydrate diet by 4.7% (68 min/24 h) (95% CI 1.3 to 8.0), p = 0.008. Time above range (>10 mmol/L) decreased by 5.9% (85 min/24 h), 95% CI -9.6 to -2.2, p = 0.003. There were no significant differences in the standard deviation of glucose levels (95% CI -0.3 to 0.0 mmol/L, p = 0.15) or hypoglycaemia in the range <3.9 mmol/L (95% CI -0.4 to 2.9%, p = 0.13) and <3.0 mmol/L (95% CI -0.4 to 1.6%, p = 0.26). Four participants withdrew, none because of adverse events. There were no serious adverse events including severe hypoglycaemia and ketoacidosis. Mean ketone levels were 0.17 (SD 0.14) mmol/L during traditional and 0.18 (SD 0.13) mmol/L during moderate carbohydrate diet (p = 0.02). Interpretation: A moderate carbohydrate diet is associated with decreases in mean glucose levels and time above range and increases in time in range without increased risk of hypoglycaemia or ketoacidosis compared with a traditional diet in individuals with T1D. Funding: The Healthcare Board, Region Västra Götaland, The Dr P Håkansson Foundation and the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement [ALFGBG-966173].

Treatment Satisfaction and Well-Being With CGM in People With T1D: An Analysis Based on the GOLD Randomized Trial.

BACKGROUND: The GOLD trial demonstrated that continuous glucose monitoring (CGM) in people with type 1 diabetes (T1D) managed with multiple daily insulin injections (MDI) improved not only glucose control but also overall well-being and treatment satisfaction. This analysis investigated which factors contributed to improved well-being and treatment satisfaction with CGM. METHODS: The GOLD trial was a randomized crossover trial comparing CGM versus self-monitored blood glucose (SMBG) over 16 months. Endpoints included well-being measured by the World Health Organization-Five Well-Being Index (WHO-5) and treatment satisfaction by the Diabetes Treatment Satisfaction Questionnaire (DTSQ) as well as glucose metrics. Multivariable R2-decomposition was used to understand which variables contributed most to treatment satisfaction. RESULTS: A total of 139 participants were included. Multivariable analyses revealed that increased convenience and flexibility contributed to 60% (95% confidence interval [CI] = 50%-69%) of the improvement in treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version [DTSQc]) observed with CGM, whereas perceived effects on hypoglycemia and hyperglycemia only contributed to 6% (95% CI = 2%-11%) of improvements. Significant improvements in well-being (WHO-5) by CGM were observed for the following: feeling cheerful (P = .025), calm and relaxed (P = .024), being active (P = .046), and waking up fresh and rested (P = .044). HbA1c reductions and increased time in range (TIR) were associated with increased treatment satisfaction, whereas glycemic variability was not. HbA1c reduction showed also an association with increased well-being and increased TIR with less diabetes-related distress. CONCLUSIONS: While CGM improves glucose control in people with T1D on MDI, increased convenience and flexibility through CGM is of even greater importance for treatment satisfaction and patient well-being. These CGM-mediated effects should be taken into account when considering CGM initiation.

Evaluation of Effects of Continuous Glucose Monitoring on Physical Activity Habits and Blood Lipid Levels in Persons With Type 1 Diabetes Managed With MDI: An Analysis Based on the GOLD Randomized Trial (GOLD 8).

BACKGROUND: People with type 1 diabetes generally view it easier to exercise when having continuous information of the glucose levels. We evaluated whether patients with type 1 diabetes managed with multiple daily insulin injections (MDI) exercised more after initiating continuous glucose monitoring (CGM) and whether the improved glycemic control and well-being associated with CGM translates into improved blood lipids and markers of inflammation. METHOD: The GOLD trial was a randomized cross-over trial over 16 months where patients used either CGM or capillary self-monitoring of blood glucose (SMBG) over six months, with a four-month wash-out period between the two treatment periods. We compared grade of physical activity, blood lipids, apolipoproteins, and high-sensitivity C-reactive protein (hsCRP) levels during CGM and SMBG. RESULTS: There were 116 patients with information of physical activity estimated by the International Physical Activity Questionnaire (IPAQ) during both CGM and SMBG. No changes were found during CGM or SMBG, IPAQ scores 3305 versus 3878 (P = .16). In 136 participants with information of blood lipid levels with no change in lipid-lowering medication during the two treatment periods, HbA1c differed by 4.2 mmol/mol (NGSP 0.39%) between SMBG and CGM treatment (P < .001). No significant changes existed in low-density lipoprotein, high-density lipoprotein, triglycerides, total cholesterol, apolipoprotein A1, apolipoprotein B1, or hsCRP, during CGM and SMBG. CONCLUSION: Although many patients experience it easier to perform physical activity when monitoring glucose levels with CGM, it does not influence the amount of physical activity in persons with type 1 diabetes. Blood lipids, apolipoprotein, and hsCRP levels were similar during CGM and SMBG.

Cerebral biomarkers in neurologic complications of preeclampsia.

BACKGROUND: There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. OBJECTIVE: We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. STUDY DESIGN: In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. RESULTS: Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. CONCLUSION: Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.

Effect of liraglutide on markers of insulin production in persons with type 2 diabetes treated with multiple daily insulin injections.

In this post-hoc analysis of data from a randomised clinical trial, we compared the effect of liraglutide to placebo on markers of insulin secretion in persons with type 2 diabetes treated with multiple daily insulin injections. Liraglutide increased insulin secretion, measured by C-peptide, by 19% after 24 weeks of treatment. CLINICAL TRIAL REGISTRATION: EudraCT 2012-001941-42.

Chest X-rays are less sensitive than multiple breath washout examinations when it comes to detecting early cystic fibrosis lung disease.

AIM: Annual chest X-ray is recommended as routine surveillance to track cystic fibrosis (CF) lung disease. The aim of this study was to investigate the clinical utility of chest X-rays to track CF lung disease. METHODS: Children at Gothenburg's CF centre who underwent chest X-rays, multiple breath washouts and chest computed tomography examinations between 1996 and 2016 were included in the study. Chest X-rays were interpreted with Northern Score (NS). We compared NS to lung clearance index (LCI) and structural lung damage measured by computed tomography using a logistic regression model. RESULTS: A total of 75 children were included over a median period of 13 years (range: 3.0-18.0 years). The proportion of children with abnormal NS was significantly lower than the proportion of abnormal LCI up to the age of 4 years (p < 0.05). A normal NS and a normal LCI at age 6 years were associated with a median (10-90th percentile) total airway disease of 1.8% (0.4-4.7%) and bronchiectasis of 0.2% (0.0-1.5%). CONCLUSION: Chest X-rays were less sensitive than multiple breath washout examinations to detect early CF lung disease. The combined results from both methods can be used as an indicator to perform chest computed tomography less frequently.

Effects of seawater scrubbing on a microplanktonic community during a summer-bloom in the Baltic Sea.

The International Maritime Organization (IMO) has gradually applied stricter regulations on the maximum sulphur content permitted in marine fuels and from January 1, 2020, the global fuel sulphur limit was reduced from 3.5% to 0.5%. An attractive option for shipowners is to install exhaust gas cleaning systems, also known as scrubbers, and continue to use high sulphur fuel oil. In the scrubber, the exhausts are led through a fine spray of water, in which sulphur oxides are easily dissolved. The process results in large volumes of acidic discharge water, but while regulations are focused on sulphur oxides removal and acidification, other pollutants e.g. polycyclic aromatic hydrocarbons, metals and nitrogen oxides can be transferred from the exhausts to the washwater and discharged to the marine environment. The aim of the current study was to investigate how different treatments of scrubber discharge water (1, 3 and 10%) affect a natural Baltic Sea summer microplanktonic community. To resolve potential contribution of acidification from the total effect of the scrubber discharge water, "pH controls" were included where the pH of natural sea water was reduced to match the scrubber treatments. Biological effects (e.g. microplankton species composition, biovolume and primary productivity) and chemical parameters (e.g. pH and alkalinity) were monitored and analysed during 14 days of exposure. Significant effects were observed in the 3% scrubber treatment, with more than 20% increase in total biovolume of microplankton compared to the control group, and an even greater effect in the 10% scrubber treatment. Group-specific impacts were recorded where diatoms, flagellates incertae sedis, chlorophytes and ciliates increased in biovolume with increasing concentrations of scrubber water while no effect was recorded for cyanobacteria. In contrast, these effects was not observed in the "pH controls", a suggestion that other parameters/stressors in the scrubber water were responsible for the observed effects.

Historical HbA1c Values May Explain the Type 2 Diabetes Legacy Effect: UKPDS 88.

OBJECTIVE: Type 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA1c values and explored the potential impact of instituting earlier, compared with delayed, glucose-lowering therapy. RESEARCH DESIGN AND METHODS: Twenty-year ACM and MI hazard functions were estimated from diagnosis of type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of HbA1c values over time was analyzed by weighting them according to their influence on downstream ACM and MI risks. RESULTS: Hazard ratios for a one percentage unit higher HbA1c for ACM were 1.08 (95% CI 1.07-1.09), 1.18 (1.15-1.21), and 1.36 (1.30-1.42) at 5, 10, and 20 years, respectively, and for MI was 1.13 (1.11-1.15) at 5 years, increasing to 1.31 (1.25-1.36) at 20 years. Imposing a one percentage unit lower HbA1c from diagnosis generated an 18.8% (95% CI 21.1-16.0) ACM risk reduction 10-15 years later, whereas delaying this reduction until 10 years after diagnosis showed a sevenfold lower 2.7% (3.1-2.3) risk reduction. Corresponding MI risk reductions were 19.7% (22.4-16.5) when lowering HbA1c at diagnosis, and threefold lower 6.5% (7.4-5.3%) when imposed 10 years later. CONCLUSIONS: The glycemic legacy effects seen in type 2 diabetes are explained largely by historical HbA1c values having a greater impact than recent values on clinical outcomes. Early detection of diabetes and intensive glucose control from the time of diagnosis is essential to maximize reduction of the long-term risk of glycemic complications.

Variables associated with insulin production in persons with type 2 diabetes treated with multiple daily insulin injections.

From the MDI-liraglutide study, we evaluated variables associated with endogenous insulin production in persons with multiple daily insulin injections-treated type 2 diabetes by relating C-peptide, proinsulin and proinsulin/C-peptide ratio at baseline to baseline variables. Lower insulin production was related to longer diabetes duration, shorter abdominal sagittal diameter and more glycaemic variability.

Study for Improving Maternal Pregnancy And Child ouTcomes (IMPACT): a study protocol for a Swedish prospective multicentre cohort study.

INTRODUCTION: First-trimester pregnancy risk evaluation facilitates individualised antenatal care, as well as application of preventive strategies for pre-eclampsia or birth of a small for gestational age infant. A range of early intervention strategies in pregnancies identified as high risk at the end of the first trimester has been shown to decrease the risk of preterm pre-eclampsia (<37 gestational weeks). The aim of this project is to create the Improving Maternal Pregnancy And Child ouTcomes (IMPACT) database; a nationwide database with individual patient data, including predictors recorded at the end of the first trimester and later pregnancy outcomes, to identify women at high risk of pre-eclampsia. A second aim is to link the IMPACT database to a biobank with first-trimester blood samples. METHODS AND ANALYSIS: This is a Swedish prospective multicentre cohort study. Women are included between the 11th and 14th weeks of pregnancy. At inclusion, pre-identified predictors are retrieved by interviews and medical examinations. Blood samples are collected and stored in a biobank. Additional predictors and pregnancy outcomes are retrieved from the Swedish Pregnancy Register. Inclusion in the study began in November 2018 with a targeted sample size of 45 000 pregnancies by end of 2021. Creation of a new risk prediction model will then be developed, validated and implemented. The database and biobank will enable future research on prediction of various pregnancy-related complications. ETHICS AND DISSEMINATION: Confidentiality aspects such as data encryption and storage comply with the General Data Protection Regulation and with ethical committee requirements. This study has been granted national ethical approval by the Swedish Ethical Review Authority (Uppsala 2018-231) and national biobank approval at Uppsala Biobank (18237 2 2018 231). Results from the current as well as future studies using information from the IMPACT database will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03831490.

Adolescent depression and subsequent earnings across early to middle adulthood: a 25-year longitudinal cohort study.

AIMS: The few available studies on early-onset depression and future earnings offer ambiguous findings, and potential sources of heterogeneity are poorly understood. We examined the differences in adult earnings of males and females with and without a history of depressive disorder in adolescence, with specific focuses on (1) future earnings in clinical subtypes of adolescent depression; (2) the growth and distribution of earnings over time within these subgroups and (3) the mediating role of subsequent depressive episodes occurring in early adulthood. METHODS: Data were drawn from the Uppsala Longitudinal Adolescent Depression Study, a community-based cohort study initiated in Uppsala, Sweden, in the early 1990s. Comprehensive diagnostic assessments were conducted at age 16-17 and in follow-up interviews 15 years later, while consecutive data on earnings for the years 1996 to 2016 (ages 20-40) were drawn from population-based registries. The current study included participants with a history of persistent depressive disorder (PDD) (n = 175), episodic major depressive disorder (MDD) (n = 82), subthreshold depression (n = 64) or no depression (n = 218) in adolescence. The association of adolescent depression with earnings in adulthood was analysed using generalised estimating equations. Estimates were adjusted for major child and adolescent psychiatric comorbidities and parental socioeconomic status. The indirect (mediated) effect of depression in early adulthood (ages 19-30) on earnings in mid-adulthood (31-40) was estimated in mediation analysis. The study followed the 'STrengthening the Reporting of OBservational studies in Epidemiology' (STROBE) guidelines. RESULTS: Earnings across early to middle adulthood were lower for participants with a history of a PDD in adolescence than for their non-depressed peers, with an adjusted ratio of mean earnings of 0.85 (0.77-0.95) for females and 0.76 (0.60-0.95) for males. The differences were consistent over time, and more pronounced in the lower percentiles of the earnings distributions. The association was partially mediated by recurrent depression in early adulthood (48% in total; 61% for females, 29% for males). No reduction in earnings was observed among participants with episodic MDD in adolescence, while results for subthreshold depression were inconclusive. CONCLUSIONS: Our findings suggest that future earnings of adolescents with depressive disorders are contingent on the duration and natural long-term course of early-onset depression, emphasising the need for timely and effective interventions to avoid loss of human capital.

Risk factors for progression of structural lung disease in school-age children with cystic fibrosis.

BACKGROUND: Computed tomography (CT) is used to monitor progression of structural lung disease (SLD) in children with cystic fibrosis (CF). Our goals were to identify the risk factors for the annual progression of SLD and the impacts of airway pathogens on SLD. METHOD: Seventy-five school-aged children diagnosed with CF underwent 200 CT scans at Gothenburg CF Centre in the period 2003-2015. SLD was evaluated with a quantitative scoring system. Mixed models were used to calculate the yearly progression rates of SLD and FEV1 and to analyse the effects of common airway pathogens in CF. RESULTS: The yearly mean progression (95% CI) rates for total disease (%Dis), bronchiectasis (%Be), and FEV1 were 0.62 (0.38-0.86), 0.43 (0.28-0.58) and -0.16 (-0.18-0.13), respectively. Adjusting for airway pathogens, the yearly mean progression rates for %Dis, %Be and FEV1 were 0.23 (-0.04-0.51), 0.12 (0.00-0.25), and -0.12 (-0.16-0.08), respectively. A single infection with P aeruginosa was associated with significant increase in lung damage, assessed as %Dis (p = 0.044) and%Be (p = 0.0047), but not in FEV1 (p = 0.96). At age of 7 years, there was a good correlation between the extent of SLD and subsequent progression of %Dis (r = 0.63, p = 0.0042) and %Be (r = 0.74, p = 0.0057) while there was no significant correlation between the FEV1 and the rate of decline of FEV1 (r = -0.22, p = 0.12). CONCLUSION: Intermittent respiratory infections with P aeruginosa were associated with significant SLD but no change in FEV1. More SLD at the age of 7 years signals a higher progression rate of SLD subsequently.

Effect of Liraglutide on Times in Glycaemic Ranges as Assessed by CGM for Type 2 Diabetes Patients Treated With Multiple Daily Insulin Injections.

INTRODUCTION: The effects of the GLP-1 analogue liraglutide on time in hypoglycaemia, time in hyperglycaemia, and time in range for type 2 diabetes patients initially treated with multiple daily insulin injections (MDI) were investigated. Variables associated with hypoglycaemia in the current population were also identified. METHODS: Analyses were based on data from a previously performed double-blind, placebo-controlled trial in which 124 MDI-treated patients with type 2 diabetes were randomized to liraglutide or placebo. Masked continuous glucose monitoring (CGM) was performed at baseline and week 24 in 99 participants. RESULTS: The mean time in hypoglycaemia was similar for participants receiving liraglutide and those receiving placebo after 24 weeks of treatment. Mean time in target was greater in the liraglutide group than in the placebo group: 430 versus 244 min/24 h (p < 0.001) and 960 versus 695 min/24 h (p < 0.001) for the two glycaemic ranges considered, 4-7 mmol/l and 4-10 mmol/l, respectively. Mean time in hyperglycaemia was lower in the liraglutide group: 457 versus 723 min/24 h (p = 0.001) and 134 versus 264 min/24 h (p = 0.023) for the two cutoffs considered, > 10 mmol/l and > 14 mmol/l, respectively. Lower mean glucose level, lower C-peptide, and higher glucose variability were associated with an increased risk of hypoglycaemia in both treatment groups. Higher proinsulin level was associated with a lower risk of hypoglycaemia in the liraglutide group. CONCLUSION: For type 2 diabetes patients initially treated with MDI, introducing liraglutide had a beneficial effect on glucose profiles estimated by masked CGM. Mean glucose level, glycaemic variability, C-peptide, and proinsulin level influenced the risk of hypoglycaemia in this population. TRIAL REGISTRATION: ClinicalTrials.gov, number (EudraCT nr: 2012-001941-42). FUNDING: Novo Nordisk funded this study. The Diabetes Research Unit, NU-Hospital Group funded the journal's Rapid Service Fee.

Predicting verbal memory decline following temporal lobe resection for epilepsy.

OBJECTIVES: The aim of the study was to develop a prediction model for verbal memory decline after temporal lobe resection (TLR) for epilepsy. The model will be used in the preoperative counselling of patients to give individualized information about risk for verbal memory decline. MATERIALS AND METHODS: A sample of 110 consecutive patients who underwent TLR for epilepsy at Sahlgrenska University Hospital between 1987 and 2011 constituted the basis for the prediction model. They had all gone through a formal neuropsychological assessment before surgery and 2 years after. Penalized regression and 20 × 10-fold cross-validation were used in order to build a reliable model for predicting individual risks. RESULTS: The final model included four predictors: side of surgery; inclusion or not of the hippocampus in the resection; preoperative verbal memory function; and presence/absence of focal to bilateral tonic-clonic seizures (TCS) the last year prior to the presurgical investigation. The impact of a history of TCS is a new finding which we interpret as a sign of a more widespread network disease which influences neuropsychological function and the cognitive reserve. The model correctly identified 82% of patients with post-operative decline in verbal memory, and the overall accuracy was 70%-85% depending on choice of risk thresholds. CONCLUSIONS: The model makes it possible to provide patients with individualized prediction regarding the risk of verbal memory decline following TLR. This will help them make more informed decisions regarding treatment, and it will also enable the epilepsy surgery team to prepare them better for the rehabilitation process.

Predictors and correlates of systolic blood pressure reduction with liraglutide treatment in patients with type 2 diabetes.

Liraglutide is associated with blood pressure reduction in patients with type 2 diabetes. However, it is not known whether this blood pressure reduction can be predicted prior to treatment initiation, and to what extent it correlates with weight loss and with improved glycemic control during follow-up. We analyzed data from a double-blind, placebo-controlled trial, in which 124 insulin-treated patients with type 2 diabetes were randomized to liraglutide or placebo. We evaluated various baseline variables as potential predictors of systolic blood pressure (SBP) reduction, and evaluated whether changes in SBP correlated with weight loss and with improved glycemic control. A greater reduction in SBP among liraglutide-treated patients was predicted by higher baseline values of SBP (P < 0.0001) and diastolic blood pressure (P = 0.012), and by lower baseline values of mean glucose measured by continuous glucose monitoring (CGM; P = 0.044), and serum fasting C-peptide (P = 0.015). The regression coefficients differed significantly between the liraglutide group and the placebo group only for diastolic blood pressure (P = 0.037) and mean CGM (P = 0.021). During the trial period, SBP reduction correlated directly with change in body weight and BMI, but not with change in HbA1c. We conclude that patients with lower mean CGM values at baseline responded to liraglutide with a larger reduction in SBP, and that improved HbA1c during follow-up was not associated with reductions of SBP. Our data suggest that some patients with type 2 diabetes may benefit from liraglutide in terms of weight and SBP reduction.