Showing papers by "Innlandet Hospital Trust published in 2021"

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

Abstract: BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial.

Abstract: Importance Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, Setting, and Participants Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main Outcomes and Measures The primary end point was clinical remission at week 30. Results Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, −8.2% to 11.1%;P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and Relevance Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates. Trial Registration ClinicalTrials.gov Identifier:NCT03074656

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

Abstract: Background In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal in...

Medical cannabis or cannabinoids for chronic pain: a clinical practice guideline.

Abstract: Clinical question What is the role of medical cannabis or cannabinoids for people living with chronic pain due to cancer or non-cancer causes? Current practice Chronic pain is common and distressing and associated with considerable socioeconomic burden globally. Medical cannabis is increasingly used to manage chronic pain, particularly in jurisdictions that have enacted policies to reduce use of opioids; however, existing guideline recommendations are inconsistent, and cannabis remains illegal for therapeutic use in many countries. Recommendation The guideline expert panel issued a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids, in addition to standard care and management (if not sufficient), for people living with chronic cancer or non-cancer pain. How this guideline was created An international guideline development panel including patients, clinicians with content expertise, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. The MAGIC Evidence Ecosystem Foundation (MAGIC) provided methodological support. The panel applied an individual patient perspective. The evidence This recommendation is informed by a linked series of four systematic reviews summarising the current body of evidence for benefits and harms, as well as patient values and preferences, regarding medical cannabis or cannabinoids for chronic pain. Understanding the recommendation The recommendation is weak because of the close balance between benefits and harms of medical cannabis for chronic pain. It reflects a high value placed on small to very small improvements in self reported pain intensity, physical functioning, and sleep quality, and willingness to accept a small to modest risk of mostly self limited and transient harms. Shared decision making is required to ensure patients make choices that reflect their values and personal context. Further research is warranted and may alter this recommendation.

Are There Differences in Video Gaming and Use of Social Media among Boys and Girls?-A Mixed Methods Approach.

Abstract: Gaming is widespread among adolescents and has typically been viewed as an activity for boys. There are however a growing number of female gamers and we need to learn more about how gender affects gaming. The aim of this study is to both quantify gaming among Norwegian adolescents and explore how gender differences are perceived. A mixed method approach was used to capture gaming experiences among boys and girls. Survey data (N = 5607) was analyzed descriptively, and five focus groups were conducted, applying thematic analysis. Statistics showed that boys from the age of 14 use video games up to 5 times more than girls, while girls are much more on social media. From the focus groups, we found that boys did not view social media as socially significant as gaming and that there is a greater social acceptance of gaming among boys than among girls. Gender differences in video gaming are not necessarily a problem per se, as they may reflect gender-specific motivations and interests. However, the study also finds that girls feel less encouraged than boys to play video games due to different gender-related experiences of video gaming. Therefore, gendered barriers in video gaming must be explored in future research.

Changes in Alcohol Consumption during the COVID-19 Pandemic-Small Change in Total Consumption, but Increase in Proportion of Heavy Drinkers.

Abstract: Little is known about possible changes in alcohol consumption distribution during the COVID-19 pandemic. We estimated how individual changes in alcohol consumption during the pandemic translated into changes in: (i) mean consumption; (ii) dispersion of consumption distribution; and (iii) prevalence of heavy drinkers. We employed data from two independent web-surveys of Norwegian adults collected between April and July 2020 and limited to those reporting past year alcohol consumption (N1 = 15,267, N2 = 1195). Self-reports of changes in drinking behavior were quantified, assuming change being relative to baseline consumption level. During the pandemic, we found a small increase (Survey 1) or no change (Survey 2) in estimated mean alcohol consumption (which parallels to total consumption). However, in both surveys, the dispersion of the distribution increased significantly (p < 0.001). For most respondents, an average modest decline in consumption was found. However, the small fraction with the highest baseline consumption increased their consumption substantially, and in effect, the proportion of heavy drinkers increased markedly (p < 0.001). In conclusion, quantifications of reported changes in alcohol consumption during the pandemic suggest that the upper 5 to 10% of the drinkers increased their consumption and hence the prevalence of heavy drinkers increased, despite little or no change in total alcohol consumption.

Five weeks of heat training increases haemoglobin mass in elite cyclists

Abstract: NEW FINDINGS What is the central question of this study? Do haemoglobin mass and red blood cell volume increase in elite cyclists training in a hot environment compared to a control group training at normal temperature? What is the main finding and its importance? Five weeks of heat training increases haemoglobin mass in elite cyclists. There are small to intermediate effect sizes for exercise parameters favouring heat training. ABSTRACT In this study we tested the hypothesis that performing 1 h of regular light exercise in a heat chamber (HEAT; 37.8 ± 0.5°C; 65.4 ± 1.8% humidity) 5 times week-1 for a total of 5 weeks increases haemoglobin mass (Hbmass ) and exercise performance in elite cyclists ( VO2max = 76.2 ± 7.6 ml min-1 kg-1 ). Twenty-three male volunteers were assigned to HEAT (n = 11) or CON (n = 12; 15.5 ± 0.1°C; 25.1 ± 0.0% humidity) training groups. Hbmass was determined before and after the intervention period in conjunction with an extensive exercise test protocol (conducted at 16-19°C). HEAT increased (P < 0.05) Hbmass by 42 g from 893 ± 78 to 935 ± 108 g whereas Hbmass remained unchanged (+6 g) in CON. Furthermore, statistical analysis revealed a time-group interaction (P < 0.05). The greater increase in Hbmass in HEAT, however, did not manifest in a greater increase in VO2max (225 ± 274 ml min-1 in HEAT and 161 ± 202 ml min-1 in CON). While HEAT reduced (P < 0.05) lactate levels during some of the submaximal exercise tests, there was no statistical difference between other performance parameters. There were, however, small to intermediate effect sizes favouring HEAT for lactate threshold power output (2.8 ± 3.9 vs. -0.4 ± 5.1% change, effect size (ES) = 0.34), gross economy in the fatigued state (0.19 ± 0.42 vs. -0.12 ± 0.49%-point change, ES = 0.52) and 15 min mean power (6.9 ± 8.4 vs. 3.4 ± 5.1% increase, ES = 0.22). This study demonstrates an increase in Hbmass and small to intermediate effect sizes on exercise variables in elite cyclists following a 5-week heat training intervention.

Locus of control moderates the association of COVID-19 stress and general mental distress: results of a Norwegian and a German-speaking cross-sectional survey.

Abstract: The Norwegian part of the study was financed by Innlandet Hospital Trust, Norway. The German speaking part was conducted in the absence of financial funding

Molecular Targets of Manganese-Induced Neurotoxicity: A Five-Year Update.

Abstract: Understanding of the immediate mechanisms of Mn-induced neurotoxicity is rapidly evolving. We seek to provide a summary of recent findings in the field, with an emphasis to clarify existing gaps and future research directions. We provide, here, a brief review of pertinent discoveries related to Mn-induced neurotoxicity research from the last five years. Significant progress was achieved in understanding the role of Mn transporters, such as SLC39A14, SLC39A8, and SLC30A10, in the regulation of systemic and brain manganese handling. Genetic analysis identified multiple metabolic pathways that could be considered as Mn neurotoxicity targets, including oxidative stress, endoplasmic reticulum stress, apoptosis, neuroinflammation, cell signaling pathways, and interference with neurotransmitter metabolism, to name a few. Recent findings have also demonstrated the impact of Mn exposure on transcriptional regulation of these pathways. There is a significant role of autophagy as a protective mechanism against cytotoxic Mn neurotoxicity, yet also a role for Mn to induce autophagic flux itself and autophagic dysfunction under conditions of decreased Mn bioavailability. This ambivalent role may be at the crossroad of mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis. Yet very recent evidence suggests Mn can have toxic impacts below the no observed adverse effect of Mn-induced mitochondrial dysfunction. The impact of Mn exposure on supramolecular complexes SNARE and NLRP3 inflammasome greatly contributes to Mn-induced synaptic dysfunction and neuroinflammation, respectively. The aforementioned effects might be at least partially mediated by the impact of Mn on α-synuclein accumulation. In addition to Mn-induced synaptic dysfunction, impaired neurotransmission is shown to be mediated by the effects of Mn on neurotransmitter systems and their complex interplay. Although multiple novel mechanisms have been highlighted, additional studies are required to identify the critical targets of Mn-induced neurotoxicity.

Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review.

Abstract: Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1–3), glutathione peroxidases (GPX1–4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1–4 and TXNRD1–3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

Copper, Iron, Selenium and Lipo-Glycemic Dysmetabolism in Alzheimer’s Disease

Abstract: The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer's disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aβ generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aβ cross-linking and up-regulation of RAGE expression. Moreover, Aβ glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aβ, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.

Abstract: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.

Genome-Wide Association Identifies the First Risk Loci for Psychosis in Alzheimer Disease

Abstract: Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype e4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of e4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease

Abstract: Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype e4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of e4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9.

Abstract: The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Trace Element and Mineral Levels in Serum, Hair, and Urine of Obese Women in Relation to Body Composition, Blood Pressure, Lipid Profile, and Insulin Resistance.

Abstract: The objective of this study was to evaluate serum, hair, and urinary trace element and mineral content in normal-weight and obese women in relation to metabolic risk factors. A total of 80 women aged 30-70 y.o. were enrolled in the obese group (n = 40) and normal-weight group (n = 40). Serum, hair, and urinary trace element and mineral levels were assessed using inductively coupled plasma spectrometry. Body fat percentage was evaluated using bioimpedance. Obese subjects were characterized by significantly higher body fat percentage, blood pressure, serum triglyceride concentration, and insulin resistance. Serum Ca, Fe, Mg, Se, V, Zn levels, hair Fe, Mg, V content, and urinary Se and V concentrations were found to be lower in obese subjects as compared to lean controls. In turn, serum Cu and urinary Fe levels in obese women were characterized by a significant increase. In multiple regression models serum Cu, Se, and Zn levels were significantly associated with BMI even after adjustment for blood biochemistry, body composition, and blood pressure. Serum trace element and mineral levels also significantly contributed to group discrimination. These findings allow to propose that obesity-associated disturbances in trace element and mineral status may at least partially contribute to metabolic risk in obese subjects.

Adipotropic effects of heavy metals and their potential role in obesity.

Abstract: Epidemiological studies demonstrated an association between heavy metal exposure and the incidence of obesity and metabolic syndrome. However, the particular effects of metal toxicity on adipose tissue functioning are unclear. Therefore, recent findings of direct influence of heavy metals (mercury, cadmium, and lead) and metalloid (arsenic) on adipose tissue physiology are discussed while considering existing gaps and contradictions. Here, we provide a literature review addressing adipose tissue as a potential target of heavy metal toxicity. Experimental in vivo studies demonstrated a significant influence of mercury, cadmium, lead, and arsenic exposure on body adiposity. In turn, in vitro experiments revealed both up- and downregulation of adipogenesis associated with aberrant expression of key adipogenic pathways, namely CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor gamma (PPARγ). Comparison of the existing studies on the basis of dose and route of exposure demonstrated that the effects of heavy metal exposure on adipose tissue may be dose-dependent, varying from increased adipogenesis at low-dose exposure to inhibition of adipose tissue differentiation at higher doses. However, direct dose-response data are available in a single study only for arsenic. Nonetheless, both types of these effects, irrespective of their directionality, contribute significantly to metabolic disturbances due to dysregulated adipogenesis. Particularly, inhibition of adipocyte differentiation is known to reduce lipid-storage capacity of adipose tissue, leading to ectopic lipid accumulation. In contrast, metal-associated stimulation of adipogenesis may result in increased adipose tissue accumulation and obesity. However, further studies are required to reveal the particular dose- and species-dependent effects of heavy metal exposure on adipogenesis and adipose tissue functioning.

Vitamin D3 supplementation does not enhance the effects of resistance training in older adults.

Abstract: Background Lifestyle therapy with resistance training is a potent measure to counteract age-related loss in muscle strength and mass. Unfortunately, many individuals fail to respond in the expected manner. This phenomenon is particularly common among older adults and those with chronic diseases (e.g. chronic obstructive pulmonary disease, COPD) and may involve endocrine variables such as vitamin D. At present, the effects of vitamin D supplementation on responses to resistance training remain largely unexplored. Methods Ninety-five male and female participants (healthy, n = 71; COPD, n = 24; age 68 ± 5 years) were randomly assigned to receive either vitamin D3 or placebo supplementation for 28 weeks in a double-blinded manner (latitude 61°N, September-May). Seventy-eight participants completed the RCT, which was initiated by 12 weeks of supplementation-only (two weeks with 10 000 IU/day, followed by 2000 IU/day), followed by 13 weeks of combined supplementation (2000 IU/day) and supervised whole-body resistance training (twice weekly), interspersed with testing and measurements. Outcome measures included multiple assessments of muscle strength (nvariables = 7), endurance performance (n = 6), and muscle mass (n = 3, legs, primary), as well as muscle quality (legs), muscle biology (m. vastus lateralis; muscle fibre characteristics, transcriptome), and health-related variables (e.g. visceral fat mass and blood lipid profile). For main outcome domains such as muscle strength and muscle mass, weighted combined factors were calculated from the range of singular assessments. Results Overall, 13 weeks of resistance training increased muscle strength (13% ± 8%), muscle mass (9% ± 8%), and endurance performance (one-legged, 23% ± 15%; whole-body, 8% ± 7%), assessed as weighted combined factors, and were associated with changes in health variables (e.g. visceral fat, -6% ± 21%; [LDL]serum , -4% ± 14%) and muscle tissue characteristics such as fibre type proportions (e.g. IIX, -3% points), myonuclei per fibre (30% ± 65%), total RNA/rRNA abundances (15%/6-19%), and transcriptome profiles (e.g. 312 differentially expressed genes). Vitamin D3 supplementation did not affect training-associated changes for any of the main outcome domains, despite robust increases in [25(OH)D]serum (∆49% vs. placebo). No conditional effects were observed for COPD vs. healthy or pre-RCT [25(OH)D]serum . In secondary analyses, vitamin D3 affected expression of gene sets involved in vascular functions in muscle tissue and strength gains in participants with high fat mass, which advocates further study. Conclusions Vitamin D3 supplementation did not affect muscular responses to resistance training in older adults with or without COPD.

Use of hypnotic drugs among children, adolescents, and young adults in Scandinavia.

Abstract: Background Hypnotic use in children and adolescents is controversial. Objective To describe the use of hypnotic drugs (melatonin, z-drugs, and sedating antihistamines) among 5- to 24-year-old Scandinavians during 2012 to 2018. Methods Aggregate-level data were obtained from public data sources in Sweden, Norway, and Denmark. We calculated annual prevalence (users/1000 inhabitants) stratified by age group, sex, and country. Quantity of use (Defined Daily Dose (DDD)/user/day) was estimated for Norway and Denmark. Results Melatonin was the most commonly used hypnotic, and its use increased markedly from 2012 to 2018, particularly among females and 15- to 24-year-old individuals. Sweden had the highest increase in use (6.5 to 25/1000) compared with Norway (10-20/1000) and Denmark (5.7-12/1000). The annual prevalence of sedating antihistamine use was also highest in Sweden, reaching 13/1000 in 2018 in comparison to 7.5/1000 in Norway and 2.5/1000 in Denmark. Z-drug use decreased in all countries toward 2018, dropping to 3.5/1000 in Sweden, 4.4/1000 in Norway, and 1.7/1000 in Denmark. The quantity of hypnotic use in Norway and Denmark was 0.8-1.0 DDD/user/day for melatonin in 2018, as compared to 0.1-0.3 for z-drugs and antihistamines. Conclusion The use of melatonin and sedating antihistamines increased among young Scandinavians during 2012-2018, and the increase was twice as high in Sweden compared with Norway and Denmark. In addition, Sweden had the highest use of sedating antihistamines. The Scandinavian variation of hypnotic use could reflect differences in frequency of sleep problems between populations or variation of healthcare access or clinical practice between countries.

Iron Deficiency in Obesity and after Bariatric Surgery.

Abstract: Iron deficiency (ID) is particularly frequent in obese patients due to increased circulating levels of acute-phase reactant hepcidin and adiposity-associated inflammation. Inflammation in obese subjects is closely related to ID. It induces reduced iron absorption correlated to the inhibition of duodenal ferroportin expression, parallel to the increased concentrations of hepcidin. Obese subjects often get decreased inflammatory response after bariatric surgery, accompanied by decreased serum hepcidin and therefore improved iron absorption. Bariatric surgery can induce the mitigation or resolution of obesity-associated complications, such as hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia, adjusting many parameters in the metabolism. However, gastric bypass surgery and sleeve gastrectomy can induce malabsorption and may accentuate ID. The present review explores the burden and characteristics of ID and anemia in obese patients after bariatric surgery, accounting for gastric bypass technique (Roux-en-Y gastric bypass—RYGB) and sleeve gastrectomy (SG). After bariatric surgery, obese subjects’ iron status should be monitored, and they should be motivated to use adequate and recommended iron supplementation.

Pain in nursing home residents with dementia and its association to quality of life.

Abstract: Objectives We aimed to describe pain, use of analgesics and quality of life (QoL) in people with dementia admitted to a Norwegian nursing home (NH), and to explore if and how pain was associated with their QoL when adjusting for sociodemographic characteristics, other health conditions and use of analgesics. Method A total of 953 Norwegian NH residents with dementia (mean age 84.0, SD 7.5 years, 35.8% men) were included at admission to the NH. Pain and QoL were assessed using the Mobilization-Observation-Behavior-Intensity-Dementia-2 (MOBID-2) Pain Scale and the Quality of Life in Late-Stage Dementia (QUALID) scale, respectively. Severity of dementia, personal level of activities of daily living, general medical health, neuropsychiatric symptoms, and the use of psychotropic drugs and analgesics were assessed. Results In total, 36% of the participants had clinically relevant pain intensity (MOBID-2 ≥ 3) and 52% received analgesics. Paracetamol was most frequently prescribed (45%). In an adjusted linear mixed model, more severe pain was associated with higher QUALID total scores, indicating poorer QoL (regression coefficient 0.52, 95% CI 0.36-0.69). Conclusion Pain prevalence at NH admission was high in residents with dementia; half used analgesics, particularly paracetamol. More severe pain was associated with poorer QoL when adjusting for sociodemographic characteristics, other health conditions, and use of analgesics. The routine assessment of pain at NH admission can uncover undiagnosed and untreated pain and allow for adequate non-pharmacological and pharmacological pain management and likely increased QoL.

Influence of receptor selectivity on benefits from SGLT2 inhibitors in patients with heart failure: a systematic review and head-to-head comparative efficacy network meta-analysis.

Abstract: Receptor selectivity of sodium-glucose cotransporter-2 inhibitors (SGLT2i) varies greatly between agents. The overall improvement of cardiovascular (CV) outcomes in heart failure (HF) patients varies between trials. We, therefore, evaluated the comparative efficacy of individual SGLT2i and the influence of their respective receptor selectivity thereon. We identified randomized controlled trials investigating the use of SGLT2i in patients with HF—either as the target cohort or as a subgroup of it. Comparators included placebo or any other active treatment. The primary endpoint was the composite of hospitalization for HF or CV death. Secondary outcomes included all-cause mortality, CV mortality, hospitalization for HF, worsening renal function (RF), and the composite of worsening RF or CV death. Evidence was synthesized using network meta-analysis. In addition, the impact of receptor selectivity on outcomes was analysed using meta-regression. We identified 18,265 patients included in 22 trials. Compared to placebo, selective and non-selective SGLT2i improved fatal and non-fatal HF events. Head-to-head comparisons suggest superior efficacy with sotagliflozin as compared to dapagliflozin, empagliflozin or ertugliflozin. No significant difference was found between canagliflozin and sotagliflozin. Meta-regression analyses show a decreasing benefit on HF events with increasing receptor selectivity of SGLT2i. In contrast, receptor selectivity did not affect mortality and renal endpoints and no significant difference between individual SGLT2i was noted. Our data point towards a class-effect of SGLT2i on mortality and renal outcomes. However, non-selective SGLT2i such as sotagliflozin may be superior to highly selective SGLT2i in terms of HF outcomes.

Endoscopic preperitoneal parastomal hernia repair (ePauli repair) : an observational study

Abstract: Aspiring endoscopic surgery with extraperitoneal mesh application to avoid adhesion and pain from mesh fixation, we adopted the principles of the open Pauli repair of parastomal hernia (PSH). We have termed the procedure ePauli repair. The aim of this account is to inform about feasibility and adverse reactions. Patients with PSH selected for ePauli repair with transversus abdominis release (TAR) were enrolled in a prospective observational study. Patients were operated with laparoscopic or robotic assistance and endoscopic Rives-Stoppa repair in cases with concomitant midline hernia. Coated meshes or a buffer mesh was used in the retromuscular pocket for this modification of the Sugarbaker principle. Fifteen patients were included: six patients were operated laparoscopically and nine patients with robotic assistance. The median age of the stomas was 33 months (7–313). Five PSHs were recurrent after previous repairs. Median operating time without midline hernia repair was 156 min (107–233) and with midline hernia repair 241 min (176–286). One serosa lesion arose during operation, prompting intraoperative revision of the ostomy without postoperative morbidity. Two patients had postoperative obstruction and were readmitted to operation: one with multiple adhesions and one had kinking of the stoma bowel caused by insufficient incision of the transversalis fascia. No infections or seromas have been observed. One patient had discoloring of the flank with spontaneous remission, and one patient had recurrence. Median postoperative admission time was 3 days (1–19). Median follow-up is 10 months (0–27). ePauli repair is technically challenging but feasible. With our limited experience, we are encouraged with the pain, complication, and functional summary after ePauli repair and hopeful for the recurrence profile. ePauli/TAR is not for every patient or every surgeon and whether it should be restrained to recurrent PSH or be offered as first-line treatment for PSH is disputable.

Postmortem toxicological analyses of blood samples from 107 patients receiving opioid agonist treatment: substances detected and pooled opioid and benzodiazepine concentrations

Abstract: AIMS To present the substances and their concentrations detected post-mortem in patients receiving opioid agonist treatment (OAT) stratified by cause of death, estimate the pooled opioid and benzodiazepine concentrations using established conversion factors for blood concentrations from the Norwegian Road Traffic Act, and explore the association between drug-induced cause of death and the pooled opioid and benzodiazepine concentrations. DESIGN Cross-sectional nationwide study. SETTING Norway. PARTICIPANTS One hundred and seven patients who died during OAT (i.e. within 5 days after the last intake of OAT medication) between 1 January 2014 and 31 December 2015, with post-mortem femoral blood available for toxicology. Data were collected from hospital records, the Norwegian Cause of Death Registry and autopsy reports. MEASUREMENTS Presence of alcohol and non-alcohol substances in the bloodstream at time of death, determined through records of toxicology of post-mortem femoral blood. FINDINGS A median of four substances was detected across the causes of death. At least one benzodiazepine was detected in 81 (76%) patients. The median pooled opioid concentration was significantly higher in drug-induced deaths compared with other causes of death (362 ng/mL versus 182 ng/mL, P < 0.001), in contrast to the pooled benzodiazepine concentration (5466 versus 5701 ng/mL, P = 0.353). The multivariate regression analysis showed that only increasing pooled opioid concentration (ng/ML) was associated with increased odds of a drug-induced cause of death (odds ratio, 1.003; 95% confidence interval: 1.001-1.006). CONCLUSIONS In Norway, overall opioid concentration seems to play an important role in drug-induced deaths during opioid agonist treatment in patients prescribed methadone or buprenorphine. Patients prescribed buprenorphine tend to replace their agonist with full agonists, while patients prescribed methadone tend to have high opioid concentrations from methadone as the only opioid.