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We performed a systematic review to investigate the effects of vasopressor-induced hemodynamic changes in adults with shock. We applied a physiological approach using the interacting domains of intravascular volume, heart pump performance, and vascular resistance to structure the interpretation of responses to vasopressors. We hypothesized that incorporating changes in determinants of cardiac output and vascular resistance better reflect the vasopressor responsiveness beyond mean arterial pressure alone. We identified 28 studies including 678 subjects in Pubmed, EMBASE, and CENTRAL databases. All studies demonstrated significant increases in mean arterial pressure (MAP) and systemic vascular resistance during vasopressor infusion. The calculated mean systemic filling pressure analogue increased (16 +/- 3.3 mmHg to 18 +/- 3.4 mmHg; P = 0.02) by vasopressors with variable effects on central venous pressure and the pump efficiency of the heart leading to heterogenous changes in cardiac output. Changes in the pressure gradient for venous return and cardiac output, scaled by the change in MAP, were positively correlated (r (2) = 0.88, P < 0.001). Changes in the mean systemic filling pressure analogue and heart pump efficiency were negatively correlated (r (2) = 0.57, P < 0.001) while no correlation was found between changes in MAP and heart pump efficiency. We conclude that hemodynamic changes induced by vasopressor therapy are inadequately represented by the change in MAP alone despite its common use as a clinical endpoint. The more comprehensive analysis applied in this review illustrates how vasopressor administration may be optimized.

Aim: Gamma-hydroxybutyrate (GHB) is a common drug of abuse with an elimination half-life of 20-45 min. However, there is some evidence that GHB might exhibit saturation kinetics after ingesting high recreational doses. The aim of this study was to investigate the elimination kinetics of GHB from blood in people apprehended by the police for impaired driving and secondary to describe concentrations in all GHB-positive drivers. Methods: Two consecutive blood samples were taken about 30-40 min apart from N =16 apprehended drivers in Norway. GHB was determined in blood by an Ultra High-Performance Liquid ChromatographyTandem Mass Spectrometry (UHPLC-MS/MS) method. The changes in GHB between the two consecutive blood samples allowed estimating GHBs elimination half-life, assuming first-order and zero-order elimination kinetics. GHB concentrations are also reported for N =1276 apprehended drivers with GHB in blood. Results: The median time interval between collecting the two blood samples was 36 min (range 20 56 min). The median concentration of GHB in the first blood sample was 56.5 mg/L (range 14.1 142 mg/L) compared with 47.8 mg/L in the second sample (range 9.75 113 mg/L). The median elimination half-life was 103 min (range 21 187 min), and GHBs median zero-order elimination rate constant was 21.0 mg/L/h (range 6.71-45A mg/L/h). Back-calculation to the time of driving resulted in GHB concentrations up to 820 mg/L assuming first-order kinetics and up to 242 ma assuming zeroorder kinetics. In all drivers (N 1276), the median GHB concentration was 73.7 ma and highest was 484 mg/L. Conclusion: The elimination half-life of GHB in blood samples from apprehended drivers was longer than expected compared with results of controlled dosing studies. Zero-order kinetics seems a more appropriate model for GHB when concentrations are back-calculated. and the median elimination rate was 21 mg/L/h. (C) 2020 The Authors. Published by Elsevier B.V.

Objectives Depression is a common illness with substantial economic consequences for society and a great burden for affected individuals. About 30% of patients with depression do not respond to repeated treatments. Psychiatric comorbidity is known to affect duration, recurrence and treatment outcome of depression. However, there is a lack of knowledge on the extent to which psychiatric comorbidity is identified in the clinical setting for depressed patients in secondary psychiatric care. Therefore, the aim of this study was to compare the agreement between traditional diagnostic assessment (TDA) and a structured and comprehensive diagnostic procedure (SCDP) for identification of personality and anxiety disorder comorbidity in depressed patients in secondary psychiatric care. Methods 274 patients aged 18-77 were referred from four secondary psychiatric care clinics in Sweden during 2012-2017. ICD-10 diagnoses according to TDA (mostly unstructured by psychiatric specialist and residents in psychiatry), were retrieved from medical records and compared to diagnoses resulting from the SCDP in the study. This included the Mini International Neuropsychiatric Interview, the Structured Interview for DSM Axis II Personality Disorders and semi-structured questions on psychosocial circumstances, life-events, psychiatric symptoms, psychiatric treatments, substance use, and suicidal and self-harm behaviour. The assessment was carried out by psychiatric specialists or by residents in psychiatry with at least three years of psychiatric training. Results SCDP identified personality disorder comorbidity in 43% of the patients compared to 11% in TDA (p<0,0001). Anxiety disorder comorbidity was identified in 58% with SCDP compared to 12% with TDA (p<0,0001). Conclusions Important psychiatric comorbidity seems to be unrecognized in depressive patients when using TDA, which is routine in secondary psychiatric care. Comorbidities are better identified using the proposed model involving structured and semi-structured interviews together with clinical evaluations by clinical experts.

The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review in vitro and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.

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Introduction and Objective:Interleukin (IL)-32 is a pro-inflammatory cytokine not previously studied in relation to abdominal aortic aneurysm (AAA). The aim of this study was to elucidate the expression and localization of IL-32 in AAA.Methods:Expression and localization of IL-32 in human aortic tissue was studied with immunohistochemical analysis and Western blot (AAA:n= 5; controls:n= 4). ELISA was used to measure IL-32 in human plasma samples (AAA:n= 140; controls:n= 37) and in media from cultured peripheral blood mononuclear cells (PBMCs) from 3 healthy donors. IL-32 mRNA in PBMCs, endothelial cells, aortic smooth muscle cells (SMCs), and aortic tissue samples of AAA (n= 16) and control aortas (n= 9) was measured with qPCR.Results:IL-32 was predominantly expressed in SMCs and T-cell-rich areas. Highest mRNA expression was observed in the intima/media layer of the AAA. A weaker protein expression was detected in non-aneurysmal aortas. Expression of IL-32 was confirmed in isolated T cells, macrophages, endothelial cells, and SMCs, where expression was also inducible by cytokines such as interferon-gamma. There was no difference in IL-32 expression in plasma between patients and controls.Conclusion:IL-32 signaling is altered locally in AAA and could potentially play an important role in aneurysm development. Further studies using animal models would be helpful to study its potential role in AAA disease.

Introduction: Impaired oxygenation in the skin may occur in disease states and after reconstructive surgery. We used tissue viability imaging (TiVi) to measure changes in oxygenation and deoxygenation of haemoglobin in an in vitro model and in the dermal microcirculation of healthy individuals. Materials and methods: Oxygenation was measured in human whole blood with different levels of oxygenation. In healthy subjects, changes in red blood cell concentration (C-RBC,(TiVi)), oxygenation (Delta C-OH,(TiVi)) and deoxygenation (Delta C-DOH,(TiVi)) of haemoglobin were measured during and after arterial and venous occlusion using TiVi and were compared with measurements from the enhanced perfusion and oxygen saturation system (EPOS). Results: During arterial occlusion, C-RBC,(TiVi) remained unchanged while Delta C-OH,(TiVi) decreased to -44.2 (10.4) AU (p = 0.04), as compared to baseline. After release, C-RBC,C-TiVi increased to 39.2 (18.8) AU (p < 0.001), Delta C-OH,C-TiVi increased to 38.5. During venous occlusion, C-RBC,C-TiVi increased to 28.9 (11.2) AU (p < 0.001), Delta C-OH,C-TiVi decreased to -52.2 (46.1) AU (p < 0.001) compared to baseline after 5 min of venous occlusion. There was a significant correlation between the TiVi Oxygen Mapper and EPOS, for arterial (r = 0.92, p < 0.001) and venous occlusion (r = 0.87, p < 0.001), respectively. Conclusion: This study shows that TiVi can measure trends in oxygenation and deoxygenation of haemoglobin during arterial and venous stasis in healthy individuals.

Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.

Treatments that include gemcitabine and carboplatin induce dose-limiting myelosuppression. The understanding of how human bone marrow is affected on a transcriptional level leading to the development of myelosuppression is required for the implementation of personalized treatments in the future. In this study, we treated human hematopoietic stem and progenitor cells (HSPCs) harvested from a patient with chronic myelogenous leukemia (CML) with gemcitabine/carboplatin. Thereafter, scRNA-seq was performed to distinguish transcriptional effects induced by gemcitabine/carboplatin. Gene expression was calculated and evaluated among cells within and between samples compared to untreated cells. Cell cycle analysis showed that the treatments effectively decrease cell proliferation, indicated by the proportion of cells in the G2M-phase dropping from 35% in untreated cells to 14.3% in treated cells. Clustering and t-SNE showed that cells within samples and between treated and untreated samples were affected differently. Enrichment analysis of differentially expressed genes showed that the treatments influence KEGG pathways and Gene Ontologies related to myeloid cell proliferation/differentiation, immune response, cancer, and the cell cycle. The present study shows the feasibility of using scRNA-seq and chemotherapy-treated HSPCs to find genes, pathways, and biological processes affected among and between treated and untreated cells. This indicates the possible gains of using single-cell toxicity studies for personalized medicine.

Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10⁻⁵), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10⁻⁴), rs6118 in SERPINA5 (P-value = 5.83 × 10⁻⁴), and rs5877 in SERPINC1 (P-value = 1.07 × 10⁻³), and the genes CAPZA2 (P-value = 4.03 × 10⁻⁴) and SERPINC1 (P-value = 1.55 × 10⁻³). The SNVs in the top-scoring pathway “Factors involved in megakaryocyte development and platelet production” (P-value = 3.34 × 10⁻⁴) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10⁻⁸), and decrease (OR = 66.82, P-value = 5.92 × 10⁻⁹). The logistic regression models predict CTCAE grades 3–4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.

Background

In recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.

Methods

The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome.

Result

Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19–9, and baseline serum bilirubin levels) were not significantly associated with survival.

Conclusion

Serum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.

Lipopolysaccharide (LPS) induces fever through cytokines like receptor-activator of nuclear factor kappa B ligand (RANKL), triggering mediators like prostaglandins (PG), endothelin-1 (ET-1), corticotrophin-releasing factor (CRF), substance P (SP) and endogenous opioids. LPS-induced fever is reduced in females compared with males except in ovariectomized (OVX) females which show increased fever mediated by PG. The present study aimed to identify the mediators involved in fever in intact and OVX female rats. Fever was induced with LPS (50 mu g/kg) intraperitoneally or CRF (2.5 mu g), ET-1 (1 pg), morphine (10 mu g) and SP (500 ng) intracerebroventricularly in sham-operated and OVX rats. The role of RANKL was evaluated with osteoprotegerin (OPG, 1 mu g, intracerebroventricularly). Expression of RANK, CRFI/II, ETB, mu-opioid (MOR) and NK1 receptors was evaluated by confocal microscopy. Besides LPS, only morphine induced fever in OVX rats while all mediators induced fever in sham-operated animals. OPG abolished LPS-induced fever in OVX but not sham-operated animals. Overall, fever involves similar central mediators in cycling females and males but only morphine induced fever in OVX females. Importantly, RANK/RANKL participates in LPS-induced fever in OVX females, as in males but not in cycling females.

Aims Heart failure describes a large and heterogeneous spectrum of underlying cardiac diseases. MicroRNAs (miRs) are small non-coding RNAs that in recent years have been shown to play an important role in the pathogenesis of heart failure. Cardiac magnetic resonance imaging is a powerful imaging modality for the evaluation of cardiac characteristics in heart failure. In this study, we sought to compare heart failure patients with a diagnosis of either idiopathic dilated cardiomyopathy (DCM) or ischaemic heart disease (IHD), in the context of serum levels of certain miRs and also magnetic resonance imaging parameters of cardiac structure and function. Methods and results A total of 135 subjects were studied: 53 patients with DCM (age: 59 +/- 12 years, mean +/- SD), 34 patients with IHD (66 +/- 9 years), and 48 controls (64 +/- 5 years). The participants underwent baseline medical examination, blood sampling, and a cardiac magnetic resonance imaging examination at 3 Tesla (Philips Ingenia). The serum levels of seven different miRs were analysed and assessed: 16-5p, 21-5p, 29-5p, 133a-3p, 191-5p, 320a, and 423-5p, all of which have been demonstrated to play potential roles in the pathogenesis of heart failure. The patients in the DCM and IHD groups had left ventricles that had larger end-diastolic volume (P &lt; 0.001), larger mass ( P &lt; 0.001), and lower ejection fraction (P &lt; 0.001) compared with controls. Serum levels of miR-29-5p were increased in DCM compared with IHD (P &lt; 0.005) and serum levels of miR-320a were elevated in DCM compared with healthy controls ( P &lt; 0.05). There was no significant association between miR levels and magnetic resonance imaging parameters of left ventricular structure and function. Conclusions Circulating miR-320a can add to the discrimination between patients with DCM and healthy controls and circulating miR-29-5p can add to the discrimination between DCM and IHD.

The prescription of medicines is one of the most common acts performed by physicians. Yet, several studies have shown that junior doctors are not well prepared for the task. The teaching of basic and clinical pharmacology varies greatly between universities, both within Sweden and in Europe. National prescribing exams have been introduced in the UK, the Netherlands and Belgium, and there is an on-going project to develop a European exam, focusing on a list of essential medicines and patient safety. With the new six year curriculum for medical education in Sweden, the license to prescribe could be linked to a national prescribing exam, to ensure good knowledge of both therapeutics and Swedish drug regulation.

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Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the hosts immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.

BACKGROUND Frailty is a multidimensional syndrome characterised by a loss of reserve and an increased risk of adverse outcomes. OBJECTIVE To study the impact of frailty on mortality in unselected intensive care patients, and to compare its discriminatory ability to an established model for outcome prediction in intensive care. DESIGN A prospective study with a comparison of two prediction models. SETTING A tertiary mixed ICU, from January 2017 to June 2018. PATIENTS AND MAIN OUTCOME MEASURES Data on premorbid frailty (clinical frailty scale; CFS), severity of illness (the simplified acute physiology score, third version; SAPS3), therapeutic procedures, limitations of care and outcome were collected in 872 adult ICU patients. A cut-off level of CFS for predicting death within 30 days was identified and unadjusted and adjusted analyses were used to evaluate the association of frailty to outcome. RESULTS The receiver operating curve, area under the curve of CFS [0.74 (95% confidence interval, 0.69 to 0.79)] did not differ significantly from that of SAPS3 [0.79 (0.75 to 0.83), P = 0.53], whereas combining the two resulted in an improved discriminatory ability [area under the curve = 0.82 (0.79 to 0.86), CFS + SAPS3 vs. SAPS3 alone, P = 0.02]. The correlation of CFS to SAPS3 was moderate (r = 0.4). A cut-off level was identified at CFS at least 5, defining 43% (n=375) of the patients as frail. Frail patients were older with higher SAPS3 and more comorbidities. Treatment in the ICU was more often withheld or withdrawn in frail patients, and mortality was higher. After adjustment for SAPS3, comorbidities, limitations of treatment, age and sex, frailty remained a strong predictor of death within 30 days [hazard ratio 2.12 (95% confidence interval, 1.44 to 3.14), P &lt; 0.001]. CONCLUSION Premorbid frailty was common in general ICU patients and was an independent predictor of death. Our study suggests that frailty could be a valuable addition in outcome prediction in intensive care.

Since their introduction, tyrosine kinase inhibitors (TKIs, eg, imatinib, nilotinib, dasatinib, bosutinib, ponatinib) have revolutionized the treatment of chronic myeloid leukemia (CML). However, long-term treatment with TKIs is associated with serious adverse events including both bleeding and thromboembolism. Experimental studies have shown that TKIs can cause platelet dysfunction. Herein, we present the first side-by-side investigation comparing the effects of currently used TKIs on platelet function and thrombin generation when used in clinically relevant concentrations. A flow cytometry multiparameter protocol was used to study a range of significant platelet activation events (fibrinogen receptor activation, alpha granule, and lysosomal exocytosis, procoagulant membrane exposure, and mitochondrial permeability changes). In addition, thrombin generation was measured in the presence of TKIs to assess the effects on global hemostasis. Results show that dasatinib generally inhibited platelet function, while bosutinib, nilotinib, and ponatinib showed less consistent effects. In addition to these general trends for each TKI, we observed a large degree of interindividual variability in the effects of the different TKIs. Interindividual variation was also observed when blood from CML patients was studied ex vivo with whole blood platelet aggregometry, free oscillation rheometry (FOR), and flow cytometry. Based on the donor responses in the side-by-side TKI study, a TKI sensitivity map was developed. We propose that such a sensitivity map could potentially become a valuable tool to help in decision-making regarding the choice of suitable TKIs for a CML patient with a history of bleeding or atherothrombotic disease.

Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.

Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57–81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.

Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1–4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000–1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7–11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.

Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose–response relationship between RA-related autoantibodies and risk of arthritis development. 

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant. Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel. Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, n = 8; girls 9 years, n = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in MYH7 (n = 2), RBM20, ALPK3, and PGM1, respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in MYBPC3, ABCC9, and FLNC, respectively. Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.

Background

Women are advised to primarily use non-oral contraceptive alternatives after Roux-en-Y gastric bypass since it is not known if the surgery affects the pharmacokinetics of oral contraceptives.

Methods

This is a multi-center, open label, phase 2 pharmacokinetic study performed at the University Hospital of Linköping and the Clinical Trials Center, Department of Obstetrics and Gynecology, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Fifteen women aged 18–40 years who had previously undergone Roux-en-Y gastric bypass surgery and reached a BMI < 30 were included. Fifteen BMI-matched women with no previous history of Roux-en-Y gastric bypass surgery served as a control group. After administration of a single dose of a combined oral contraceptive containing 0.03 mg ethinylestradiol/0.15 mg levonorgestrel, serum levonorgestrel concentrations were determined during a 24-h period using ultra performance liquid chromatography/tandem mass spectrometry. The area under the plasma concentration time curve of levonorgestrel (AUC0–24h) was the main outcome measure.

Results

There were no significant differences in the studied pharmacokinetic parameters, AUC0–24h, total AUC, peak serum concentration (Cmax), time to peak serum concentrations (Tmax), apparent oral clearances of levonorgestrel (CLoral), or terminal half-lives (t½) between the groups.

Conclusion

This is to our knowledge the first study to evaluate the pharmacokinetics of oral levonorgestrel in women with a BMI < 30 at least 1 year after RYGB compared with a BMI-matched group of women. We could not find any significant pharmacokinetic differences between the groups, suggesting that oral levonorgestrel may be used in non-obese women after Roux-en-Y gastric bypass once a stable body weight has been reached.

Background The ED Stressor Scale outlines 15 stressors that are of importance for ED staff. Limited research has identified how commonly such stressors occur, or whether such factors are perceived with similar importance across different hospitals. This study sought to examine the frequency or perceived severity of these 15 stressors using a multicentre cohort of emergency clinicians (nurses and physicians) in EDs in two countries (Australia and Sweden). Method This was a cross-sectional survey of staff working in eight hospitals in Australia and Sweden. Data were collected between July 2016 and June 2017 (depending on local site approvals) via a printed survey incorporating the 15-item ED stressor scale. The median stress score for each item and the frequency of experiencing each event was reported. Results Events causing most distress include heavy workload, death or sexual abuse of a child, inability to provide optimum care and workplace violence. Stressors reported most frequently include dealing with high acuity patients, heavy workload and crowding. Violence, workload, inability to provide optimal care, poor professional relations, poor professional development and dealing with high-acuity patients were reported more commonly by Australian staff. Swedish respondents reported more frequent exposure to mass casualty incidents, crisis management and administrative concerns. Conclusions Workload, inability to provide optimal care, workplace violence and death or sexual abuse of a child were consistently reported as the most distressing events across sites. The frequency with which these occurred differed in Australia and Sweden, likely due to differences in the healthcare systems.

Background

Patient‐controlled sedation (PCS) with propofol accompanied by a bedside nurse anaesthetist is an alternative sedation method for endoscopic procedures compared with midazolam administered by a nurse or endoscopist. Increasing costs in health care demands an economic perspective when introducing alternative methods. We applied a hospital perspective on a cost analysis comparing different methods of sedation and the resource use that were expected to affect cost differences related to the sedation.

Methods

Based on two randomised previous studies, the direct costs were determined for different sedation methods during two advanced endoscopic procedures: endoscopic retrograde cholangiopancreatography (ERCP) and flexible bronchoscopy including endobronchial ultrasound. ERCP comparisons were made between midazolam sedation by the endoscopic team, PCS with a bedside nurse anaesthetist and propofol sedation administered by a nurse anaesthetist. Bronchoscopy comparisons were made between midazolam sedation by the endoscopic team and PCS with a bedside nurse anaesthetist, categorised by premedication morphine‐scopolamine or glycopyrronium.

Results

Propofol PCS with a bedside nurse anaesthetist resulted in lower costs per patient for sedation for both ERCP (233 USD) and bronchoscopy (premedication morphine‐scopolamine 267 USD, premedication glycopyrronium 269 USD) compared with midazolam (ERCP 425 USD, bronchoscopy 337 USD). Aborted procedures that needed to be repeated and prolonged hospital stays significantly increased the cost for the midazolam groups.

Conclusion

Propofol PCS with a bedside nurse anaesthetist reduces the direct sedation costs for ERCP and bronchoscopy procedures compared with midazolam sedation.

Background: Patient-controlled sedation (PCS) is a documented method for endoscopic procedures considered to facilitate early recovery. Limited data have been reported, however, on its use during flexible bronchoscopy (FB).

Materials and Methods: This study hypothesized that PCS with propofol during FB would facilitate early recovery, with similar bronchoscopist and patient satisfaction compared with nurse-controlled sedation (NCS) with midazolam. A total of 150 patients were randomized 1:1:1 into a control group (premedication with morphine-scopolamine and NCS with midazolam), PCS-MS group (premedication with morphine-scopolamine and PCS with propofol), and PCS-G group (premedication with glycopyrronium and PCS with propofol).

Results: The procedures included transbronchial biopsy, transbronchial needle aspiration, cryotherapy/biopsy, and/or multistation endobronchial ultrasound. FB duration values in median (range) were 40 (10 to 80), 39 (12 to 68), and 44 (10 to 82) minutes for the groups NCS, PCS-MS, and PCS-G, respectively. An overall 81% of the patients in the combined PCS groups were ready for discharge (modified Post Anaesthetic Discharge Scoring System, score 10) 2 hours after bronchoscopy compared with 40% in the control group (P<0.0001). Between PCS groups, 96% of the PCS-G group patients were ready for discharge compared with 65% in the PCS-MS group (P=0.0002) at 2 hours. Bronchoscopists’ and patients’ satisfaction scores were high in all groups. Postdischarge quality scores showed no differences among the groups.

Conclusion: PCS with propofol during FB is feasible, as it shortened recovery time without compromising procedure conditions for bronchoscopists or patients. A rapid postsedation stabilization of vital signs facilitates surveillance before the patient leaves the hospital.

New psychoactive substances are emerging on the illegal drug market. Synthetic opioids including fentanyl analogues are of special concern due to their high potency. This indicates the possibility of low drug concentrations in vivo and calls for sensitive analytical methods and identification of the most appropriate analytical targets. In this study the in vitro metabolism of ortho-, meta- and para-fluorofentanyl, three fluorinated derivatives of fentanyl, has been investigated using human hepatocytes and compared to the results from an authentic human urine sample. Based on knowledge on the metabolism of similar fentanyl analogues N-dealkylation and hydroxylation was hypothesized to be the most central pathways. The three fluorofentanyl isomers were incubated with pooled human hepatocytes at 1, 3 and 5 h. Liquid chromatography quadrupole time of flight mass spectrometry operating in data-dependent mode was used to analyse the hepatocyte samples, as well as the hydrolysed and non-hydrolysed authentic urine sample. Data were analysed by a targeted approach with a database of potential metabolites. The major metabolite formed in vitro was the N-dealkylation product norfluorofentanyl. In addition various hydroxylated metabolites, a N-oxide, dihydrodiol metabolites and a hydroxymethoxy metabolite were found. In total, 14 different metabolites were identified for each fluorofentanyl isomer. In the authentic urine sample, three metabolites were detected in addition to the ortho-fluorofentanyl parent compound, with hydroxymethoxy metabolite having the highest abundance followed by norfluorofentanyl and a metabolite hydroxylated on the ethylphenyl ring. This in vitro study showed that the metabolic pattern for ortho-, meta-, and para-fluorofentanyl was close to those previously reported for other fentanyl analogues. We suggest that the hydroxymethoxy metabolite and the metabolite hydroxylated on the ethylphenyl ring should be the metabolites primarily investigated in further studies to determine the most appropriate marker for intake of fluorofentanyl derivatives in urine drug screening for human subjects.

INTRODUCTION: A coeliac disease (CD) diagnosis is likely in children with levels of tissue transglutaminase autoantibodies (anti-TG2) >10 times the upper reference value, whereas children with lower anti-TG2 levels need an intestinal biopsy to confirm or rule out CD. A blood sample is easier to obtain than an intestinal biopsy sample, and stabilised blood is suitable for routine diagnostics because transcript levels are preserved at sampling. Therefore, we investigated gene expression in stabilised whole blood to explore the possibility of gene expression-based diagnostics for the diagnosis and follow-up of CD.

DESIGN: We performed RNA sequencing of stabilised whole blood from active CD cases (n=10), non-CD cases (n=10), and treated CD cases on a gluten-free diet (n=10) to identify diagnostic CD biomarkers and pathways involved in CD pathogenesis.

RESULTS: No single gene was differentially expressed between the sample groups. However, by using gene set enrichment analysis (GSEA), significantly differentially expressed pathways were identified in active CD, and these pathways involved the inflammatory response, negative regulation of viral replication, translation, as well as cell proliferation, differentiation, migration, and survival. The results indicate that there are differences in pathway regulation in CD, which could be used for diagnostic purposes. Comparison between GSEA results based on stabilised blood with GSEA results based on small intestinal biopsies revealed that type I interferon response, defence response to virus, and negative regulation of viral replication were identified as pathways common to both tissues.

CONCLUSIONS: Stabilised whole blood is not a suitable sample for clinical diagnostics of CD based on single genes. However, diagnostics based on a pathway-focused gene expression panel may be feasible, but requires further investigation.

Background The efficiency of transdermal drug delivery may be increased by pretreating the skin with microneedles, but distinct effects of microneedles and the microneedle-enhanced delivery of vasoactive drugs on the skin microvasculature are still not well investigated. Materials and Methods In eight healthy human subjects, we measured the microvascular response to microneedle-induced microtraumas in the skin microvasculature using polarized light spectroscopy imaging (Tissue Viability imaging, TiVi). The microvascular response was assessed for up to 48 hours for three microneedle sizes (300 mu m, 500 mu m, and 750 mu m) and for different pressures and application times. Results In our results, microneedle application increased the local red blood cell (RBC) concentration for up to 24 hours dependent on the needle lengths, applied time, and force. Conclusion Optimization of microneedles size, pressure, and application time should be taken into account for future protocols for drug delivery and experimental provocations.

Background: Ringers solution might be used to treat volume depletion (extracellular dehydration) and hemorrhage, but there is no integrated view of how these fluid balance disorders influence the kinetics of the infused volume. Methods: Acute dehydration (mean 1.7 L) was induced by repeated doses of furosemide (5 mg) in 10 healthy male volunteers, and 0.5 L and 0.9 L of blood was withdrawn in random order on different occasions in another 10 male volunteers, just before administration of Ringers acetate solution. Infusions performed in the normovolemic state served as controls. Measurements of blood hemoglobin and urinary excretion were used to create volume kinetic profiles that were analyzed using mixed-effects modeling software. Results: Infusions over 15 to 30 min showed a marked distribution phase during which the plasma volume transiently increased by 50% to 75% of the administered volume. Dehydration and hemorrhage accelerated redistribution but retarded the elimination; the half-life of the infused fluid increased from 36 to 51 min (mean) from 1 L of dehydration and to 95 min from 1 L of hemorrhage. Extravascular accumulation decreased with the dehydration volume and increased with the hemorrhage volume. Simulations show that 60% as much Ringer is needed to replace volume depletion amounting to 1 L as compared with hemorrhage over a 2-h period. A continued but slower drip after the initial fluid resuscitation prevents rebound hypovolemia. Conclusions: Furosemide-induced dehydration and blood withdrawal in normotensive volunteers had modest effects on the Ringers acetate kinetics. Urinary excretion was inhibited more by hemorrhage than by dehydration.

The Revised (or "Extended") Starling principle is based on highly controlled laboratory-based frog and rodent experiments and remains a hypothesis awaiting clinical validation. A key point is that the endothelial glycocalyx layer moves the oncotic gradient from being between the plasma and the interstitium to between the plasma and a virtually protein-free space between the glycocalyx and the endothelial cell membrane, which dramatically changes the prerequisites for fluid absorption from tissue to plasma. However, many experimental and clinical observations in humans agree poorly with the new microcirculatory proposals. The most troubling aspect of the explanation regarding the role of the glycocalyx in the Revised Starling principle is the effective reabsorption of fluid by skeletal muscle when the capillary filtration pressure is acutely reduced. Other issues include the plasma volume effects of hypertonic saline, iso-oncotic and hyper-oncotic albumin, fluid distribution during cardio-pulmonary bypass, and the virtually identical capillary leakage of plasma and albumin despite marked inflammation found in our fluid therapy studies. The Revised Starling principle deals mainly with steady-state conditions, but the circulatory system is highly dynamic. Second to second vasomotion is always operational and must be considered to understand what we observe in humans.

Background Infusion with 0.9% saline is a mainstay in the treatment of severe hyperglycemia, but the kinetics of the saline volume in this setting has not been studied. Methods An intravenous infusion of 1 L of 0.9% saline over 30 minutes was given on 31 occasions to 17 patients with hyperglycemia due to poorly controlled diabetes (mean age 51 years). A two-volume kinetic model was fitted to serial data on the hemodilution and urinary excretion, using mixed-effects modeling software. Results Plasma glucose was 36 +/- 9 mmol/L on arrival to the hospital. The central volume of distribution (the plasma) was only 2.38 L (mean; 95% confidence interval 1.73-3.04) on the day of admission. Uptake into a remote compartment, believed to be the cells, amounted to 300 mL of the first liter of saline, although only small amounts of insulin were given. Plasma glucose, plasma bicarbonate, urine glucose, and plasma creatinine served as covariates in the kinetic model and mathematically affected the urinary excretion. For example, elimination of the infused fluid tripled from an increase in plasma glucose from 5 to 35 mmol/L and doubled from a reduction in plasma bicarbonate from 24 to 5 mmol/L. Conclusions The excretion of 0.9% saline was increased depending on the degree of hyperglycemia. The kinetics was characterized by glucose-accelerated diuresis, and an intracellular uptake that occurred at two thirds the urine flow rate. These data could help to determine appropriate volumes and rates of infusion of crystalloids in hyperglycemia.

Previous studies have shown that the injection of adipose stem cells and stromal vascular fraction(SVF) into the tunica albuginea (TA) during the inflammatory phase in a rat model of Peyronies disease(PD) prevented the development of TA fibrosis. Our aim was to investigate whether local injection of SVF can reduce established fibrosis in a rat model of chronic phase of PD. Eighteen-male 12-wk-old Sprague-Dawley rats were divided in three equal groups: sham, PD without treatment (PD) and PD treated with SVF(PD-SVF). Sham rats underwent 2 injections of vehicle into the TA one month apart. PD rats underwent TGF-beta 1 injection and injection of vehicle one month later. PD-SVF rats underwent TGF-beta 1 injection followed by SVF (1-million cells) one month later. One month after the last treatment, the animals, n = 6 rats per group, underwent measurement of intracorporal and mean arterial pressure during electrostimulation of the cavernous nerve. Following euthanasia, penises were harvested for in-vitro study. Erectile function was not statistically significantly different between groups. PD animals developed subtunical areas of fibrosis and elastosis with upregulation of collagen III protein. These fibrotic changes were reversed after injection of SVF. We provide evidence that local injection of SVF reverses TA fibrosis in a rat model of chronic phase of PD.

Läkemedelsverket rapporterar att man inte, utifrån sitt etablerade arbetssätt, kan genomföra nytta–riskvärdering av läkemedel utanför godkänd indikation. 

Sjukvården har ett behov av en nationell process för värdering av off label-användning av vissa läkemedel. 

Sjukvården behöver också fler och innovativa akademiskt drivna läkemedelsstudier.

Objective: To compare the assessments of 10-year probability by patients and their physicians of cardiovascular complications of hypertension with actual outcomes. Design: Patients with uncomplicated hypertension treated with at least one antihypertensive drug at inclusion were followed for 10 years through mandatory national health registers. Setting: 55 primary health care centres, 11 hospital outpatient clinics in Sweden Patients: 848 patient, 212 physicians. Main outcome measures: Patients and physicians estimated the probability of hypertension-related complications with treatment (death, heart failure, acute myocardial infarction/AMI, and stroke) for each patient in 848 pairs. Estimates were compared with the clinical outcomes 10 years later using data from the Mortality Register and the National Patient Register. Results: Patients were significantly better (p &lt; 0.001) than their physicians in estimating the average probability of heart failure compared with actual outcome data (14% vs. 24%, outcome 15%), AMI (16% vs. 26%, outcome 8%), and stroke (15% vs. 25%, outcome 11%). Patients were significantly worse (p &lt; 0.001) at estimating the average probability of death (10% vs. 18%, actual outcome 20%). Neither the patients nor the physicians were able to distinguish reliably between low-risk and high-risk patients after adjustment for age and sex. Conclusions: Patients were better than their physicians in estimating the average probability of morbidity due to hypertension. Both the patients and their attending physicians had difficulty in estimating the individual patients risk of complications. The results support the use of evidence-based tools in consultations for assessing the risk of cardiovascular complications associated with hypertension.

Aim: Claimed intake of alcohol after a traffic incident, called the hip-flask defence, can be objectively assessed by different methods. One of them is the use of two consecutive ethanol concentrations in urine and the ratio between ethanol concentrations in urine and blood. Another one is the concentrations of ethyl glucuronide (EtG) and ethyl sulphate (EtS) in blood and their ratio to ethanol. The experimental basis for both these models is from single dose studies only. The aim of this study was therefore to describe the kinetics of ethanol, EtG and EtS after ingestion of two repeated doses of ethanol and to investigate the usefulness of the different models for the assessment of the hip-flask defence. Methods: Thirty-five subjects ingested a first dose of 0.51 g of ethanol per kilo body weight, and two hours later a second dose (the hip-flask drink) of 0.25, 0.51 or 0.85 g of ethanol per kilo body weight. Ten urine and 17 blood samples were collected and analysed for ethanol, EtG and EtS using fully validated methods. It was investigated if all subjects fulfilled the criteria for recent drinking, according to the two different models, when using the samples collected 180-240 minutes after start of first dose drinking. According to the first model, increase in urinary ethanol concentrations and a ratio UAC/BAC below 1.3 indicated recent drinking. According to the second model, increase in blood EtG concentrations and a ratio ethanol (g/kg)/EtG (mg/L) above 1 indicated recent drinking. Results: All subjects in the high dose group fulfilled all criteria for recent drinking. One subject in the medium dose group and nine subjects in the low dose group failed to show increasing UAC and/or a UAC/ BAC ratio below 1.3. One subject in the low dose group failed to show increasing concentrations of blood EtG, but all subjects showed a ratio ethanol/EtG above 1. Conclusions: The present study showed, by the use of experimental data, that both two models used to investigate the hip-flask defence can be used, but only when the hip-flask dose is sufficiently high. (C) 2020 The Author(s). Published by Elsevier B.V.

Background The echocardiography working group of the European Society of Intensive Care Medicine recognized the need to provide structured guidance for future CCE research methodology and reporting based on a systematic appraisal of the current literature. Here is reported this systematic appraisal. Methods We conducted a systematic review, registered on the Prospero database. A total of 43 items of common interest to all echocardiography studies were initially listed by the experts, and other "topic-specific" items were separated into five main categories of interest (left ventricular systolic function, LVSF n = 15, right ventricular function, RVF n = 18, left ventricular diastolic function, LVDF n = 15, fluid management, FM n = 7, and advanced echocardiography techniques, AET n = 17). We evaluated the percentage of items reported per study and the fraction of studies reporting a single item. Results From January 2000 till December 2017 a total of 209 articles were included after systematic search and screening, 97 for LVSF, 48 for RVF, 51 for LVDF, 36 for FM and 24 for AET. Shock and ARDS were relatively common among LVSF articles (both around 15%) while ARDS comprised 25% of RVF articles. Transthoracic echocardiography was the main echocardiography mode, in 87% of the articles for AET topic, followed by 81% for FM, 78% for LVDF, 70% for LVSF and 63% for RVF. The percentage of items per study as well as the fraction of study reporting an item was low or very low, except for FM. As an illustration, the left ventricular size was only reported by 56% of studies in the LVSF topic, and half studies assessing RVF reported data on pulmonary artery systolic pressure. Conclusion This analysis confirmed sub-optimal reporting of several items listed by an expert panel. The analysis will help the experts in the development of guidelines for CCE study design and reporting.

This review summarizes current evidence on the abuse and misuse of the gabapentinoids pregabalin and gabapentin. Pharmacovigilance studies, register-based studies, surveys, clinical toxicology studies, and forensic toxicology studies were identified and scrutinized with the goal to define the problem, identify risk factors, and discuss possible methods to reduce the potential for abuse and misuse. Studies found that gabapentinoids are abused and misused and that individuals with a history of psychiatric disorders or substance use disorder seem to be at high risk. Moreover, some evidence supports the notion that patients with opioid use disorders may be at an increased risk of abusing gabapentinoids. Available evidence also suggests that abuse and misuse are more frequent in users of pregabalin compared with users of gabapentin. Health professionals and prescribers should be aware of the risk for misuse of pregabalin and gabapentin, which eventually could lead to abuse, substance dependence, and intoxications. Prescribing to patients belonging to risk populations such as those with psychiatric disorders or substance use disorder should be avoided if possible and, if prescribed, signs of misuse and abuse should be monitored.

BACKGROUND There are no instruments specifically developed for the measurement of nursing workload in postanaesthesia care units (PACUs). An objective and valid instrument is essential for planning work flow and staffing in this unique hospital environment that encompasses elements of elective and acute postsurgical care. Previous studies show that increased workload is associated with increased complication rates in ICUs. Thus, workload assessment may be an important tool for improving postsurgical outcomes. OBJECTIVE The aim of this study was to develop and validate a postanaesthesia workload instrument (PAWI) for measurement of workload in PACUs for adults above 18 years of age. DESIGN Development and validation consisted of three parts: Delphi consensus to establish content validity; internal validation including feasibility, face validity and inter-rater reliability testing; and national external validation consisting of feasibility, inter-rater reliability, criterion validity, construct and face validities. SETTING PACUs in nine university and regional hospitals in Sweden. RESULTS The final instrument consisted of 11 workload domains. The response rate was 98% and overall feasibility of PAWI was 100%. Content and face validity were demonstrated by consensus after two Delphi rounds. In national external validation, good agreement between experts was demonstrated with Cohens kappa greater than 0.75 in nine domains and 0.6 to 0.74 in the remaining two domains. A significant relationship was seen between PAWI and the nine equivalents of nursing manpower use score (NEMS) (r = 0.439, P &lt; 0.001). There were no floor or ceiling effects. There was a significant association between PAWI points and American Society of Anesthesiologists (ASA) physical status grade (P = 0.007) but not between PAWI points and age. CONCLUSION We developed and validated PAWI, an instrument for objectively measuring workload in postanaesthesia care units. PAWI demonstrated good feasibility and metric properties.

Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0 center dot 6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0 center dot 4 (95% CI: -0 center dot 7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.

Analysis of postmortem samples with the presence of morphine can sometimes be challenging to interpret. Tolerance complicates interpretation of intoxications and causes of death due to overlap in therapeutic and fatal concentrations. Determination of metabolites and metabolic ratios can potentially differentiate between abstinence, continuous administration, and perhaps time of administration. The purpose of this study was to (a) develop and validate a method for quantitation of morphine-3 beta-D-glucuronide, morphine-6 beta-D-glucuronide, normorphine, codeine-6 beta-D-glucuronide, norcodeine, codeine, 6-acetylmorphine, and ethylmorphine in urine using liquid chromatography-tandem mass spectrometry; (b) apply the method to opiate related deaths; (c) compare metabolic ratios in urine in different causes of death (CoD) and after different drug intakes and (d) compare heroin intoxications in rapid and delayed deaths. Validation parameters such as precision, bias, matrix effects, stability, process efficiency, and dilution integrity were assessed and deemed acceptable. Lower limits of quantitation ranged from 0.01-0.2 mu g/mL for all analytes. Autopsy cases (n=135) with paired blood and urine samples were analyzed. Cases were divided into three groups based on CoD; opiate intoxication, intoxication with other drugs than opiates, and other CoD. The cases were classified by intake: codeine (n=42), heroin (n=36), morphine (n=49), and ethylmorphine (n=3). Five cases were classified as mixed intakes and excluded. Heroin intoxications (n=35) were divided into rapid (n=15) or delayed (n=20) deaths. Parent drug groups were compared using metabolic ratio morphine-3 beta-D-glucuronide/morphine and significant differences were observed between codeine vs morphine (p=0.005) and codeine vs heroin (p &lt;= 0.0001). Urine and blood concentrations, and metabolic ratios in rapid and delayed heroin intoxications were compared and determined a significant difference for morphine (p=0.001), codeine (p=0.009), 6-acetylmorphine (p=0.02) in urine, and morphine (p=0.02) in blood, but there was no significant difference (p=0.9) between metabolic ratios. Morphine-3 beta-D-glucuronide results suggested a period of abstinence prior to death in 25% of the heroin intoxications.

Background Long-term outcomes of patients admitted to intensive care units (ICUs) after surgery are unknown. We investigated the long-term effects of surgical exposure prior to ICU admission. Methods Registry-based cohort study. The adjusted effect of surgical exposure for mortality was examined using Cox regression. Secondary analysis with conditional logistic regression in a case-control subpopulation matched for age, gender, and Simplified Acute Physiology Score III (SAPS3) was also conducted. Results 72 242 adult patients (56.9% males, median age 66 years [IQR 50-76]), admitted to Swedish ICUs in 3-year (2012-2014) were followed for a median of 2026 days (IQR 1745-2293). Cardiovascular diseases (17.5%), respiratory diseases (15.8%), trauma (11.2%), and infections (11.4%) were the leading causes for ICU admission. Mortality at longest follow-up was 49.4%. Age; SAPS3; admissions due to malignancies, respiratory, cardiovascular and renal diseases; and transfer to another ICU were associated with increased mortality. Surgical exposure prior to ICU admission (adjusted hazard ratio [aHR] 0.90; 95% CI 0.87-0.94; P &lt; .001), admissions from the operation theatre (aHR 0.94; CI 0.90-0.99; P = .022) or post-anaesthesia care unit (aHR 0.92; CI 0.87-0.97; P = .003) were associated with decreased mortality. Conditional logistic regression confirmed the association between surgical exposure and decreased mortality (adjusted odds ratio 0.82; CI 0.75-0.91; P &lt; .001). Conclusions Long-term ICU mortality was associated with known risk factors such as age and SAPS3. Transfer to other ICUs also appeared to be a risk factor and requires further investigation. Prior surgical exposure was associated with better outcomes, a noteworthy observation given limited ICU admissions after surgery in Sweden.

This controlled study aimed to measure concentrations of tramadol (TRA) and its two main metabolites, N-desmethyltramadol (NDMT) and O-desmethyltramadol (ODMT), in hair following a single dose ingestion and to investigate the distribution patterns in hair by segmental analysis of hair samples taken at several sampling time points after ingestion. An oral dose (50 or 100 mg) of TRA was administered to 17 healthy volunteers. Hair samples were collected prior to drug administration and 14, 30, 60 and 120 days after ingestion. Each sample was segmented in 5 mm segments and washed. The analytes were extracted from pulverized hair by incubation in extraction media for 18 h at 37 degrees C. A validated UHPLC-MS/MS method was used to quantify the analytes at a LLOQ of 0.001 ng/mg. Hair segments corresponding to the time of ingestion were positive for TRA and the metabolites of each sampling time point, although neighboring segments also showed positive results. The highest concentrations for both dosage groups were observed in the proximal segment of hair collected 14 days after ingestion for all subjects: 0.061-0.95 ng TRA/mg, 0.012-0.86 ng NDMT/mg and 0.009-0.17 ng ODMT/mg (n = 16). Generally, the TRA concentration was higher than the metabolites concentrations but depended on the CYP2D6 phenotype. The metabolite to TRA ratios were stable within a subject over the sampling time points, however it varied greatly between subjects. No significant differences in hair concentrations were found between the two dosage groups at each sampling time. Several confounding factors were identified such as hair pigmentation and internal sweat. We showed that analysis of 5 mm segments improved the determination of the exposure time after a single ingestion of TRA. In addition, in the later sampling time points the analytes were spread more between segments and the total drug amount of each later sampling time point declined up to a 100% (median: 75%) due to wash out. The presented results are important additions to the sparse literature reporting single dose of psychoactive drugs in hair. (C) 2020 Elsevier B.V. All rights reserved.

Variability in the blood-breath ratio (BBR) of alcohol is important, because it relates a measurement of the blood-alcohol concentration (BAC) with the co-existing breath-alcohol concentration (BrAC). The BBR is also used to establish the statutory BrAC limit for driving from the existing statutory BAC limits in different countries. Thein-vivoBBR depends on a host of analytical, sampling and physiological factors, including subject demographics, time after end of drinking (rising or falling BAC), the nature of the blood draw (whether venous or arterial) and the subjects breathing pattern prior to exhalation into the breath analyzer. The results from a controlled drinking study involving healthy volunteers (85 men and 15 women) from three ethnic groups (Caucasians, Hispanics and African Americans) were used to evaluate various factors influencing the BBR. Ethanol in breath was determined with a quantitative infrared analyzer (Intoxilyzer 8000) and BAC was determined by headspace gas chromatography (HS-GC). The BAC and BrAC were highly correlated (r = 0.948) and the BBR in the post-absorptive state was 2 382 +/- 119 (mean +/- SD). The BBR did not depend on gender (female: 2 396 +/- 101 and male: 2 380 +/- 123,P &gt; 0.05) nor on racial group (Caucasians 2 398 +/- 124, African Americans 2 344 +/- 119 and Hispanics 2 364 +/- 104,P &gt; 0.05). The BBR was lower in subjects with higher breath- and body-temperatures (P &lt; 0.05) and it also decreased with longer exhalation times into the breath-analyzer (P &lt; 0.001). In the post-absorptive state, none of the 100 subjects had a BBR of less than 2 100:1.

Mitochondria play crucial roles in cellular metabolism, signaling, longevity, and immune defense. Recent evidences have revealed that the host microbiota, including bacterial pathogens, impact mitochondrial behaviors and activities in the host. The pathogenicity of Pseudomonas aeruginosa requires quorum sensing (QS) cell-cell communication allowing the bacteria to sense population density and collectively control biofilm development, virulence traits, adaptation and interactions with the host. QS molecules, like N-3-oxo-dodecanoyl-L-homoserine lactone (3O-C-12-HSL), can also modulate the behavior of host cells, e.g., epithelial barrier properties and innate immune responses. Here, in two types of cells, fibroblasts and intestinal epithelial cells, we investigated whether and how P. aeruginosa 3O-C-12-HSL impacts the morphology of mitochondrial networks and their energetic characteristics, using high-resolution transmission electron microscopy, fluorescence live-cell imaging, assay for mitochondrial bioenergetics, and quantitative mass spectrometry for mitoproteomics and bioinformatics. We found that 3O-C-12-HSL induced fragmentation of mitochondria, disruption of cristae and inner membrane ultrastructure, altered major characteristics of respiration and energetics, and decreased mitochondrial membrane potential, and that there are distinct cell-type specific details of these effects. Moreover, this was mechanistically accompanied by differential expression of both common and cell-type specific arrays of components in the mitochondrial proteome involved in their structural organization, electron transport chain complexes and response to stress. We suggest that this effect of 3O-C-12-HSL on mitochondria may represent one of the events in the interaction between P. aeruginosa and host mitochondria and may have an impact on the pathogens strategy to hijack host cell activities to support their own survival and spreading.

The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan (TM), GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T-1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T-1 mapping and, to a lesser degree,T-1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by massive inflammation of the arterial endothelium accompanied by vasoconstriction and widespread pulmonary micro thrombi. As a result, due to the destruction of nitric oxide ((NO)-N-center dot) by inflammatory superoxide (O-2(center dot-)), pulmonary (NO)-N-center dot concentration ceases, resulting in uncontrolled platelet aggregation and massive thrombosis, which kills the patients. Introducing (NO)-N-center dot by inhalation (INO) may replace the loss of endothelium-derived (NO)-N-center dot. The first results from clinical trials with INO in SARS-CoV-2 patients show a rapid and sustained improvement in cardiopulmonary function and decreased inflammation. An ongoing phase III study is expected to confirm the methods efficacy. INO may hence become a first line treatment in SARS-CoV-2 patients. However, due to the rapid inactivation of (NO)-N-center dot by deoxyhemoglobin to nitrate, pulmonary administration of (NO)-N-center dot will not protect remote organs. Another INO-related pharmacological approach to protect SARS-CoV-2 patients from developing life-threatening disease is to inhibit the O-2(center dot-)-driven destruction of (NO)-N-center dot by neutralizing inflammatory O-2(center dot-). By making use of low molecular weight compounds that mimic the action of the enzyme manganese superoxide dismutase (MnSOD). The MnSOD mimetics of the so-called porphyrin type (e.g., AEOL 10150), salen type (e.g., EUK-8) and cyclic polyamine type (e.g., M40419, today known as GC4419 and avasopasem manganese) have all been shown to positively affect the inflammatory response in lung epithelial cells in preclinical models of chronic obstructive pulmonary disease. The Manganese diPyridoxyL EthylDiamine (MnPLED)-type mangafodipir (manganese dipyridoxyl diphosphate-MnDPDP), a magnetic resonance imaging (MRI) contrast agent that possesses MnSOD mimetic activity, has shown promising results in various forms of inflammation, in preclinical as well as clinical settings. Intravenously administration of mangafodipir will, in contrast to INO, reach remote organs and may hence become an important supplement to INO. From the authors viewpoint, it appears logical to test mangafodipr in COVID-19 patients at risk of developing life-threatening SARS-CoV-2. Five days after submission of the current manuscript, Galera Pharmaceuticals Inc. announced the dosing of the first patient in a randomized, double-blind pilot phase II clinical trial with GC4419 for COVID-19. The study was first posted on ClinicalTrials.gov (Identifier: NCT04555096) 18 September 2020.

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.

Methoxyacetylfentanyl is one of many fentanyl analogs available as new psychoactive substances. It have been encountered in both the European Union and the United States, and existing literature suggest that methoxyacetylfentanyl is around 3- to 5-fold less potent than fentanyl. The aim of the present work was to combine case information with blood concentrations and abundance of urinary metabolites to investigate the importance of these parameters for toxicological interpretation. Quantification of methoxyacetylfentanyl in femoral blood was performed by LCMS-MS and urinary metabolites were analyzed by LC-QTOF-MS with and without hydrolysis with beta-glucuronidase/arylsulfatase. For confirmation of identified metabolites, methoxyacetylfentanyl was incubated with hepatocytes for up to 5 hours and analyzed with the same method as the urine samples. In eleven postmortem cases (27 to 41 years old and including one female) methoxyacetylfentanyl was reported in femoral blood. The cause of death was intoxication by methoxyacetylfentanyl alone or in combination with other drugs in all but one case, where death was attributed to acute complications of an underlying heart disease but with possible contribution from methoxyacetylfentanyl. In total, 27 urinary metabolites were found, including eight glucuronides. Major biotransformations were O-demethylation, dealkylation to form the nor-metabolite, monoand dihydroxylations of the phenethyl moiety, as well as combinations thereof. The most abundant metabolites in hydrolyzed urine included O-desmethyl-, O-desmethyl-phenethyl-hydroxy-, Odesmethyl-phenethyl-hydroxymethoxy- and nor-methoxyacetylfentanyl. Differences in the abundance of methoxyacetylfentanyl and its major metabolites could be interpreted to indicate fatal intoxications in abstinent or chronic users. We postulate that urinary concentrations of methoxyacetylfentanyl and two metabolites, in combination with the methoxyacetylfentanyl concentration in femoral blood, might be good indicators of the time between administration and death as well as prior use.

Purpose A tert-leucinate derivative synthetic cannabinoid, methyl (2S)-2-([1-(4-fluorobutyl)-1H-indazole-3-carbonyl]amino)-3,3-dimethylbutanoate (4F-MDMB-BINACA, 4F-MDMB-BUTINACA or 4F-ADB) is known to adversely impact health. This study aimed to evaluate the suitability of three different modes of monitoring metabolism: HepG2 liver cells, fungus Cunninghamella elegans (C. elegans) and pooled human liver microsomes (HLM) for comparison with human in-vivo metabolism in identifying suitable urinary marker(s) for 4F-MDMB-BINACA intake. Methods Tentative structure elucidation of in-vitro metabolites was performed on HepG2, C. elegans and HLM using liquid chromatography-tandem mass spectrometry and high-resolution mass spectrometry analysis. In-vivo metabolites obtained from twenty authentic human urine samples were analysed using liquid chromatography-Orbitrap mass spectrometry. Results Incubation with HepG2, C. elegans and HLM yielded nine, twenty-three and seventeen metabolites of 4F-MDMB-BINACA, respectively, formed via ester hydrolysis, hydroxylation, carboxylation, dehydrogenation, oxidative defluorination, carbonylation or reaction combinations. Phase II metabolites of glucosidation and sulfation were also exclusively identified using C. elegans model. Eight in-vivo metabolites tentatively identified were mainly products of ester hydrolysis with or without additional dehydrogenation, N-dealkylation, monohydroxylation and oxidative defluorination with further oxidation to butanoic acid. Metabolites with intact terminal methyl ester moiety, i.e., oxidative defluorination with further oxidation to butanoic acid, were also tentatively identified. Conclusions The in-vitro models presented proved useful in the exhaustive metabolism studies. Despite limitations, HepG2 identified the major 4F-MDMB-BINACA ester hydrolysis metabolite, and C. elegans demonstrated the capacity to produce a wide variety of metabolites. Both C. elegans and HLM produced all the in-vivo metabolites. Ester hydrolysis and ester hydrolysis plus dehydrogenation 4F-MDMB-BINACA metabolites were recommended as urinary markers for 4F-MDMB-BINACA intake.