Is the Pattern Changing? Atrial Fibrillation and Screening with Holter Electrocardiograms among Ischemic Stroke Patients in Greenland from 2016 to 2021.

A standardized examination regime for ischemic stroke (IS) patients was implemented in Greenland in 2010. Prevalence of atrial fibrillation (AF) of 32% was found among discharged IS patients from 2011 to 2012, and our study aims to estimate the use of Holter ECGs for AF diagnostics and the current prevalence of AF among IS patients in Greenland. Patients discharged from Queen Ingrid's Hospital in Nuuk between 2016 and 2021 with an ICD-10 diagnosis of IS or stroke without specification were included. Data on Holter recordings, age, gender, medical treatment with rivaroxaban or warfarin, and ICD-10 and ICPC codes for AF were extracted for each patient. The overall incidence of IS from 2016 to 2021 was 133/100,000 and unchanged since 2012. Sixty-eight of the study's IS patients (14.5%) had AF, and 46% of IS patients with Holter data accessible had a recording according to international recommendations. Our results indicate that fewer IS patients in Greenland have AF than previously. However, the insufficient use of Holter as a diagnostic tool may explain part of the drop, as well as improved preventive treatment with rivaroxaban among AF patients in Greenland. Regardless, IS remains common, and a focus on diagnostics and preventable risk factors should be maintained.

Treatment Provided in Children and Adolescents with Functional Seizures-A Danish Nationwide Cohort.

BACKGROUND: Functional seizures (FS) are episodes of paroxysmal involuntary movements and altered consciousness without the typical changes in the electroencephalography as with epilepsy. A multidisciplinary approach is the golden standard in the treatment of FS. This study examined the cross-sectoral collaboration and treatment modalities provided to children and adolescents after a diagnosis of FS. METHOD: A Danish nationwide cohort, consisting of 334 children and adolescents, aged 5-17 years, with a validated diagnosis of FS during the period 2004-2014 was studied. Medical record data were collected from diagnosing hospital departments. Management and treatment modalities from the time of diagnosis up to three months after diagnosis were explored. RESULTS: The most used treatment modalities were psychoeducation (n = 289, 86.5%) and follow-up in outpatient care (n = 192, 70.6%). A cross-sectoral collaboration was initiated for a third of cases (n = 98, 29.3%). The most commonly provided treatment combination consisted of psychoeducation, follow-up in outpatient care and psychotherapy; however, only a few patients received this specific combination (n = 14, 4.2%). CONCLUSIONS: The treatment applied was individualized and consisted of varying use of treatment modalities. Initiatives to curate clinical guidelines and implement a multidisciplinary treatment approach should be further explored to improve treatment for this young group of patients.

Lithium induced hypercalcemia: an expert opinion and management algorithm.

BACKGROUND: Lithium is the gold standard prophylactic treatment for bipolar disorder. Most clinical practice guidelines recommend regular calcium assessments as part of monitoring lithium treatment, but easy-to-implement specific management strategies in the event of abnormal calcium levels are lacking. METHODS: Based on a narrative review of the effects of lithium on calcium and parathyroid hormone (PTH) homeostasis and its clinical implications, experts developed a step-by-step algorithm to guide the initial management of emergent hypercalcemia during lithium treatment. RESULTS: In the event of albumin-corrected plasma calcium levels above the upper limit, PTH and calcium levels should be measured after two weeks. Measurement of PTH and calcium levels should preferably be repeated after one month in case of normal or high PTH level, and after one week in case of low PTH level, independently of calcium levels. Calcium levels above 2.8 mmol/l may require a more acute approach. If PTH and calcium levels are normalized, repeated measurements are suggested after six months. In case of persistent PTH and calcium abnormalities, referral to an endocrinologist is suggested since further examination may be needed. CONCLUSIONS: Standardized consensus driven management may diminish the potential risk of clinicians avoiding the use of lithium because of uncertainties about managing side-effects and consequently hindering some patients from receiving an optimal treatment.

Sexual health in parous women with a history of polycystic ovary syndrome: A national cross-sectional study in Denmark.

OBJECTIVE: To examine associations between polycystic ovary syndrome (PCOS) and sexual health in midlife. METHODS: We included 31 645 mothers from the Danish National Birth Cohort who participated in a Maternal Follow up in 2013-14. A lifetime PCOS diagnosis was self-reported. Sexual health was assessed by specific sexual problems including reduced sexual desire, insufficient lubrication, difficulty in obtaining orgasm, vaginismus and pain during intercourse within the past year. We also generated a combined outcome which was positive if the women reported one or more sexual problems. Logistic regression was used to estimate adjusted odds ratios (aOR) for sexual problems with 95% confidence intervals (CI). RESULTS: Participants were on average 44 years old, and 920 women (2.9%) had ever had PCOS. One or more sexual problems were more often reported in women with PCOS compared with other women (42.6% versus 36.3%, aOR 1.29, 95% CI 1.13-1.48). Especially reduced sexual desire (25.6% versus 21.0%, aOR 1.29, 95% CI 1.10-1.50) and dyspareunia (11.4% versus 8.7%, aOR 1.34, 95% CI 1.09-1.66) were more frequent in women with PCOS. These associations were slightly weakened when further adjusting for mental and somatic health problems. CONCLUSION: Our data suggest that PCOS is linked to long-term impaired sexual health, especially reduced sexual desire and dyspareunia.

Psychiatric Disorders in Children and Adolescents With Psychogenic Nonepileptic Seizures.

OBJECTIVE: Knowledge regarding psychiatric disorders in children and adolescents with psychogenic nonepileptic seizures (PNES) is limited. This study outlines the spectrum and risk of psychiatric disorders in childhood-onset PNES. METHODS: We performed a nationwide matched cohort study of children and adolescents with PNES 5 to 17 years of age at the time of diagnosis between January 1, 1996, and December 31, 2014. Two matched comparison groups were included: children and adolescents with epilepsy (ES) and children and adolescents without PNES or epilepsy, called healthy controls (HC). Outcomes were prevalent psychiatric disorders before index (i.e., date of diagnosis or corresponding date for HC) and incident psychiatric disorders 2 years after index. Relative risks (RRs) were calculated and adjusted for potential confounders. RESULTS: We included 384 children and adolescents with validated PNES, 1,152 with ES, and 1,920 HC. Among the cases of PNES, 153 (39.8%) had prevalent psychiatric disorders and 150 (39.1%) had incident psychiatric disorders. Compared to the ES and HC groups, children and adolescents with PNES had elevated risks of both prevalent psychiatric disorders (adjusted RRPNES/ES 1.87, 95% confidence interval [CI] 1.59-2.21, adjusted RRPNES/HC 5.54, 95% CI 4.50-6.81) and incident psychiatric disorders (adjusted RRPNES/ES 2.33, 95% CI 1.92-2.83, adjusted RRPNES/HC 8.37, 95% CI 6.31-11.11). A wide spectrum of specific psychiatric disorders displayed elevated RRs. CONCLUSIONS: Children and adolescents with PNES are at higher risk of a wide range of psychiatric disorders compared to children and adolescents with ES and HC. A careful psychiatric evaluation is warranted to optimize and individualize treatment.

Dietary Change Enables Robust Growth-Coupling of Heterologous Methyltransferase Activity in Yeast.

Genetic modifications of living organisms and proteins are made possible by a catalogue of molecular and synthetic biology tools, yet proper screening assays for genetic variants of interest continue to lag behind. Synthetic growth-coupling (GC) of enzyme activities offers a simple, inexpensive way to track such improvements. In this follow-up study we present the optimization of a recently established GC design for screening of heterologous methyltransferases (MTases) and related pathways in the yeast Saccharomyces cerevisiae. Specifically, upon testing different media compositions and genetic backgrounds, improved GC of different heterologous MTase activities is obtained. Furthermore, we demonstrate the strength of the system by screening a library of catechol O-MTase variants converting protocatechuic acid into vanillic acid. We demonstrated high correlation (R2 = 0.775) between vanillic acid and cell density as a proxy for MTase activity. We envision that the improved MTase GC can aid evolution-guided optimization of biobased production processes for methylated compounds with yeast in the future.

OptCouple: Joint simulation of gene knockouts, insertions and medium modifications for prediction of growth-coupled strain designs.

Biological production of chemicals is an attractive alternative to petrochemical-based production, due to advantages in environmental impact and the spectrum of feasible targets. However, engineering microbial strains to overproduce a compound of interest can be a long, costly and painstaking process. If production can be coupled to cell growth it is possible to use adaptive laboratory evolution to increase the production rate. Strategies for coupling production to growth, however, are often not trivial to find. Here we present OptCouple, a constraint-based modeling algorithm to simultaneously identify combinations of gene knockouts, insertions and medium supplements that lead to growth-coupled production of a target compound. We validated the algorithm by showing that it can find novel strategies that are growth-coupled in silico for a compound that has not been coupled to growth previously, as well as reproduce known growth-coupled strain designs for two different target compounds. Furthermore, we used OptCouple to construct an alternative design with potential for higher production. We provide an efficient and easy-to-use implementation of the OptCouple algorithm in the cameo Python package for computational strain design.

Coupling S-adenosylmethionine-dependent methylation to growth: Design and uses.

We present a selection design that couples S-adenosylmethionine-dependent methylation to growth. We demonstrate its use in improving the enzyme activities of not only N-type and O-type methyltransferases by 2-fold but also an acetyltransferase of another enzyme category when linked to a methylation pathway in Escherichia coli using adaptive laboratory evolution. We also demonstrate its application for drug discovery using a catechol O-methyltransferase and its inhibitors entacapone and tolcapone. Implementation of this design in Saccharomyces cerevisiae is also demonstrated.

[Functional neurological symptoms and the positive diagnostic process].

Functional neurological symptoms are common in neurology and general medical practice. Functional neurological symptoms refer to neurological symptoms, which are not explained by a defined disease. The most common are functional weakness and non-epileptic seizures. Psychiatric models have dominated the classification, aetiology and treatment, limiting the neurologist's role to making the diagnosis by excluding disease and pronouncing the symptoms to be psychogenic. In this review, we outline the possibility of a positive diagnostic process, which can be the first step of treatment.

Selecting the Best: Evolutionary Engineering of Chemical Production in Microbes.

Microbial cell factories have proven to be an economical means of production for many bulk, specialty, and fine chemical products. However, we still lack both a holistic understanding of organism physiology and the ability to predictively tune enzyme activities in vivo, thus slowing down rational engineering of industrially relevant strains. An alternative concept to rational engineering is to use evolution as the driving force to select for desired changes, an approach often described as evolutionary engineering. In evolutionary engineering, in vivo selections for a desired phenotype are combined with either generation of spontaneous mutations or some form of targeted or random mutagenesis. Evolutionary engineering has been used to successfully engineer easily selectable phenotypes, such as utilization of a suboptimal nutrient source or tolerance to inhibitory substrates or products. In this review, we focus primarily on a more challenging problem-the use of evolutionary engineering for improving the production of chemicals in microbes directly. We describe recent developments in evolutionary engineering strategies, in general, and discuss, in detail, case studies where production of a chemical has been successfully achieved through evolutionary engineering by coupling production to cellular growth.

Cameo: A Python Library for Computer Aided Metabolic Engineering and Optimization of Cell Factories.

Computational systems biology methods enable rational design of cell factories on a genome-scale and thus accelerate the engineering of cells for the production of valuable chemicals and proteins. Unfortunately, the majority of these methods' implementations are either not published, rely on proprietary software, or do not provide documented interfaces, which has precluded their mainstream adoption in the field. In this work we present cameo, a platform-independent software that enables in silico design of cell factories and targets both experienced modelers as well as users new to the field. It is written in Python and implements state-of-the-art methods for enumerating and prioritizing knockout, knock-in, overexpression, and down-regulation strategies and combinations thereof. Cameo is an open source software project and is freely available under the Apache License 2.0. A dedicated Web site including documentation, examples, and installation instructions can be found at http://cameo.bio . Users can also give cameo a try at http://try.cameo.bio .

Systems biology solutions for biochemical production challenges.

There is an urgent need to significantly accelerate the development of microbial cell factories to produce fuels and chemicals from renewable feedstocks in order to facilitate the transition to a biobased society. Methods commonly used within the field of systems biology including omics characterization, genome-scale metabolic modeling, and adaptive laboratory evolution can be readily deployed in metabolic engineering projects. However, high performance strains usually carry tens of genetic modifications and need to operate in challenging environmental conditions. This additional complexity compared to basic science research requires pushing systems biology strategies to their limits and often spurs innovative developments that benefit fields outside metabolic engineering. Here we survey recent advanced applications of systems biology methods in engineering microbial production strains for biofuels and -chemicals.

Examination for a viral co-factor in postweaning multisystemic wasting syndrome (PMWS).

In order to test the hypothesis that a putative co-factor for the development of postweaning multisystemic wasting syndrome (PMWS) in pigs could be of viral origin, we performed extensive virological examinations on organ material from pigs diagnosed with PMWS originating from within a Danish PMWS-transmission study. Virus isolation attempts were carried out on a large panel of different cell types including primary pig kidney cells and lung macrophages, primary rabbit kidney cells and seven established cell lines (MARC-145, ST117, PK15, BHK21, HeLa, Vero, and MDCK). Although these represent cells with susceptibility to a wide range of known viruses, the results did not provide evidence for a specific virus other than PCV2 contributing to the development of PMWS. Furthermore, in order to test whether specific genotypes of PCV2 may trigger the switch from PCV2 infection to clinical disease, we compared complete DNA genome sequences of PCV2 derived from PMWS-positive as well as PMWS-negative pigs. On the basis of the DNA sequences, the PCV2 isolates were divided into two groups. Group 1 consisting of one isolate originating from a herd unaffected by PMWS, with group 2 consisting of nine isolates originating from four PMWS-affected herds, four PMWS-positive pigs plus one unaffected herd. The PCV2 genomes from the two groups showed 95.5% identity. Alignment analyses of the sequences encoding the replicase and capsid protein from group 1 and group 2 PCV2 isolates showed two amino acid differences encoded in the replicase protein, while 19 amino acid differences were predicted among the capsid protein sequences. The PCV2 DNA sequence analysis supports recent observations from studies in USA as well as Europe, which suggest that strain variations may influence the clinical outcome of PCV2 infection.

Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects.

OBJECTIVE: The objective of the study was a comparison of insulin aspart (IAsp) with human insulin (HI) in basal-bolus therapy with neutral protamine Hagedorn for fetal and perinatal outcomes of type 1 diabetes in pregnancy. STUDY DESIGN: This was a randomized, parallel, open-label, controlled, multicenter, multinational study. Subjects were pregnant (gestational age; <10 weeks) or planning pregnancy at enrollment. Three hundred twenty-two women with type 1 diabetes received IAsp (n = 157) or HI (n = 165). RESULTS: For IAsp and HI, respectively, there were 137 and 131 live births and 14 and 21 fetal losses. Perinatal mortality was 14 and 22 per 1000 births; number of congenital malformations were 6 and 9; mean (SEM) birthweight corrected for gestational age was 3438 g (71.5) and 3555 g (72.9; P = .091). Mean gestational age was 37.6 vs 37.4 weeks. Preterm delivery occurred in 20.3% (IAsp) and 30.6% (HI) of pregnancies (P = .053). CONCLUSION: The fetal outcome using IAsp was comparable with HI with a tendency toward fewer fetal losses and preterm deliveries.