Midwives' experiences of facilitating normal birth in midwifery-led units in Norway: A qualitative study.

INTRODUCTION: Normal birth has significant benefits for mothers and infants. However, the advancement of technology has led to increased medicalization of childbirth. Midwives play a pivotal role in promoting normal birth, and positive outcomes are seen in births led by a midwife. The purpose of the study is to gain a deeper understanding of midwives' experiences of facilitating normal birth in midwifery-led units. METHODS: The study has a qualitative design. It was conducted in 2022 and included semi- structured interviews with seven midwives throughout Norway. They were all currently working, or had previously worked, in a midwifery-led unit. The data material was analyzed using systematic text condensation. RESULTS: The data analysis resulted in three result categories. The first category concerned the importance of relationships, continuity and a safe atmosphere. The second concerned being a midwife in the hand, in the heart, and in the mind. The third related to having confidence in the physiological process of childbirth, midwifery autonomy, and a common ideology. CONCLUSIONS: The study highlights several elements that may help to promote normal birth in midwifery units. Relationships, midwifery skills, confidence in normal birth and a supportive collegial environment that fosters midwife autonomy, are prominent factors. These elements were viewed by the midwives as key to their ability to promote normal birth in a midwifery-led unit.

A Longitudinal Study of Disability, Cognition and Gray Matter Atrophy in Early Multiple Sclerosis Patients According to Evidence of Disease Activity.

New treatment options may make "no evidence of disease activity" (NEDA: no relapses or disability progression and no new/enlarging MRI lesions, as opposed to "evidence of disease activity" (EDA) with at least one of the former), an achievable goal in relapsing-remitting multiple sclerosis (RRMS). The objective of the present study was to determine whether early RRMS patients with EDA at one-year follow-up had different disability, cognition, treatment and gray matter (GM) atrophy rates from NEDA patients and healthy controls (HC). RRMS patients (mean age 34 years, mean disease duration 2.2 years) were examined at baseline and one-year follow-up with neurological (n = 72), neuropsychological (n = 56) and structural MRI (n = 57) examinations. Matched HC (n = 61) were retested after three years. EDA was found in 46% of RRMS patients at follow-up. EDA patients used more first line and less second line disease modifying treatment than NEDA (p = 0.004). While the patients groups had similar disability levels at baseline, they differed in disability at follow-up (p = 0.010); EDA patients progressed (EDSS: 1.8-2.2, p = 0.010), while NEDA patients improved (EDSS: 2.0-1.7, p<0.001). Cognitive function was stable in both patient groups. Subcortical GM atrophy rates were higher in EDA patients than HC (p<0.001). These results support the relevance of NEDA as outcome in RRMS and indicate that pathological neurodegeneration in RRMS mainly occur in patients with evidence of disease activity.

Multiple Sclerosis Risk Allele in CLEC16A Acts as an Expression Quantitative Trait Locus for CLEC16A and SOCS1 in CD4+ T Cells.

For multiple sclerosis, genome wide association studies and follow up studies have identified susceptibility single nucleotide polymorphisms located in or near CLEC16A at chromosome 16p13.13, encompassing among others CIITA, DEXI and SOCS1 in addition to CLEC16A. These genetic variants are located in intronic or intergenic regions and display strong linkage disequilibrium with each other, complicating the understanding of their functional contribution and the identification of the direct causal variant(s). Previous studies have shown that multiple sclerosis-associated risk variants in CLEC16A act as expression quantitative trait loci for CLEC16A itself in human pancreatic ß-cells, for DEXI and SOCS1 in thymic tissue samples, and for DEXI in monocytes and lymphoblastoid cell lines. Since T cells are major players in multiple sclerosis pathogenesis, we have performed expression analyses of the CIITA-DEXI-CLEC16A-SOCS1 gene cluster in CD4+ and CD8+ T cells isolated from multiple sclerosis patients and healthy controls. We observed a higher expression of SOCS1 and CLEC16A in CD4+ T cells in samples homozygous for the risk allele of CLEC16A rs12927355. Pair-wise linear regression analysis revealed high correlation in gene expression in peripheral T cells of CIITA, DEXI, CLEC16A and SOCS1. Our data imply a possible regulatory role for the multiple sclerosis-associated rs12927355 in CLEC16A.

Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis.

OBJECTIVE: Determine whether MS-specific DNA methylation profiles can be identified in whole blood or purified immune cells from untreated MS patients. METHODS: Whole blood, CD4+ and CD8+ T cell DNA from 16 female, treatment naïve MS patients and 14 matched controls was profiled using the HumanMethylation450K BeadChip. Genotype data were used to assess genetic homogeneity of our sample and to exclude potential SNP-induced DNA methylation measurement errors. RESULTS: As expected, significant differences between CD4+ T cells, CD8+ T cells and whole blood DNA methylation profiles were observed, regardless of disease status. Strong evidence for hypermethylation of CD8+ T cell, but not CD4+ T cell or whole blood DNA in MS patients compared to controls was observed. Genome-wide significant individual CpG-site DNA methylation differences were not identified. Furthermore, significant differences in gene DNA methylation of 148 established MS-associated risk genes were not observed. CONCLUSION: While genome-wide significant DNA methylation differences were not detected for individual CpG-sites, strong evidence for DNA hypermethylation of CD8+ T cells for MS patients was observed, indicating a role for DNA methylation in MS. Further, our results suggest that large DNA methylation differences for CpG-sites tested here do not contribute to MS susceptibility. In particular, large DNA methylation differences for CpG-sites within 148 established MS candidate genes tested in our study cannot explain missing heritability. Larger studies of homogenous MS patients and matched controls are warranted to further elucidate the impact of CD8+ T cell and more subtle DNA methylation changes in MS development and pathogenesis.

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general.

Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.

Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis.

BACKGROUND: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. OBJECTIVE: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. METHODS: Norwegian MS patients (n = 639) and healthy controls (n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients (n = 1997) and controls (n = 708). RESULTS: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts (P << 10(-22)). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. CONCLUSION: The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Establishing a brain-death donor model in pigs.

INTRODUCTION: An animal model that imitates human conditions might be useful not only to monitor pathomechanisms of brain death and biochemical cascades but also to investigate novel strategies to ameliorate organ quality and functionality after multiorgan donation. METHODS: Brain death was induced in 15 pigs by inserting a catheter into the intracranial space after trephination of the skull and augmenting intracranial pressure until brain stem herniation. Intracranial pressure was monitored continuously; after 60 minutes, brain death diagnostics were performed by a neurologist including electroencephalogram (EEG) and clinical examinations. Clinical examinations included testing of brain stem reflexes as well as apnoe testing; then intensive donor care was performed according to standard guidelines until 24 hours after confirmation of brain death. Intensive donor care was performed according to standard guidelines for 24 hours after brain death. RESULTS: Sixty minutes after brain-death induction, neurological examination and EEG examination confirmed brain death. Intracranial pressure increased continuously, remaining stable after the occurrence of brain death. All 15 animals showed typical signs of brain death such as diabetes insipidus, hypertensive and hypotensive periods, as well as tachycardia. All symptoms were treated with standard medications. After 24 hours of brain death we performed successful multiorgan retrieval. DISCUSSION: Brain death can be induced in a pig model by inserting a catheter after trephination of the skull. According to standard guidelines the brain-death diagnosis was established by a flat-line EEG, which occurred in all animals at 60 minutes after induction.

Establishing a donation after cardiac death model in pigs.

INTRODUCTION: Due to the lack of human donors, several strategies have sought to expand the organ pool. Efforts to characterize donation after cardiac death (DCD) have included studies of cell viability, histological and immunohistochemical changes, and oxidative stress, which is known to negatively impact graft survival. A large animal model would be useful for these inquiries. Therefore, we sought to establish a DCD animal model in pigs. METHODS: We simulated non-heart-beating donation Maastricht II and III conditions in 24 pigs. Cardiac fibrillation was induced using 9-V direct current. After various times of ventricular fibrillation (1-10 minutes) with no mechanical and/or medical treatment to achieve cardiac output, reanimation was performed for 30 minutes prior to multiorgan donation. Then, a neurological status was performed. Blood samples were obtained at defined times tissue samples were stored in liquid nitrogen and subsequently embedded in paraffin and subjected to further analysis. RESULTS: We established a DCD pig model in our laboratory by inducing cardiac fibrillation. Up to now, only DCD donation according to the Maastricht criteria II and III has been performed, but establishing all Maastricht criteria of DCDs seems to be feasible. CONCLUSION: A DCD model in pigs enables us to characterize organ quality more precisely as well as evaluate amelioration of storage conditions and donor treatments in a large-animal model.

Maternal consumption of coffee and caffeine-containing beverages and oral clefts: a population-based case-control study in Norway.

A large, population-based case-control study of facial clefts was carried out in Norway between 1996 and 2001. The study included 573 cases -- 377 with cleft lip with or without cleft palate and 196 with cleft palate only -- and 763 randomly selected controls. Maternal consumption of coffee and other caffeine-containing beverages in early pregnancy was recorded shortly after birth. Compared with that for no coffee consumption, the adjusted odds ratios for cleft lip with or without cleft palate were 1.39 (95% confidence interval: 1.01, 1.92) for less than 3 cups a day and 1.59 (95% confidence interval: 1.05, 2.39) for 3 cups or more. Coffee consumption was not associated with risk of cleft palate only (for > or = 3 cups vs. none, adjusted odds ratio = 0.96, 95% confidence interval: 0.55, 1.67). Tea consumption was associated with a reduced odds ratio of both cleft lip with or without cleft palate and cleft palate only. There was little evidence of an association between caffeine exposure and clefts when all sources of caffeine were considered. Adjustment for known confounding factors in general had minor effects on risk estimates. Still, the authors could not rule out the possibility of uncontrolled confounding by factors associated with the habit of drinking coffee.

Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.

An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case-parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one-carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi-Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway-wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P-values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role.

Maternal dietary intake of vitamin A and risk of orofacial clefts: a population-based case-control study in Norway.

A population-based case-control study was carried out in Norway between 1996 and 2001. The aim was to evaluate the association between maternal intake of vitamin A from diet and supplements and risk of having a baby with an orofacial cleft. Data on maternal dietary intake were available from 535 cases (188 with cleft palate only and 347 with cleft lip with or without cleft palate) and 693 controls. The adjusted odds ratio for isolated cleft palate only was 0.47 (95% confidence interval: 0.24, 0.94) when comparing the fourth and first quartiles of maternal intake of total vitamin A. In contrast, there was no appreciable association of total vitamin A with isolated cleft lip with or without cleft palate. An intake of vitamin A above the 95th percentile was associated with a lower estimated risk of all isolated clefts compared with the 40th-60th percentile (adjusted odds ratio = 0.48, 95% confidence interval: 0.20, 1.14). Maternal intake of vitamin A is associated with reduced risk of cleft palate only, and there is no evidence of increased risk of clefts among women in our study with the highest 5% of vitamin A intake.

Continuous non-invasive blood pressure monitoring using concentrically interlocking control loops.

A new method and apparatus for non-disruptive blood pressure (BP) recording in the finger based on the vascular unloading technique is introduced. The instrument, in contrast to intermittent set point readjustments of the conventional vascular unloading technique, delivers BP without interruptions, thus refining the Penáz' principle. The method is based on concentrically interlocking control loops for correct long-term tracing of finger BP, including automatic set point adaptation, light control and separate inlet and outlet valves for electro-pneumatic control. Examples of long-term BP recordings at rest and during autonomic function tests illustrate the potential of the new instrument.

[Anesthesia monitoring: degree of compliance with guidelines in Austria]. / Narkosemonitoring: Erfüllungsgrad der Empfehlungen in Osterreich.

PURPOSE: For the first time an evaluation of standard anesthetic monitoring was performed according to the guidelines of the Austrian Society for Anesthesiology, Resuscitation und Intensive Care Medicine (OGARI). METHODS: A questionnaire was delivered to all medical institutions performing anesthesia in Austria. A descriptive statistical evaluation was performed on all returned and completed questionnaires. RESULTS: Generally, there is a high standard in compulsory monitoring and in PACU (actual compliance > 99%/85.8%). Supplemental equipment is required for disconnection alarm and measurement of inspired oxygen concentration (actual compliance: 98.3%/98.9%). Furthermore, measurement for inspired concentration of volatile anesthetics and relaxometry (actual compliance 68.7%/47.3%) has yet to be completed. University departments and regional hospitals have comparable standards (82.2% vs. 79.6%). CONCLUSIONS: For the first time an Austrian-wide evaluation of anesthetic monitoring investigated the compliance with the 1992 recommendations of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine. The data demonstrate that these recommendations including the anesthetic monitoring equipment have already been implemented to a high degree.