Search

Abstract Background Threatened preterm delivery is a serious obstetrical complication and has for decades been prescribed physical activity restrictions (AR). Adherence to the recommended level of physical AR is however unknown. This study aimed to assess the objectively measured different physical positions and activities of pregnant women recommended AR due to threatened preterm delivery complications, compared to a reference group of uncomplicated pregnant women without restrictions, and to explore if admission status influenced adherence to AR. Methods A Danish descriptive, clinical multi-center study included singleton pregnancies between 22–33 gestational weeks admitted to an antenatal ward or during midwife consultations either prescribed AR due to threatened preterm delivery or uncomplicated controls without restrictions. For seven days participants wore two tri-axial accelerometric SENS® monitors. Accelerometric data included time spent in five different positions, activities, and step counts. At inclusion demographic and obstetric information was collected. Results Seventy-two pregnant women participated; 31% were prescribed strict AR, 15% moderate, 3% light, 8% unspecified, and 43% had no AR. Strict AR participants rested in the supine/lateral position for 17.7 median hours/day (range:9.6–24.0); sat upright 4.9 h/day (0.11–11.7); took 1,520steps/day (20–5,482), and 64% were inpatients. Moderate AR participants rested in the supine/lateral position for 15.1 h/day (11.5–21.6); sat upright 5.6 h/day (2.0–9.3); took 3,310steps/day (467–6,968), and 64% were outpatients. Participants with no AR rested 10.5 h/day (6.3–15.4) in supine/lateral position; sat upright 7.6 h/day (0.1–11.4) and took 9,235steps/day (3,225–20,818). Compared to no restrictions, participants with strict or moderate AR spent significant more time in physical resting positions and took significant fewer mean steps. Among strict AR admission status did not alter time spent in the physical positions, nor the step count. Conclusions Overall, participants adhered highly to the recommended AR. However, discriminating between strict and moderate AR recommendations did not alter how physical resting positions and activities were carried out. The admission status did not influence how participants adhered to strict AR.

Functional amyloids, beneficial to the organism producing them, are found throughout life, from bacteria to humans. While disease‐related amyloids form by uncontrolled aggregation, the fibrillation of functional amyloid is regulated by complex cellular machinery and optimized sequences, including so‐called gatekeeper residues such as Asp. However, the molecular basis for this regulation remains unclear. Here we investigate how the introduction of additional gatekeeper residues affects fibril formation and stability in the functional amyloid CsgA from E. coli. Step‐wise introduction of additional Asp gatekeepers gradually eliminated fibrillation unless preformed fibrils were added, illustrating that gatekeepers mainly affect nucleus formation. Once formed, the mutant CsgA fibrils were just as stable as wild‐type CsgA. HSQC NMR spectra confirmed that CsgA is intrinsically disordered, and that the introduction of gatekeeper residues does not alter this ensemble. NMR‐based Dark‐state Exchange Saturation Transfer (DEST) experiments on the different CsgA variants, however, show a decrease in transient interactions between monomeric states and the fibrils, highlighting a critical role for these interactions in the fibrillation process. We conclude that gatekeeper residues affect fibrillation kinetics without compromising structural integrity, making them useful and selective modulators of fibril properties. [ABSTRACT FROM AUTHOR]

Truncating genetic variants of SORL1, encoding the endosome recycling receptor SORLA, have been accepted as causal of Alzheimer's disease (AD). However, most genetic variants observed in SORL1 are missense variants, for which it is complicated to determine the pathogenicity level because carriers come from pedigrees too small to be informative for penetrance estimations. Here, we describe three unrelated families in which the SORL1 coding missense variant rs772677709, that leads to a p.Y1816C substitution, segregates with Alzheimer's disease. Further, we investigate the effect of SORLA p.Y1816C on receptor maturation, cellular localization, and trafficking in cell-based assays. Under physiological circumstances, SORLA dimerizes within the endosome, allowing retromer-dependent trafficking from the endosome to the cell surface, where the luminal part is shed into the extracellular space (sSORLA). Our results showed that the p.Y1816C mutant impairs SORLA homodimerization in the endosome, leading to decreased trafficking to the cell surface and less sSORLA shedding. These trafficking defects of the mutant receptor can be rescued by the expression of the SORLA 3Fn-minireceptor. Finally, we find that iPSC-derived neurons with the engineered p.Y1816C mutation have enlarged endosomes, a defining cytopathology of AD. Our studies provide genetic as well as functional evidence that the SORL1 p.Y1816C variant is causal for AD. The partial penetrance of the mutation suggests this mutation should be considered in clinical genetic screening of multiplex early-onset AD families. [ABSTRACT FROM AUTHOR]

Abstract SORL1 is strongly associated with both sporadic and familial forms of Alzheimer’s disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl). SORL1-38b transcript levels were significantly reduced in AD cerebellum in three independent cohorts of postmortem brains, whereas no changes were observed for SORL1-fl. A trend of lower 38b transcript level in cerebellum was found for individuals carrying the risk variant at rs2282649 (known as SNP24), although not reaching statistical significance. These findings suggest synaptic functions for SORL1-38b in the brain, uncovering novel aspects of SORL1 that can be further explored in AD research.

A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as i.v. PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade. [ABSTRACT FROM AUTHOR]

Background and objectiveDuring pregnancy, absence from work increases significantly. Job adjustments have been shown to decrease absences; however, studies show only half of pregnant women who need job adjustments receive them. Little is known about the viewpoints of managers and possible challenges in the management of pregnant employees. The aim of this study was to investigate the experiences and considerations of managers in relation to managing pregnant hospital staff members and to describe the experiences of an active management policy for pregnant individuals.MethodsA qualitative study based on five focus group interviews was conducted at five public hospitals in Zealand, Denmark with participation of 19 hospital managers, from 17 different wards, representing six different medical specialties. The interviews took place from February to May 2019. Thematic analysis was used to analyze the data.ResultsFour themes were identified: (1) The everyday management, (2) Managerial dilemmas, (3) Acknowledging the workplace culture, and (4) Dialogue as a means for the working relationship. The managers' experiences revolved around investing a lot of effort into the working relationship with pregnant staff members by adjusting job tasks and work schedules while balancing work tasks between all staff members. The dialogue was considered central in order to identify the needs of the individual staff member.ConclusionsOverall, management dialogue constituted a central tool in order to identify the needs of the individual staff member. A proactive and open approach increased the chances of a fruitful dialogue. The individual staff member, the influence of the workplace culture, and the everyday management of the workplace all shaped the experiences of the managers. The concept of an active management policy for pregnant individuals was perceived to entail useful elements, but also as replicating what managers already did.

Research on the influence of packaging on consumer perception of beer and other alcoholic beverages suggest an important role in capturing consumers’ attention and generating expectations on perceived product quality, and in particular that color, bottle shape, and label design are key aspects. There is, however, a paucity of research looking at interactions between different aspects of packaging design. This is a topical issue given an increasingly saturated market where especially craft breweries strive for differentiation and brand recognition. Situated within this context, the present research used a conjoint analytic approach to investigate the effect of packaging design on consumer perceived quality and liking for beers. Beer images were designed to systematically vary in four design factors—label color, label shape, label complexity, and bottle shape—and evaluated in an online survey with a representative sample of Danish beer drinkers. Two of the design factors—label color and bottle type—significantly affected consumers’ product evaluations, whereas the other two factors did not. Post-hoc analyses of the main effects indicated that the combination of a “Bomber” bottle shape and a warm color scheme in the label as the optimal combination of design factors to maximize consumer preferences. Preference for the Bomber bottle was linked to a perceived premiumness associated with a preference for curvatures (as opposed to angularity), whereas the preference for warm colors was tentatively explained as due to crossmodal correspondences generating favorable sensory expectations for this color scheme.

Urosepsis is a potentially life-threatening, systemic reaction to uropathogenic bacteria entering the bloodstream of the host. One of the hallmarks of sepsis is early thrombocyte activation with a following fall in circulating thrombocytes as a result of intravascular aggregation and sequestering of thrombocytes in the major organs. Development of a thrombocytopenic state is associated with a poorer outcome of sepsis. Uropathogenic Escherichia coli frequently produce the pore-forming, virulence factor α-haemolysin (HlyA), of which the biological effects are mediated by ATP release and subsequent activation of P2 receptors. Thus, we speculated that inhibition of thrombocyte P2Y1 and P2Y12 receptors might ameliorate the septic response to HlyA-producing E. coli. The study combined in vitro measurements of toxin-induced thrombocyte activation assessed as increased membrane abundance of P-selectin, fibronectin and CD63 and data from in vivo murine model of sepsis-induced by HlyA-producing E. coli under infusion of P2Y1 and P2Y12 antagonists. Our data show that the P2Y1 receptor antagonist almost abolishes thrombocyte activation by pore-forming bacterial toxins. Inhibition of P2Y1, by constant infusion of MRS2500, markedly increased the survival in mice with induced sepsis. Moreover, MRS2500 partially prevented the sepsis-induced depletion of circulating thrombocytes and dampened the sepsis-associated increase in proinflammatory cytokines. In contrast, P2Y12 receptor inhibition had only a marginal effect in vivo and in vitro. Taken together, inhibition of the P2Y1 receptor gives a subtle dampening of the thrombocyte activation and the cytokine response to bacteraemia, which may explain the improved survival observed by P2Y1 receptor antagonists.

Background: Focal congenital hyperinsulinism (CHI) may be cured by resection of the focal, but often non-palpable, pancreatic lesion. The surgical challenge is to minimize removal of normal pancreatic tissue.Aim: To evaluate the results of intraoperative ultrasound-guided, tissue-sparing pancreatic resection in CHI patients at an international expert center.Methods: Retrospective study of CHI patients treated at Odense University Hospital, Denmark, between January 2010 and March 2017.Results: Of 62 consecutive patients with persistent CHI, 24 (39%) had focal CHI by histology after surgery. All patients had a paternal ABCC8 or KCNJ11 mutation and a focal lesion by 18F-DOPA-PET/CT. Intraoperative ultrasound localized the focal lesion in 16/20 patients (sensitivity 0.80), including one ectopic lesion in the duodenal wall. Intraoperative ultrasound showed no focal lesion in 11/11 patients with diffuse CH (specificity 1.0). The positive predictive value for focal histology was 1.0, negative predictive value 0.73.Tissue-sparing pancreatic resection (focal lesion enucleation, local resection of tail or uncinate process) was performed in 67% (n = 16). In 11/12 having tissue-sparing resection and intraoperative ultrasound, the location of the focal lesion was exactly identified. Eight patients had resection of the pancreatic head or head/body, four with Roux-en-Y, three with pancreatico-gastrostomy and one without reconstruction. None had severe complications to surgery. Cure of hypoglycaemia was seen in all patients after one (n = 21) or two (n = 3) pancreatic resections.Conclusion: In focal CHI, tissue-sparing pancreatic resection was possible in 67%. Intraoperative ultrasound was a helpful supplement to the mandatory use of genetics, preoperative 18F-DOPA-PET/CT and intraoperative frozen sections.

Low back pain is highly prevalent among pregnant women, but evidence of an effective treatment are still lacking. Supervised exercise-either land or water based-has shown benefits for low back pain, but no trial has investigated the evidence of an unsupervised water exercise program on low back pain. We aimed to assess the effect of an unsupervised water exercise program on low back pain intensity and days spent on sick leave among healthy pregnant women.In this randomised, controlled, parallel-group trial, 516 healthy pregnant women were randomly assigned to either unsupervised water exercise twice a week for a period of 12 weeks or standard prenatal care. Healthy pregnant women aged 18 years or older, with a single fetus and between 16-17 gestational weeks were eligible. The primary outcome was low back pain intensity measured by the Low Back Pain Rating scale at 32 weeks. The secondary outcomes were self-reported days spent on sick leave, disability due to low back pain (Roland Morris Disability Questionnaire) and self-rated general health (EQ-5D and EQ-VAS).Low back pain intensity was significantly lower in the water exercise group, with a score of 2.01 (95% CI 1.75-2.26) vs. 2.38 in the control group (95% CI 2.12-2.64) (mean difference = 0.38, 95% CI 0.02-0.74 p = 0.04). No difference was found in the number of days spent on sick leave (median 4 vs. 4, p = 0.83), disability due to low back pain nor self-rated general health. There was a trend towards more women in the water exercise group reporting no low back pain at 32 weeks (21% vs. 14%, p = 0.07).Unsupervised water exercise results in a statistically significant lower intensity of low back pain in healthy pregnant women, but the result was most likely not clinically significant. It did not affect the number of days on sick leave, disability due to low back pain nor self-rated health.ClinicalTrials.gov NCT02354430.

The human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug‐related material in humans through the use of 14C‐labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re‐think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company. The paper also provides a framework for continuing the discussion in the application of further shifts in the paradigm. [ABSTRACT FROM AUTHOR]