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Abstract Background Midwives encounter various difficulties while aiming to achieve excellence in providing maternity care to women with mobility disabilities. The study aimed to explore and describe midwives’ experiences of caring for women with mobility disabilities during pregnancy, labour and puerperium in Eswatini. Methods A qualitative, exploratory, descriptive, contextual research design with a phenomenological approach was followed. Twelve midwives working in maternal health facilities in the Hhohho and Manzini regions in Eswatini were interviewed. Purposive sampling was used to select midwives to participate in the research. In-depth phenomenological interviews were conducted, and Giorgi’s descriptive phenomenological method was used for data analysis. Results Three themes emerged from the data analysis: midwives experienced physical and emotional strain in providing maternity care to women with mobility disabilities, they experienced frustration due to the lack of equipment to meet the needs of women with mobility disabilities, and they faced challenges in providing support and holistic care to women with mobility disabilities during pregnancy, labour and puerperium. Conclusions Midwives experienced challenges caring for women with mobility disabilities during pregnancy, labour and the puerperium in Eswatini. There is a need to develop and empower midwives with the knowledge and skill to implement guidelines and enact protocols. Moreover, equipment and infrastructure are required to facilitate support and holistic maternity care for women with mobility disabilities.

Thermal transients of small or thermally well-conducting components typically relax with a very short time constant. In some cases, the fastest changes occur on a time scale of a few tens to hundreds of microseconds. Providing a sampling rate higher than 1 kHz is challenging, even for modern infrared cameras. This work presents a periodic non-uniform sampling technique for measuring thermographic transients, which increases the effective sampling rate by one order of magnitude to 10 kHz, resulting in a temporal resolution of 100 μs. The practical application of this technique captures parts of the thermal transient that would otherwise be missed for standard sampling rates. The results confirm the algorithm’s ability to enhance the effective sampling rate, providing a more detailed thermal analysis of rapid transient processes in small-scale electronic components.

Introduction: IgG4-related disease is an immune-mediated condition characterized by tissue infiltration of IgG4-positive plasma cells. Involvement of the spinal meninges results in hypertrophic spinal pachymeningitis (HSP), causing spinal cord and nerve root compression. Research question and case description: In this review, we present a case of IgG4-related hypertrophic spinal pachymeningitis. Furthermore, we provide an updated literature review on IgG4-related HSP. Materials and methods: We describe the case of a 45-year-old male presenting with cervical myelopathy. MR-imaging showed a ventrodorsal thickening of the meninges resulting in spinal cord compression. The patient underwent surgical decompression through laminectomy and excision of the dural thickening. The pathological findings demonstrated hypertrophic pachymeningitis with further examination showing large-scale dural infiltration of IgG4-positive lymphocytes. Adjuvant therapy with methylprednisolone and rituximab resulted in full neurological recovery with no signs of recurrence on MRI or clinically 12 months postoperatively.An updated review of the literature regarding IgG4-related HSP was performed according to PRISMA-guidelines. Relevant articles were searched from the PubMed, Web of Science and Embase databases. Patient characteristics, MRI- and histopathological findings, treatment modality and outcome were reviewed. Results: The literature review provided a summary of 52 available cases, which included the one cases from our centre. Progressive worsening of neurological impairment was observed in 28 patients (58%). The lesions involved the thoracic spine (n = 33, 62.2%), cervical spine (n = 35, 70%), lumbar spine (n = 10, 20%), and sacral spine (n = 1, 2.2%). The dural thickening typically appeared as striated, fusiform, or oval changes, with homogeneous and patterns being the most common. Surgical decompression followed by immunosuppressive treatment was the main choice of therapy. The disease proved fatal in one case. Discussion and conclusion: IgG4-related HSP usually affects the cervical and thoracic dura and therefore often presents with myelopathy. Surgical decompression in cases of neurological deficits may prevent permanent neurological impairment. Immunosuppressive therapy constitutes the cornerstone in the treatment IgG4-related HSP.

Abstract Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein–kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first‐in‐class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first‐in‐human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose‐related PD effects were observed (e.g., a mechanism‐based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically‐based pharmacokinetic (mPBPK) models with target‐mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa‐mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Abstract Background Pelvic brooding is a form of uni-parental care, and likely evolved in parallel in two lineages of Sulawesi ricefishes. Contrary to all other ricefishes, females of pelvic brooding species do not deposit eggs at a substrate (transfer brooding), but carry them until the fry hatches. We assume that modifications reducing the costs of egg carrying are beneficial for pelvic brooding females, but likely disadvantageous in conspecific males, which might be resolved by the evolution of sexual dimorphism via sexual antagonistic selection. Thus we hypothesize that the evolution of pelvic brooding gave rise to female-specific skeletal adaptations that are shared by both pelvic brooding lineages, but are absent in conspecific males and transfer brooding species. To tackle this, we combine 3D-imaging and morphometrics to analyze skeletal adaptations to pelvic brooding. Results The morphology of skeletal traits correlated with sex and brooding strategy across seven ricefish species. Pelvic brooding females have short ribs caudal of the pelvic girdle forming a ventral concavity and clearly elongated and thickened pelvic fins compared to both sexes of transfer brooding species. The ventral concavity limits the body cavity volume in female pelvic brooders. Thus body volumes are smaller compared to males in pelvic brooding species, a pattern sharply contrasted by transfer brooding species. Conclusions We showed in a comparative framework that highly similar, sexually dimorphic traits evolved in parallel in both lineages of pelvic brooding ricefish species. Key traits, present in all pelvic brooding females, were absent or much less pronounced in conspecific males and both sexes of transfer brooding species, indicating that they are non-beneficial or even maladaptive for ricefishes not providing extended care. We assume that the combination of ventral concavity and robust, elongated fins reduces drag of brooding females and provides protection and stability to the egg cluster. Thus ricefishes are one of the rare examples where environmental factors rather than sexual selection shaped the evolution of sexually dimorphic skeletal adaptations.

Abstract Background It remains unclear if ad libitum water drinking, as a hydration strategy, prevents exercise-associated hyponatremia (EAH) during prolonged exercise. The aim of this study was to determine the incidence of EAH within the broader context of fluid regulation among soldiers performing a 40-km route-march ingesting water ad libitum. Methods Twenty-eight healthy male soldiers participated in this observational trial. Pre- and post-exercise body mass, blood and urine samples were collected. Blood samples were assessed for serum sodium ([Na+]), glucose, creatinine, urea nitrogen (BUN), plasma osmolality, creatine kinase (CK), and plasma arginine vasopressin (AVP) concentrations. Plasma volume (PV) was calculated using hematocrit and hemoglobin. Urine samples were analyzed for osmolality and [Na+]. Water intake was assessed by weighing bottles before, during and after the march. The mean relative humidity was 55.7% (21.9–94.3%) and the mean dry bulb temperature was 27.1 °C (19.5 °C - 37.0 °C) during the exercise. Results Twenty-five soldiers (72 ± 10 kg) (Mean ± SD) completed the march in 09:11 ± 00:43 (hr:min). Participants consumed 736 ± 259 ml/h of water and lost 2.8 ± 0.9 kg (4.0% ± 1.4%, P 1000 mOsmol/kg H2O) and plasma AVP. No single hydration strategy likely prevents EAH, but hypernatremia (cellular dehydration) was not seen despite > 2% body mass losses and high urine osmolality.

Active thermography is an established technique for non-destructive testing and defect localisation. For external excitation, powerful light sources are commonly used. In addition to a high optical output, a good signal shape and response characteristic as well as control ports, which allow for multiple operation modes, are important for active thermography applications. In this work, the schematics for an excitation source based on infrared LEDs is presented. It features multiple control modes for easy integration into existing measurement setups as well as sophisticated control electronics to realize a wide range of excitation patterns. The phase and amplitude stability of this prototype is investigated and compared to the performance of a modulated halogen lamp as well as a halogen lamp and mechanical chopper combination.

The luminous intensity distribution from luminescent glass disks is investigated. For this, the disks are placed on top of an ultraviolet and a blue LED and the emission from the optically-activated glass is recorded in the far field. The luminous intensity distribution of the LED light and the Eu3+luminescence is considered separately by filtering the LED excitation, the same applies to the measured total luminous flux. Angle-dependent spectra are also measured and the changes in color coordinates are examined versus the viewing angle. The experimental results of the luminous intensity distribution curves are compared with ray-tracing simulations. Keywords: Borate glass, Lanthanide doping, Luminous intensity distribution

Network identification by deconvolution is a proven method for determining the thermal structure function of a given device. The method allows to derive the thermal capacitances as well as the resistances of a one-dimensional thermal path from the thermal step response of the device. However, the results of this method are significantly affected by noise in the measured data, which is unavoidable to a certain extent. In this paper, a post-processing procedure for network identification from thermal transient measurements is presented. This so-called optimization-based network identification provides a much more accurate and robust result compared to approaches using Fourier or Bayesian deconvolution in combination with Foster-to-Cauer transformation. The thermal structure function obtained from network identification by deconvolution is improved by repeatedly solving the inverse problem in a multi-dimensional optimization process. The result is a non-diverging thermal structure function, which agrees well with the measured thermal impedance. In addition, the associated time constant spectrum can be calculated very accurately. This work shows the potential of inverse optimization approaches for network identification.

The determination of thermal structure functions from transient thermal measurements using network identification by deconvolution is a delicate process as it is sensitive to noise in the measured data. Great care must be taken not only during the measurement process but also to ensure a stable implementation of the algorithm. In this paper, a method is presented that quantifies the absolute accuracy of network identification on the basis of different test structures. For this purpose, three measures of accuracy are defined. By these metrics, several variants of network identification are optimized and compared against each other. Performance in the presence of noise is analyzed by adding Gaussian noise to the input data. In the cases tested, the use of a Bayesian deconvolution provided the best results.

Abstract Background Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. Methods Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. Results We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. Conclusions Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.

Freshwater sculpins represent a diverse but poorly-understood constituent of the Holarctic ichthyofauna. Sculpins are considered sensitive to pollution and habitat change, serving as aquatic bioindicators in ecotoxicology. Many species are protected by conservation agencies, due to anthropogenic activity within restricted geographic distributions. Here, we provide the first complete mitochondrial DNA sequences for three freshwater sculpins (Cottus asper, C. perifretum, C. rhenanus). These data are used to infer an updated mtDNA phylogeny for the genus Cottus, which supports results of previous research. These data are likely to be useful for future studies in biogeography, conservation, and functional genomics.

Factor XII initiates the intrinsic blood coagulation cascade and the kinin system. Here the authors show that Factor XII is elevated in the blood of multiple sclerosis patients, activates dendritic cells via CD87 and cAMP, and its blockade inhibits immunopathology in a mouse model of the disease.

Coated platelets, formed by collagen and thrombin activation, have been characterized in different ways: i) by the formation of a protein coat of α-granular proteins; ii) by exposure of procoagulant phosphatidylserine; or iii) by high fibrinogen binding. Yet, their functional role has remained unclear. Here we used a novel transglutaminase probe, Rhod-A14, to identify a subpopulation of platelets with a cross-linked protein coat, and compared this with other platelet subpopulations using a panel of functional assays. Platelet stimulation with convulxin/thrombin resulted in initial integrin αIIbβ3 activation, the appearance of a platelet population with high fibrinogen binding, (independently of active integrins, but dependent on the presence of thrombin) followed by phosphatidylserine exposure and binding of coagulation factors Va and Xa. A subpopulation of phosphatidylserine-exposing platelets bound Rhod-A14 both in suspension and in thrombi generated on a collagen surface. In suspension, high fibrinogen and Rhod-A14 binding were antagonized by combined inhibition of transglutaminase activity and integrin αIIbβ3. Markedly, in thrombi from mice deficient in transglutaminase factor XIII, platelet-driven fibrin formation and Rhod-A14 binding were abolished by blockage of integrin αIIbβ3. Vice versa, star-like fibrin formation from platelets of a patient with deficiency in αIIbβ3 (Glanzmann thrombasthenia) was abolished upon blockage of transglutaminase activity. We conclude that coated platelets, with initial αIIbβ3 activation and high fibrinogen binding, form a subpopulation of phosphatidylserine-exposing platelets, and function in platelet-dependent star-like fibrin fiber formation via transglutaminase factor XIII and integrin αIIbβ3.

BACKGROUND AND PURPOSE:Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. METHODS:For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. RESULTS:Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. CONCLUSIONS:With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.

Minipigs are frequently used in (neuro-)interventional research. Longitudinal experiments may require repeated vessel access via the femoral artery. Anticoagulation and incompliance of the animals necessitates the use of a vascular closure device (VCD). The effects of the Angio-Seal VCD in minipigs were longitudinally assessed. Minipig (42±8.4 kg body weight) femoral arteries were sealed using the 8F (n = 6) or 6F (n = 7) Angio-Seal VCD. The pre-interventional femoral artery diameter was 5.1±0.4 mm (4.3-5.8 mm). Sealed puncture sites were analysed angiographically as well as by computed tomography angiography (CTA) for a mean period of 14.1±8.0 weeks (1-22 weeks). All animals were constantly treated with acetylsalicylic acid (ASS) (450 mg/d (n = 7) or 100 mg/d (n = 1)) and clopidogrel (75 mg/d (n = 8)). Non-instrumented (n = 2) and arteries sealed using the VCD (n = 2) were examined histologically. No postoperative hemorrhagic complications were observed. Three arteries were occluded after VCD placement (1 animal diagnosed after 4 weeks (8F), 2 animals after 1 week (6F)) and remained so until the end of the experiments after 22, 12 and 4 weeks, respectively. In one artery a 50% stenosis 8 weeks after application of a 6F Angio-Seal was detected. In 69.2% (n = 9) the VCD was applied without complications. Histopathological analysis of the sealed arterial segments showed subtotal obliteration of the vessel lumen, formation of collagenous tissue and partial damage of the internal elastic lamina. The Angio-Seal VCD prevents relevant hemorrhagic complications in minipigs treated with dual platelet inhibition, but is associated with increased vessel occlusion rates.

In relation to the recent trials of Intravenous Immunoglobulin (IVIG) in Alzheimer's Disease (AD) it was demonstrated that different IgG preparations contain varying amounts of natural anti-amyloid β (Aβ) antibodies as measured by ELISA. We therefore investigated the relevance of ELISA data for measuring low-affinity antibodies, such as anti-Aβ. We analysed the binding of different commercial Immunoglobulin G (IgG) preparations to Aβ, actin and tetanus toxoid in different binding assays to further investigate the possible cause for observed differences in binding to Aβ and actin between different IgG preparations. We show that the differences of commercial IgG preparations in binding to Aβ and actin in ELISA assays are artefactual and only evident in in vitro binding assays. In functional assays and in vivo animal studies the different IVIG preparations exhibited very similar potency. ELISA data alone are not appropriate to analyse and rank the binding capacity of low-affinity antibodies to Aβ or other endogenous self-antigens contained in IgG preparations. Additional analytical methods should be adopted to complement ELISA data.

Neural transplantation has been investigated experimentally and clinically for the purpose of developing new treatment options for intractable epilepsy. In the present study we assessed the anticonvulsant efficacy and safety of bilateral allotransplantation of genetically engineered striatal GABAergic rat cell lines into the substantia nigra pars reticulata (SNr). Rats with previously-established seizures, induced by amygdala kindling, were used as a model of temporal lobe epilepsy. Three cell lines were transplanted: (1) immortalized GABAergic cells (M213-2O) derived from embryonic rat striatum; (2) M213-2O cells (CL4) transfected with human GAD67 cDNA to obtain higher GABA synthesis than the parent cell line; and (3) control cells (121-1I), also derived from embryonic rat striatum, but which did not show GAD expression. A second control group received injections of medium alone. Transplantation of M213-2O cells into the SNr of kindled rats resulted in significant but transient anticonvulsant effects. Neither control cells nor medium induced anticonvulsant effects. Strong tissue reactions were, however, induced in the host brain of kindled but not of non-kindled rats, and only in animals that received grafts of genetically modified CL4 cells. These tissue reactions included graft rejection, massive infiltration of inflammatory immune cells, and gliosis. The anticonvulsant effect of M213-2O cells emphasizes the feasibility of local manipulations of seizures by intranigral transplantation of GABA-producing cells. On the other hand, the present data suggest that kindling-induced activation of microglia in the SNr can enhance immune reactions to transplanted cells. In this case, under conditions of further immunological stimulation by CL4 cells, transfected with a human cDNA, substantial immune reactions occurred. Thus, it appears that the condition of the host brain and the production of foreign proteins by transplanted cells have to be considered in estimating the risks of rejection of transplants into the brain.

It is well known that epileptogenesis is associated with widespread neuronal network changes in brain regions adjacent to the seizure focus but also in remote structures including basal ganglia. Besides the superior colliculus, the pedunculopontine tegmental nucleus (PPN) is one of three main target regions of basal ganglia output activity and is reciprocally connected with the substantia nigra pars reticulata (SNr), which is critically involved in seizure propagation and manipulation. We here tested the hypothesis if, apart from the traditional view that the superior colliculus mediates seizure-gating mechanisms of the SNr, the PPN is involved in kindling-induced network changes. Rats were electrically kindled via the ipsilateral basolateral amygdala. In vivo extracellular single unit recordings of right PPN neurons were performed in kindled rats 1 day after a generalized seizure in order to examine kindling-associated rather than seizure-associated activity changes. The main findings of the study were (1) a seizure-outlasting drastically reduced firing rate of PPN neurons and (2) an increase in burst and irregular firing pattern in kindled rats compared with sham-kindled and naïve controls. These changes are likely to be caused by an altered inhibitory input from the SNr. Furthermore, kindling caused (3) the oscillation frequency of PPN neurons to shift towards lower frequencies. The kindling-induced activity changes were found to be anatomically restricted to the PPN, indicating that network changes follow distinct anatomical routes. We demonstrated that the PPN is strongly affected by the functional reorganization of neurocircuitry associated with kindling. The underlying mechanisms are discussed. The findings are relevant for a better understanding of kindling-associated network changes and might provide new targets for therapeutic manipulations in epilepsies.