Understanding Psychological Symptoms of Endometriosis from a Research Domain Criteria Perspective.

Endometriosis is currently the second most common gynecological disease and is associated with severe pain, vegetative impairment, and infertility. In association, there are considerable psychological symptoms that limit the quality of life of those affected. In this narrative review, the Research Domain Criteria (RDoC) framework was utilized to display the different transdiagnostic processes involved in disease progression and maintenance in regard to psychosocial functioning. Using the RDoC framework, it becomes clear that immune/endocrinological dysregulation is interlocked with (pelvic) pain chronification processes and psychological symptoms such as depressive mood, loss of control, higher vigilance toward the onset or worsening of symptoms, social isolation, and catastrophizing. This paper will discuss and identify promising treatment approaches, in addition to medical care, as well as further research implications. Endometriosis can come with substantial psychosomatic and social burden, requiring more research to understand the interdependence of different factors involved in its chronic development pathway. However, it is already clear that standard care should be extended with multifaceted treatments addressing pain, as well as the psychological and social burden, in order to halt the cycle of aggravation of symptoms and to improve quality of life for patients.

Internet-based cognitive behavioral therapy for improving health-related quality of life in patients with endometriosis: study protocol for a randomized controlled trial.

BACKGROUND: The trial investigates the efficacy of internet-based cognitive behavioral therapy (iCBT) in improving health-related QoL in patients with endometriosis, which is a chronic gynecological condition affecting up to 15% of people with female-assigned reproductive organs. Endometriosis is stress-related and comes with various physical symptoms such as pelvic pain and infertility. It has a substantial impact on health-related quality of life (QoL), and mind-body interventions seem promising in reducing the psychological burden. METHODS: This is a monocentric randomized-controlled trial recruiting 120 patients with endometriosis. The intervention consists of eight iCBT modules focusing on psychoeducation, cognitive restructuring, pacing, and emotion regulation. Participants will receive written feedback from a trained therapist weekly. The comparator is a waitlist control group. All participants will be followed up 3 months after the intervention, and the intervention group will additionally be followed up 12 months after the intervention. Trial participants will not be blinded to the allocated trial arm. Primary outcome measures are endometriosis-related QoL, pain, and pain-related disability. Secondary outcomes include coping, illness representations, and psychological flexibility. Statistical analyses will be performed following intention-to-treat principles. DISCUSSION: This randomized-controlled trial is the first trial to test the efficacy of iCBT for improving endometriosis-related QoL. Potential predictor variables and key mechanisms in treatment will be investigated to enable further progression in medical and psychological care for patients with endometriosis. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05098444 Registered on October 28, 2021.

Aortic valve replacement in sheep with a novel trileaflet mechanical heart valve prosthesis without anticoagulation.

Background: Even after decades of intensive research, an ideal heart valve prosthesis remains elusive. Shortcomings of conventional devices include reduced durability of bioprostheses and the thrombogenicity of mechanical substitutes, necessitating anticoagulation and resulting in imperfect hemodynamics. Here we present in vivo results of a novel mechanical heart valve prosthesis aiming for freedom from anticoagulation. Methods: Four female sheep had their aortic valves replaced using the novel mechanical heart valve (size 21 mm), with no postoperative anticoagulation treatment. This trileaflet heart valve was designed with the pivots in the systolic central flow. Hemodynamics, biochemistry, hematology, and macroscopy and microscopy were studied at 90 days in 2 sheep and at 1 year in the other 2 sheep. Results: Mean (<6 mm Hg) and peak (<10 mm Hg) aortic transvalvular gradients remained low during the study period. Aortic regurgitation was trivial, and central traces were only rarely observed. The rate of thrombotic events was very low, with none macroscopically and microscopically visible thrombotic material on the device. Biochemistry and hemotology were unchanged without hemolysis. In 3 sheep, the fibrous pannus and mitral leaflet were partially folded over the edge of the annular body. Apart from organic/inorganic deposits on the leaflets after 1 year, the ultrastructurally evaluated leaflets were similar to those of nonimplanted controls. Conclusions: The preliminary in vivo results of this novel anticoagulation-free aortic mechanical heart valve are promising with excellent hemodynamics and a very low risk of thrombotic events.

In vitro 4D Flow MRI evaluation of aortic valve replacements reveals disturbed flow distal to biological but not to mechanical valves.

BACKGROUND AND AIM OF THE STUDY: Aortic hemodynamics influence the integrity of the vessel wall and cardiac afterload. The aim of this study was to compare hemodynamics distal to biological (BV) and mechanical aortic valve (MV) replacements by in vitro 4D Flow MRI excluding confounding factors of in-vivo testing potentially influencing hemodynamics. METHODS: Two BV (Perimount MagnaEase [Carpentier-Edwards], Trifecta [Abbott]) and two MV (On-X [CryoLife], prototype trileaflet valve) were scanned in a flexible aortic phantom at 3T using a recommended 4D Flow MR sequence. A triphasic aortic flow profile with blood-mimicking fluid was established. Using GTFlow (Gyrotools), area and velocity of the ejection jet were measured. Presence and extent of sinus vortices and secondary flow patterns were graded on a 0 to 3 scale. RESULTS: A narrow, accelerated central ejection jet (Area = 27 ± 7% of vessel area, Velocity = 166 ± 13 cm/s; measured at sinotubular junction) was observed in BV as compared to MV (Area = 53 ± 13%, Velocity = 109 ± 21 cm/s). As opposed to MV, the jet distal to BV impacted the outer curvature of the ascending aorta and resulted in large secondary flow patterns (BV: n = 4, grades 3, 3, 2, 1; MV: n = 1, grade 1). Sinus vortices only formed distal to MV. Although physiologically configured, they were larger than normal (grade 3). CONCLUSIONS: In contrast to mechanical valves, biological valve replacements induced accelerated and increased flow patterns deviating from physiological ones. While it remains speculative whether this increases the risk of aneurysm formation through wall shear stress changes, findings are contrasted by almost no secondary flow patterns and typical, near-physiological sinus vortex formation distal to mechanical valves.

A novel trileaflet mechanical heart valve: first in vitro results.

OBJECTIVES: Heart valve prostheses are the therapy of choice for patients with severe heart valve diseases. Two types of prostheses that can be implanted in patients are available: biological and mechanical. Though mechanical heart valves have some disadvantages like necessity of life-long anticoagulation, biological heart valve prostheses often necessitate reinterventions due to limited durability. Therefore, a new trileaflet mechanical heart valve was developed, featuring hinges in the systolic flow with the aim of function and thrombogenicity. METHODS: We first compared the new trileaflet mechanical heart valve to conventional bileaflet heart valves (St. Jude Medical and On-X valves) in vitro. Haemodynamic measurements were performed in a pulse duplicator system, and clot formation was examined with an implemented method using enzyme-activated milk as the test medium. RESULTS: Haemodynamic measurements showed the largest effective orifice areas and smallest pressure gradients for the trileaflet prosthesis compared to the bileaflet valve. Opening and closing characteristics of the trileaflet valve and of the St. Jude Medical valve were comparable. Clotting tests depicted only minor isolated deposits for the new trileaflet valve whereas the bileaflet valves showed distinct clots in the area of the hinge in all experiments. CONCLUSIONS: Haemodynamic and clotting tests showed improvements for the new trileaflet valve compared to common bileaflet valves. The off-wall systolic position of the hinges, which eluded adverse flow areas, was a major advantage of the new valve.

The influence of different inflow configurations on computational fluid dynamics in a novel three-leaflet mechanical heart valve prosthesis.

OBJECTIVES: A novel mechanical heart valve was developed with a special focus on avoiding anticoagulation. Computational fluid dynamics were used for the research design. Here, the effect of different anatomical inflow geometries on flow characteristics is evaluated. METHODS: Flow and pressure simulations were performed on a novel 3-leaflet mechanical heart valve in a fully open position at 2 flow rates related to the peak and end-systolic flow. The computational fluid dynamics model was designed according to 4 different (1 cylindrical, 3 conical with increasing diameter) anatomical configurations of the left ventricular outflow tract derived from an inverse heart model. RESULTS: With increasing inflow diameter, the flow velocity decreased for both flow rates, from 1543 mm/s in cylindrical configuration to 1475 mm/s in conical configuration for a flow rate of 18 l/min. However, there was no further decrease for the inflow diameters 38 and 48 mm. The velocity profile became broader with increasing inflow diameter and the maximal pressure decreased. At the leading edge, velocity almost stagnated, while the pressure increased and the reflection point moved downstream. No occurrence of dead space was observed with the different configurations and flow rates. CONCLUSIONS: An analysis of different anatomical inflow configurations by computational fluid dynamic simulations showed a more homogenous velocity profile and lower flow velocity values with increasing inflow diameter up to 38 mm in this novel 3-leaflet mechanical heart valve.

Pathogenic mitochondrial mt-tRNA(Ala) variants are uniquely associated with isolated myopathy.

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA(Ala) variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA(Ala) levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA(Ala) variants. Previously described mt-tRNA(Ala) mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.

A novel m.7539C>T point mutation in the mt-tRNA(Asp) gene associated with multisystemic mitochondrial disease.

Mitochondrial transfer RNA (mt-tRNA) mutations are the commonest sub-type of mitochondrial (mtDNA) mutations associated with human disease. We report a patient with multisytemic disease characterised by myopathy, spinal ataxia, sensorineural hearing loss, cataract and cognitive impairment in whom a novel m.7539C>T mt-tRNA(Asp) transition was identified. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for the mutation whilst single muscle fibre segregation studies revealed statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres. Absence from control databases, hierarchical mt-tRNA mutation segregation within tissues, and occurrence at conserved sequence positions, further confirm this novel mt-tRNA mutation to be pathogenic. To date only three mt-tRNA(Asp) gene mutations have been described with clear evidence of pathogenicity. The novel m.7539C>T mt-tRNA(Asp) gene mutation extends the spectrum of pathogenic mutations in this gene, further supporting the notion that mt-tRNA(Asp) gene mutations are associated with multisystemic disease presentations.

Revisiting electroblotting of immobilized pH gradient gels: a new protocol for studying post-translational modification of proteins.

Currently, one of the most important techniques in proteome analysis is two-dimensional electrophoresis that is widely used for separation of thousands of different protein spots. Nevertheless, characterization of special aspects in protein patterns, e.g., separation of protein isoforms generated by post-translational modifications, requires individual detection methods, e.g., immunoblotting. Blotting of proteins after fractionation in immobilized pH gradients has always caused some problems. In this paper we present an optimized protocol for immunoblotting after isoelectric focusing using immobilized pH gradient (IPG) strips cast on Net-Fix as an internal support that is permeable to electric current. The focusing procedure can be carried out in commonly used IPG systems, e.g., the IPGphor by Amersham Biosciences, where electrically assisted rehydration can be performed. This may be of interest for many laboratories, because the same system as used for the first dimension of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) is involved. As an example, we describe separation and detection of up to seven isoforms of recombinant erythropoietin beta using semidry blotting of IPG strips and visualization by chemiluminescence detection.