Walk before you run: Feasibility challenges and lessons learned from the PROCLAIM study, a multicenter randomized controlled trial of misoprostol for prevention of recurrent Clostridioides difficile during COVID-19.

We analyzed our challenging experience with a randomized controlled trial of misoprostol for prevention of recurrent C. difficile. Despite careful prescreening and thoughtful protocol modifications to facilitate enrollment, we closed the study early after enrolling just 7 participants over 3 years. We share lessons learned, noting the importance of feasibility studies, inclusion of biomarker outcomes, and dissemination of such findings to inform future research design and implementation successes.

Delayed reinforcement learning converges to intermittent control for human quiet stance.

The neural control of human quiet stance remains controversial, with classic views suggesting a limited role of the brain and recent findings conversely indicating direct cortical control of muscles during upright posture. Conceptual neural feedback control models have been proposed and tested against experimental evidence. The most renowned model is the continuous impedance control model. However, when time delays are included in this model to simulate neural transmission, the continuous controller becomes unstable. Another model, the intermittent control model, assumes that the central nervous system (CNS) activates muscles intermittently, and not continuously, to counteract gravitational torque. In this study, a delayed reinforcement learning algorithm was developed to seek optimal control policy to balance a one-segment inverted pendulum model representing the human body. According to this approach, there was no a-priori strategy imposed on the controller but rather the optimal strategy emerged from the reward-based learning. The simulation results indicated that the optimal neural controller exhibits intermittent, and not continuous, characteristics, in agreement with the possibility that the CNS intermittently provides neural feedback torque to maintain an upright posture.

Right ventricular pressure-strain relationship-derived myocardial work reflects contractility: Validation with invasive pressure-volume analysis.

Three-dimensional (3D) echocardiography-derived right ventricular (RV) ejection fraction (EF) and global longitudinal strain (GLS) are valuable RV functional markers; nevertheless, they are substantially load-dependent. Global myocardial work index (GMWI) is a novel parameter calculated by the area of the RV pressure-strain loop. By adjusting myocardial deformation to instantaneous pressure, it may reflect contractility. To test this hypothesis, we enrolled 60 patients who underwent RV pressure-conductance catheterization to determine load-independent markers of RV contractility and ventriculo-arterial coupling. Detailed 3D echocardiography was also performed, and we calculated RV EF, RV GLS, and using the RV pressure trace curve, RV GWMI. While neither RV EF nor GLS correlated with Ees, GMWI strongly correlated with Ees. In contrast, RV EF and GLS showed a relationship with Ees/Ea. By dividing the population based on their Reveal Lite 2 risk classification, different characteristics were seen among the subgroups. RV GMWI may emerge as a useful clinical tool for risk stratification and follow-up in patients with RV dysfunction.

Loss of Right Ventricular Outflow Function in Pulmonary Hypertension.

Right ventricular outflow tract (RVOT) function is not systematically quantified by three-dimensional (3D) echocardiography. We tested the hypothesis that loss of RVOT function in pulmonary hypertension (PH) is related to disease severity independently of other echocardiographic parameters. In this observational study, patients with PH, disease controls, and a matched healthy control group underwent 3D echocardiography and RVOT analysis using ReVISION software. The study included 43 patients (38 with PH, 5 disease controls) and 43 healthy controls. Median 3D RVOT ejection fraction (EF) was 30.4% in the patients and 44.2% in the healthy controls (p < 0.001). Patients with low 3D RVOT-EF (<30.4%) were more frequently categorized in higher risk groups and had a higher incidence of clinical worsening than those with high 3D RVOT-EF. Even in patients with RV-EF ≥35%, those with low 3D RVOT-EF had worse outcomes. Segmental RVOT analysis identifies high-risk patients even with normal overall RV function.

Shared Autonomy Locomotion Synthesis With a Virtual Powered Prosthetic Ankle.

Virtual environments provide a safe and accessible way to test innovative technologies for controlling wearable robotic devices. However, to simulate devices that support walking, such as powered prosthetic legs, it is not enough to model the hardware without its user. Predictive locomotion synthesizers can generate the movements of a virtual user, with whom the simulated device can be trained or evaluated. We implemented a Deep Reinforcement Learning based motion controller in the MuJoCo physics engine, where autonomy over the humanoid model was shared between the simulated user and the control policy of an active prosthesis. Despite not optimising the controller to match experimental dynamics, realistic torque profiles and ground reaction force curves were produced by the agent. A data-driven and continuous representation of user intent was used to simulate a Human Machine Interface that controlled a transtibial prosthesis in a non-steady state walking setting. The continuous intent representation was shown to mitigate the need for compensatory gait patterns from their virtual users and halve the rate of tripping. Co-adaptation was identified as a potential challenge for training human-in-the-loop prosthesis control policies. The proposed framework outlines a way to explore the complex design space of robot-assisted gait, promoting the transfer of the next generation of intent driven controllers from the lab to real-life scenarios.

Association of Right Ventricular Functional Parameters With Adverse Cardiopulmonary Outcomes: A Meta-analysis.

AIMS: We aimed to confirm that three-dimensional echocardiography-derived right ventricular ejection fraction (RVEF) is better associated with adverse cardiopulmonary outcomes than the conventional echocardiographic parameters. METHODS: We performed a meta-analysis of studies reporting the impact of unit change of RVEF, tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and free-wall longitudinal strain (FWLS) on clinical outcomes (all-cause mortality and/or adverse cardiopulmonary outcomes). Hazard ratios (HRs) were rescaled by the within-study SDs to represent standardized changes. Within each study, we calculated the ratio of HRs related to a 1 SD reduction in RVEF versus TAPSE, or FAC, or FWLS, to quantify the association of RVEF with adverse outcomes relative to the other metrics. These ratios of HRs were pooled using random-effects models. RESULTS: Ten independent studies were identified as suitable, including data on 1,928 patients with various cardiopulmonary conditions. Overall, a 1 SD reduction in RVEF was robustly associated with adverse outcomes (HR = 2.64 [95% CI, 2.18-3.20], P < .001; heterogeneity: I2 = 65%, P = .002). In studies reporting HRs for RVEF and TAPSE, or RVEF and FAC, or RVEF and FWLS in the same cohort, head-to-head comparison revealed that RVEF showed significantly stronger association with adverse outcomes per SD reduction versus the other 3 parameters (vs TAPSE, HR = 1.54 [95% CI, 1.04-2.28], P = .031; vs FAC, HR = 1.45 [95% CI, 1.15-1.81], P = .001; vs FWLS, HR = 1.44 [95% CI, 1.07-1.95], P = .018). CONCLUSION: Reduction in three-dimensional echocardiography-derived RVEF shows stronger association with adverse clinical outcomes than conventional right ventricular functional indices; therefore, it might further refine the risk stratification of patients with cardiopulmonary diseases.

Clinical and functional relevance of right ventricular contraction patterns in pulmonary hypertension.

BACKGROUND: The right ventricle has a complex contraction pattern of uncertain clinical relevance. We aimed to assess the relationship between right ventricular (RV) contraction pattern and RV-pulmonary arterial (PA) coupling defined by the gold-standard pressure-volume loop-derived ratio of end-systolic/arterial elastance (Ees/Ea). METHODS: Prospectively enrolled patients with suspected or confirmed pulmonary hypertension underwent three-dimensional echocardiography, standard right heart catheterization, and RV conductance catheterization. RV-PA uncoupling was categorized as severe (Ees/Ea < 0.8), moderate (Ees/Ea 0.8-1.29), and none/mild (Ees/Ea ≥ 1.3). Clinical severity was determined from hemodynamics using a truncated version of the 2022 European Society of Cardiology/European Respiratory Society risk stratification scheme. RESULTS: Fifty-three patients were included, 23 with no/mild, 24 with moderate, and 6 with severe uncoupling. Longitudinal shortening was decreased in patients with moderate vs no/mild uncoupling (p <0.001) and intermediate vs low hemodynamic risk (p < 0.001), discriminating low risk from intermediate/high risk with an optimal threshold of 18% (sensitivity 80%, specificity 87%). Anteroposterior shortening was impaired in patients with severe vs moderate uncoupling (p = 0.033), low vs intermediate risk (p = 0.018), and high vs intermediate risk (p = 0.010), discriminating high risk from intermediate/low risk with an optimal threshold of 15% (sensitivity 100%, specificity 83%). Left ventricular (LV) end-diastolic volume was decreased in patients with severe uncoupling (p = 0.035 vs no/mild uncoupling). CONCLUSIONS: Early RV-PA uncoupling is associated with reduced longitudinal function, whereas advanced RV-PA uncoupling is associated with reduced anteroposterior movement and LV preload, all in a risk-related fashion. CLINICALTRIALS: GOV: NCT04663217.

Cardiorespiratory fitness status of elite handball referees in Hungary.

In various team sports, such as handball, referees work on the court by continuously moving with the players. Therefore, their physical fitness also has an impact on their reaction time, which could affect their professional decisions. The cardiorespiratory fitness status of healthy Hungarian elite handball referees was examined via body composition analysis and vita maxima cardiopulmonary exercise testing with lactate measurements. One hundred referees were examined (age: 29.0 ± 7.9 years; male: 64.0%; training: 4.3 ± 2.0 hours/week; ratio of former elite handball players: 39.0%; 51.0% first and 49.0% second division referees of the Hungarian National Handball Leagues). A resting heart rate (HR) of 79.0 ± 12.6 BPM was measured. On the basis of the body composition analysis the fat-free mass index proved to be 19.9 ± 2.6 kg/m2. The referees achieved a maximal oxygen uptake (V̇O2max) of 44.6 ± 6.1 ml/kg/min, with a maximal HR of 187.2 ± 11.1 BPM (which was 98.1 ± 4.6% of their calculated maximal HR) and a peak lactate of 9.2 ± 3.2 mmol/l at 557.1 ± 168.3 sec on our continuous speed, increasing slope treadmill protocol. Second division referees were younger, on a weekly average they trained more, achieved higher treadmill exercise time (respectively, 463.8 ± 131.9 vs 658.4 ± 143.9 sec, p < 0.001) and anaerobic threshold time (respectively, 265.8 ± 100.9 vs 348.2 ± 117.1 sec, p < 0.001), while the two different divisional referees had similar V̇O2max values. Regarding our physical fitness measurements, huge individual differences were observed between the referees (exercise time range: 259.0-939.0 sec, V̇O2max range: 25.3-62.4 ml/kg/min). Since it can affect their performance as referees, individual training planning, regular physical fitness measurements, and strict selection methods are suggested.

Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis.

BACKGROUND: Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far. DESIGN: A systematic review and meta-analysis was conducted to evaluate vaccines' efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020. OBJECTIVE: response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented. RESULTS: Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively. In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI[5%,13%]). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI[1%,7%]). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema. Median PFS was 2.6 months (95% confidence interval (CI)[1.9,2.9]) and 13.0 months (95%CI[8.5,16.3]) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI[15.0,46.0]) and 39.0 months (95%CI[31.0,49.0]). In almost all cases, the observed toxicity was only moderate. CONCLUSION: Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.

Right ventricular mechanical pattern in patients undergoing mitral valve surgery: a predictor of post-operative dysfunction?

AIMS: The PREPARE-MVR study (PRediction of Early PostoperAtive Right vEntricular failure in Mitral Valve Replacement/Repair patients) sought to investigate the alterations of right ventricular (RV) contraction pattern in patients undergoing mitral valve replacement/repair (MVR) and to explore the associations between pre-operative RV mechanics and early post-operative RV dysfunction (RVD). METHODS AND RESULTS: We prospectively enrolled 42 patients (63 ± 11 years, 69% men) undergoing open-heart MVR. Transthoracic three-dimensional (3D) echocardiography was performed pre-operatively, at intensive care unit discharge, and 6 months after surgery. The 3D model of the RV was reconstructed, and RV ejection fraction (RVEF) was calculated. We decomposed the motion of the ventricle to compute longitudinal ejection fraction (LEF) and radial ejection fraction (REF). Pulmonary artery catheterization was performed to monitor RV stroke work index (RVSWi). RVEF was slightly decreased after MVR [52 (50-55) vs. 51 (46-54)%; P = 0.001], whereas RV contraction pattern changed notably. Before MVR, the longitudinal shortening was the main contributor to global systolic RV function [LEF/RVEF vs. REF/RVEF; 0.53 (0.47-0.58) vs. 0.33 (0.22-0.42); P < 0.001]. Post-operatively, the radial motion became dominant [0.33 (0.28-0.43) vs. 0.46 (0.37-0.51); P = 0.004]. However, this shift was temporary as 6 months later the two components contributed equally to global RV function [0.44 (0.38-0.50) vs. 0.41 (0.36-0.49); P = 0.775]. Pre-operative LEF was an independent predictor of post-operative RVD defined as RVSWi < 300 mmHg⋅mL/m2 [OR = 1.33 (95% CI: 1.08-1.77), P < 0.05]. CONCLUSIONS: MVR induces a significant shift in the RV mechanical pattern. Advanced indices of RV mechanics are associated with invasively measured parameters of RV contractility and may predict post-operative RVD.

Central neurocytoma with malignant course. Neuronal and glial differentiation and craniospinal dissemination.

Central neurocytoma is a benign neuronal tumor of young adults in the lateral cerebral ventricles with characteristic X ray and light microscopic findings. In many respects typical central neurocytoma is reported below, with recurrence in the third month requiring reoperation. Death ensued in the fifth postoperative month. Subsequent histology proved progressive vascular proliferation and increasing, unusual glial differentiation of the neuronal tumor. At autopsy tumorous seeding blocked the liquor circulation. A thin tumorous layer covered the surface of all ventricles, the cerebellum and medulla oblongata. The GFAP positive cells out-numbered the synaptophysin positive ones. Increase of GFAP positivity and vascular proliferation of the central neurocytoma may be alarming signs suggesting a malignant course in addition to the other atypical features.

Effect of vasoactive intestinal polypeptide (VIP) on growth hormone (GH) and prolactin (PRL) release and cell morphology in human pituitary adenoma cell cultures.

Six GH adenomas and three prolactinomas were investigated by light- and electron-microscopic morphological and immunocytochemical methods and the effect of vasoactive intestinal polypeptide (VIP) on growth hormone (GH) and prolactin (PRL) secretion was tested in vitro. The tumour cells of the acromegalic patients revealed both GH and PRL immunoreactivity while prolactinomas showed only PRL activity. All the adenomas stained immunocytochemically also for VIP. By electron microscopy, the tumours included two densely and two sparsely granulated GH, two mixed GH/PRL, and three sparsely granulated PRL adenomas. The dissociated cells were explanted, and cultured in vitro. The cultures in micro test plates were treated with VIP at different concentrations between 10(-5)-10(-12) M. GH and PRL contents in the culture media were measured by radioimmunoassay. GH release was significantly stimulated by VIP in a dose-dependent manner over the whole concentration range, while VIP was effective on the PRL release only at 10(-6)-10(-7) M concentration. The cells of a mixed adenoma were grown in Petri dishes and used for ultrastructural and immunocytochemical studies. The cytoplasmic structure of the cells treated with VIP corresponded to that of active hormone-secreting cells with large ergastoplasmic fields and Golgi zones containing secretory granules. Massive exocytotic events were encountered mainly in the GH-type cells. GH and PRL double immunocytochemistry showed the predominance of GH cells, many of them containing low amounts of PRL as well. Cells predominantly containing PRL were spread among them, they also might contain GH as well. Some of the cells contained only a single immunoreactive hormone. The intensity of gold labelling of the secretory granules appeared higher in the VIP-treated cells than in the untreated control ones which showed a cytoplasmic structure characteristic of glandular cells with low secretory activity. As all the adenoma cells both contained and reacted to VIP, our results are in agreement with an autocrine or paracrine effect of this peptide. The fine structure of the cells in the cultures treated with VIP supply an additional argument to the assumption that VIP may serve as a growth factor for these cell types.

Secretory component of cystic craniopharyngiomas: a mucino-histochemical and electron-microscopic study.

Ten cases with cystic craniopharyngioma were investigated. Histologically, eight of them belonged to the adamantinomatous group and two were squamous epithelial type. Histochemical investigation revealed mucin secretion in microcysts, and electron microscopy demonstrated zymogen granules in the epithelial cells. When the protein content of the cyst fluid was analyzed by polyacrylamide-gel electrophoresis, the electrophoretic pattern and immunological properties were found to be similar to the normal human serum control. The results of the morphological study suggest that cystic craniopharyngiomas have a secretory component in addition to the classical histological structures.

Treatment of cystic craniopharyngiomas with yttrium-90 colloid solution.

The authors analyzed long-term follow-up data to assess the value of intracavitary irradiation with stereotactically implanted beta-emitting radioisotope (90)Y-silicate colloid for the treatment of craniopharyngiomas. Fifty-seven craniopharyngiomas in 42 patients were selected for retrospective analysis. The yttrium-90 was implanted intracavitally, using computerized tomography-guided and three-dimensional stereotactic treatment planning. The cumulative dose aimed at the inner surface of the cyst wall was 300 Gy. An average of 75% shrinkage of the initial cyst volume was observed. In 18 cases the reduction was more than 91%, and the cyst disappeared totally in 11 cases. A 50% decrease in cyst volume was usually apparent between the 2nd and 4th months. A 70% decrease in cyst volume was seen by the 5th and 6th months and an 80% reduction by the 7th and 8th months. Cysts that were unchanged remained so throughout the observation period. The time course of volume reduction could be expressed mathematically by the formula of 0.73 X e(-0.62 X T) + 0.27, where "e" is the basic number of natural logarithm and "T" is the time expressed in months. Mean survival duration after intracavitary irradiation was 9.4 years. The shrinkage of the cyst was a consequence of fibrosis of the wall, as seen on histopathological examination. The neuroophthalmological prognosis was favorable only when the optic disc was normal or nearly normal at the time of the treatment. In the presence of preexisting optic atrophy, visual deterioration proved to be irreversible. The long-term results support the view that intracavitary (90)Y-irradiation is a noninvasive and very effective method of treatment for craniopharyngioma cysts. Because of the 1.1 mm half-life decay of beta irradiation, it cannot influence the solid part of the tumor; therefore, the best result can be expected in solitary cysts.

Supraclavicular abscess caused by Salmonella enteritidis in patient without gastrointestinal symptoms.

Soft tissue infections are among the rare manifestations of extra intestinal salmonellosis and occur more frequently in immunocompromised patients. Herein we report a case of a 51-year-old white male with type II. diabetes mellitus, diagnosed with supraclavicular abscess caused by Salmonella enteritidis. The patient denied any gastrointestinal symptoms, and stool cultures were negative. After incision, drainage, and administration of intravenous ampicillin (4 x 1.5 g/day for two weeks) the patient recovered completely. To our knowledge, this is the first reported case of cervical soft tissue abscess caused by Salmonella enteritidis without preceding gastrointestinal symptoms. We feel that the presence of diabetes was a risk factor for developing the infection.

[Surgical treatment of pituitary apoplexy]. / A hypophysis apoplexia sebészi kezeléséröl.

Hypophysis apoplexy is a clinical syndrome characterized by the sudden development of headache, visual disturbance, associated with nausea, vomiting, signs of meningeal irritation and ophthalmoplegia. The symptoms are caused by the hemorrhage of a hypophyseal adenoma. This leads to the swelling of the tumor and compression of the perisellar structures. The authors processed the clinical and pathological characteristics of 28 cases occurring among the patient material of the National Institute of Neurosurgery of the past 10 years. According to the experiences the most important factor of a successful treatment of hypophyseal apoplexy is an early diagnosis and quick admittance to an institute of neurosurgery of satisfactory conditions. Thereafter a steroid hormone therapy of large doses and decompression operation performed by transnasal-transsphenoidal approach leads in the majority of cases to recovery.