Search

Multiple randomized controlled trials (RCTs) have examined first-line pharmacological agents such as anticholinergics and β3 agonists for the management of overactive bladder symptoms (OAB). Although earlier systematic reviews and (network) meta-analyses aimed to summarize the evidence, a substantial number of trials were not included, so a comprehensive and methodologically rigorous evaluation of the comparative effectiveness of all first-line pharmacological treatments is lacking. We aim to conduct a series of systematic reviews and network meta-analyses (NMAs) for a comprehensive assessment of the effectiveness and safety of first-line pharmacological treatments for OAB. Eligible studies will include RCTs comparing anticholinergics and β3 agonists to one another or to placebo in adults with OAB or detrusor overactivity. Pairs of reviewers with methodological training will independently evaluate candidate studies to determine eligibility and extract relevant data. We will incorporate patient-important outcomes, including urinary urgency episodes, urgency incontinence episodes, any type of incontinence episodes, urinary frequency, nocturia, and adverse events. We will conduct the NMAs using a frequentist framework and a graph theory model for each outcome. Analysis will follow rigorous methodologies, including handling of missing data and assessment of the risk of bias. We will conduct sensitivity and subgroup analyses and will apply the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to rate evidence certainty. Our approach aims to address the knowledge gap in the treatment of OAB by synthesizing evidence from RCTs worldwide. We will employ robust statistical methods, including frequentist NMA, to general clinically relevant and patient-important insights. Sensitivity and subgroup analyses will enhance the robustness and generalizability of our findings. Our reviews strive to inform evidence-based decisions in the management of OAB, to ultimate improve patient outcomes. Our study results may guide health policy decisions, such as reimbursement policies, and future studies in functional urology.The protocol for the review series is registered on PROSPERO as CRD42023266915.

Drugs blocking the renin–angiotensin–aldosterone system may offer benefit on endothelial function, inflammation, and hemostasis in addition to the effects of reducing blood pressure. We have shown antithrombin effects by treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril. As thrombin is a key inducer of platelet aggregation, we hypothesized that treatment with ramipril could modulate platelet reactivity and endothelial glycocalyx (eGCX) function. This study assessed platelet activity (CD40 ligand and P-selectin) and eGCX markers (E-selectin, hyaluronan, syndecan-1, and thrombomodulin) in 59 individuals with mild-to-moderate hypertension, randomized double-blind to ramipril 10 mg or doxazosin 8 mg od for 12 weeks. Ramipril and doxazosin similarly reduced blood pressure. Antihypertensive treatment reduced CD40 ligand (p

ST-segment elevation myocardial infarction (STEMI) is usually caused by a ruptured atherosclerotic plaque, with subsequent thrombus formation. Platelet inhibition and primary percutaneous coronary intervention (PCI) are essential treatments. Morphine, used to relieve pain and anxiety in STEMI patients, delays the onset of P2Y12 inhibitors. This study aimed to further explore the association between platelet activity and morphine treatment in patients with STEMI. In this sub-study of the VALIDATE-SWEDHEART trial, 89 STEMI patients treated with ticagrelor, and primary PCI were included. Platelet aggregation and biomarkers of platelet activity, coagulation, and inflammation (sP-selectin, thrombin-antithrombin complexes, prothrombin fragments 1 + 2, CD40L, CRP, beta-thromboglobulin, and pentraxin3) were assessed at three time points: before, one, and twelve hours after PCI. Of the 89 patients, 40 received morphine before hospital arrival. There were no significant differences in age, sex, medical history, or coronary disease extent. One hour after PCI, ADP-induced (36 vs 61, p

Background: Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis. Purpose: This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT. Material and methods: This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured. Patients: Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0–1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants. Interpretation: This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.

Pharmacological inhibition of the platelet ADP-receptor P2Y12 is a cornerstone in the prevention of atherothrombotic events in adult patients with acute coronary syndrome (ACS). Thienopyridines such as clopidogrel and prasugrel exert their antithrombotic effect by means of active metabolites that irreversibly inhibit P2Y12. Due to the short half-life of these metabolites, a subpopulation of ADP-responsive platelets will form in between dosing. With increased platelet turnover rate or poor patient compliance, the fraction of ADP-responsive platelets will increase, potentially increasing the risk for new thrombotic events. In contrast, the reversible P2Y12 inhibition produced by direct-acting ADP blockers such as ticagrelor and cangrelor inhibit the entire platelet population. In this study, we evaluated the impact of these pharmacological differences on thrombus formation in an ex vivo flow chamber model. A customized image analysis pipeline was used for automatized, large-scale identification and tracking of single platelets incorporated into the thrombus, enabling quantitative analysis of the relative contribution of inhibited and uninhibited platelets to thrombus growth and consolidation. Comparative experiments were conducted using the irreversible and reversible P2Y12 inhibitors prasugrel active metabolite (PAM) and ticagrelor, respectively. Our results show that PAM inhibited thrombus platelet recruitment more gradually than ticagrelor, with a slower onset of inhibition. Further, we show that the presence of a small fraction (

Purpose Ambulatory, cuff-less blood pressure (BP) measurement devices are a promising trend to alleviate the strains of conventional, cuff-based BP determination. Cuff-less devices circumvent discomfort and nocturnal arousal reactions which can be triggered by cuff inflation from conventional, cuff-based ambulatory blood pressure measurement devices. Mitigating these discomforts is especially desirable when performing measurement in children. In this study we want to assess the clinical validity of a cuff-less BP measurement device for 24-h measurements in children and adolescents. Materials and methods We compared the simultaneously retrieved BP data of the cuff-less SOMNOtouch NIBP and the cuff-based Mobil-O-Graph in 24-h use in 90 children in the range from 5 to 17 years old. Results A total of 1218 valid measurement pairs showed a mean deviation of 0.99 mmHg (limits of agreement: 21.44/-19.46) for systolic and 3.03 mmHg (limits of agreement: 24.37/−18.31) for diastolic BP values. Patient-specific difference of means was within 15 mmHg in 97.7% (systolic BP) and 93.2% (diastolic BP) patients. 25.6% of nocturnal cuff inflations led to determinable, BP-relevant arousal reactions. Conclusions The SOMNOtouch NIBP demonstrated little measurement deviation of mean BP compared to the cuff-based technique over a broad spectrum of 24-h, ambulatory BP measurements in children and adolescents. Cuff-less blood pressure measurement relieves the issue of nocturnal arousal reactions which are shown to be frequently induced by cuff-based measurements. Driven by these promising results, we encourage ongoing efforts to create enough evidence on cuff-less BP measurement to promote it into broad clinical application.

Abstract Background Sulfur mustard (SM) is a chemical warfare vesicant that severely injures exposed eyes, lungs, and skin. Mechlorethamine hydrochloride (NM) is widely used as an SM surrogate. This study aimed to develop a depilatory double‐disc (DDD) NM skin burn model for investigating vesicant pharmacotherapy countermeasures. Methods Hair removal method (clipping only versus clipping followed by a depilatory), the effect of acetone in the vesicant administration vehicle, NM dose (0.5–20 μmol), vehicle volume (5–20 μl), and time course (0.5–21 days) were investigated using male and female CD‐1 mice. Edema, an indicator of burn response, was assessed by biopsy skin weight. The ideal NM dose to induce partial‐thickness burns was assessed by edema and histopathologic evaluation. The optimized DDD model was validated using an established reagent, NDH‐4338, a cyclooxygenase, inducible nitric oxide synthase, and acetylcholinesterase inhibitor prodrug. Results Clipping/depilatory resulted in a 5‐fold higher skin edematous response and was highly reproducible (18‐fold lower %CV) compared to clipping alone. Acetone did not affect edema formation. Peak edema occurred 24–48 h after NM administration using optimized dosing methods and volume. Ideal partial‐thickness burns were achieved with 5 μmol of NM and responded to treatment with NDH‐4338. No differences in burn edematous responses were observed between males and females. Conclusion A highly reproducible and sensitive partial‐thickness skin burn model was developed for assessing vesicant pharmacotherapy countermeasures. This model provides clinically relevant wound severity and eliminates the need for organic solvents that induce changes to the skin barrier function.

NDH-4338 is a highly lipophilic prodrug comprising indomethacin and an acetylcholinesterase inhibitor. A design of experiments approach was used to synthesize, characterize, and evaluate the wound healing efficacy of optimized NDH-4338 nanosuspensions against nitrogen mustard-induced skin injury. Nanosuspensions were prepared by sonoprecipitation in the presence of a Vitamin E TPGS aqueous stabilizer solution. Critical processing parameters and material attributes were optimized to reduce particle size and determine the effect on dissolution rate and burn healing efficacy. The antisolvent/solvent ratio (A/S), dose concentration (DC), and drug/stabilizer ratio (D/S) were the critical sonoprecipitation factors that control particle size. These factors were subjected to a Box–Behnken design and response surface analysis, and model quality was assessed. Maximize desirability and simulation experiment optimization approaches were used to determine nanosuspension parameters with the smallest size and the lowest defect rate within the 10–50 nm specification limits. Optimized and unoptimized nanosuspensions were prepared and characterized. An established depilatory double-disc mouse model was used to evaluate the healing of nitrogen mustard-induced dermal injuries. Optimized nanosuspensions (A/S = 6.2, DC = 2% w/v, D/S = 2.8) achieved a particle size of 31.46 nm with a narrow size range (PDI = 0.110) and a reduced defect rate (42.2 to 6.1%). The optimized nanosuspensions were stable and re-dispersible, and they showed a ~45% increase in cumulative drug release and significant edema reduction in mice. Optimized NDH-4338 nanosuspensions were smaller with more uniform sizes that led to improved physical stability, faster dissolution, and enhanced burn healing efficacy compared to unoptimized nanosuspensions.

The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.

Abstract We aimed to develop and test a novel metric for the relative performance of blood pressure estimation systems (B-Score). The B-Score sets absolute blood pressure estimation model performance in contrast to the dataset the model is tested upon. We calculate the B-Score based on inter- and intrapersonal variabilities within the dataset. To test the B-Score for reliable results and desired properties, we designed generic datasets with differing inter- and intrapersonal blood pressure variability. We then tested the B-Score’s real-world functionality with a small, published dataset and the largest available blood pressure dataset (MIMIC IV). The B-Score demonstrated reliable and desired properties. The real-world test provided allowed the direct comparison of different datasets and revealed insights hidden from absolute performance measures. The B-Score is a functional, novel, and easy to interpret measure of relative blood pressure estimation system performance. It is easily calculated for any dataset and enables the direct comparison of various systems tested on different datasets. We created a metric for direct blood pressure estimation system performance. The B-Score allows researchers to detect promising trends quickly and reliably in the scientific literature. It further allows researchers and engineers to quickly assess and compare performances of various systems and algorithms, even when tested on different datasets.

PurposeThe pulse-wave-velocity, is used for indirect, cuff-less, continuous blood pressure estimation. It is commonly detected by measuring the time delay between a defined point in an ECG and the arrival of the peripheral pulse wave (e.g., oxygen saturation sensor). The period between electrical stimulation of the heart (ECG) and actual blood ejection from the heart is called the pre-ejection period (PEP). This study aims at characterizing the PEP under mental and physical stress with focus on its relations to other cardiovascular parameters such as heart rate and importance for blood pressure (BP) estimation.MethodsWe measured the PEP in 71 young adults at rest, under mental (TSST) and physical stress (ergometer) via impedance-cardiography.ResultsThe PEP is highly dependent on mental and physical load. It is strongly correlated with indicators of sympathetic strain (p < 0.001). At rest (mean 104.5 ms), the PEP shows a high interindividual variability but small intraindividual variability. Mental stress decreases the PEP by 16% (mean 90.0 ms) while physical stress halves PEP (mean 53.9 ms). The PEP does correlate differently with heart rate under differing circumstances (rest: R2 0.06, mental stress: R2 0.29, physical stress: R2 0.65). Subsequently, using PEP and heart rate enables the discrimination of rest, mental and physical strain with a positive predictive value of 93%.ConclusionThe PEP is a cardiovascular parameter with large interindividual variability at rest and subject-depended dynamic under load which is of great importance for ECG-based pulse-wave-velocity (PWV) determination. Considering its variability and large impact on the pulse arrival time, PEP is a crucial factor in PWV based BP estimation.

Abstract Mitochondria are highly dynamic organelles with strict quality control processes that maintain cellular homeostasis. Within axons, coordinated cycles of fission-fusion mediated by dynamin related GTPase protein (DRP1) and mitofusins (MFN), together with regulated motility of healthy mitochondria anterogradely and damaged/oxidized mitochondria retrogradely, control mitochondrial shape, distribution and size. Disruption of this tight regulation has been linked to aberrant oxidative stress and mitochondrial dysfunction causing mitochondrial disease and neurodegeneration. Although pharmacological induction of Parkinson’s disease (PD) in humans/animals with toxins or in mice overexpressing α-synuclein (α-syn) exhibited mitochondrial dysfunction and oxidative stress, mice lacking α-syn showed resistance to mitochondrial toxins; yet, how α-syn influences mitochondrial dynamics and turnover is unclear. Here, we isolate the mechanistic role of α-syn in mitochondrial homeostasis in vivo in a humanized Drosophila model of Parkinson’s disease (PD). We show that excess α-syn causes fragmented mitochondria, which persists with either truncation of the C-terminus (α-syn1–120) or deletion of the NAC region (α-synΔNAC). Using in vivo oxidation reporters Mito-roGFP2-ORP1/GRX1 and MitoTimer, we found that α-syn-mediated fragments were oxidized/damaged, but α-syn1–120-induced fragments were healthy, suggesting that the C-terminus is required for oxidation. α-syn-mediated oxidized fragments showed biased retrograde motility, but α-syn1–120-mediated healthy fragments did not, demonstrating that the C-terminus likely mediates the retrograde motility of oxidized mitochondria. Depletion/inhibition or excess DRP1-rescued α-syn-mediated fragmentation, oxidation, and the biased retrograde motility, indicating that DRP1-mediated fragmentation is likely upstream of oxidation and motility changes. Further, excess PINK/Parkin, two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, rescued α-syn-mediated membrane depolarization, oxidation and cell death in a C-terminus-dependent manner, suggesting a functional interaction between α-syn and PINK/Parkin. Taken together, our findings identify distinct roles for α-syn in mitochondrial homeostasis, highlighting a previously unknown pathogenic pathway for the initiation of PD.

Several earlier studies have reported increased risk of bleeding in women with myocardial infarction, (MI) compared to men. The reasons for the observed difference are incompletely understood, but one suggested explanation has been excess dosing of antithrombotic drugs in women. The aim of this prospective observational study was to assess sex differences in platelet activity in patients treated with three different platelet inhibitors. We recruited 125 patients (37 women and 88 men) with MI, scheduled for coronary angiography. All patients received clopidogrel and aspirin. A subgroup of patients received glycoprotein (GP) IIb/IIIa-inhibitor. Platelet aggregation in whole blood was assessed at several time points, using impedance aggregometry. Soluble P-selectin was measured 3 days after admission. There were no significant differences between women and men in baseline features or comorbidities except higher frequency of diabetes, lower hemoglobin value, and lower estimated glomerular filtration rate, in women on admission. We observed significantly more in-hospital bleeding events in women compared to men (18.9% vs. 6.8%, p = .04). There were no differences in platelet aggregation using three different agonists, reflecting treatment effect of GPIIb/IIIa-inhibitors, clopidogrel, and aspirin, 6–8 hours, 3 days, 7–9 days, or 6 months after loading dose. Moreover, there was no significant difference in soluble P-selectin. The main finding of this study was a consistent lack of difference between the sexes in platelet aggregation, using three different agonists at several time-points. Our results do not support excess dosing of anti-platelet drugs as a major explanation for increased bleeding risk in women.