Fragility of overactive bladder medication clinical trials: A systematic review.

PURPOSE: Overactive bladder (OAB) syndrome significantly impairs quality of life, often necessitating pharmacological interventions with associated risks. The fragility of OAB trial outcomes, as measured by the fragility index (FI: smallest number of event changes to reverse statistical significance) and quotient (FQ: FI divided by total sample size expressed as a percentage), is critical yet unstudied. MATERIALS AND METHODS: We conducted a systematic search for randomized controlled trials on OAB medications published between January 2000 and August 2023. Inclusion criteria were trials with two parallel arms reporting binary outcomes related to OAB medications. We extracted trial details, outcomes, and statistical tests employed. We calculated FI and FQ, analyzing associations with trial characteristics through linear regression. RESULTS: We included 57 trials with a median sample size of 211 participants and a 12% median lost to follow-up. Most studies investigated anticholinergics (37/57, 65%). The median FI/FQ was 5/3.5%. Larger trials were less fragile (median FI 8; FQ 1.0%) compared to medium (FI: 4; FQ 2.5%) and small trials (FI: 4; FQ 8.3%). Double-blinded studies exhibited higher FQs (median 2.9%) than unblinded trials (6.7%). Primary and secondary outcomes had higher FIs (median 5 and 6, respectively) than adverse events (FI: 4). Each increase in 10 participants was associated with a +0.19 increase in FI (p < 0.001). CONCLUSIONS: A change in outcome for a median of five participants, or 3.5% of the total sample size, could reverse the direction of statistical significance in OAB trials. Studies with larger sample sizes and efficacy outcomes from blinded trials were less fragile.

Evaluation of a catch-up strategy for the vaccination in patients with hepatitis C virus.

Vaccination in patients with advanced chronic liver disease (ACLD) is an essential part of their comprehensive healthcare. These individuals may have impaired phagocytic function and diminished production of opsonizing antibodies, resulting in increased susceptibility to bacterial infections, particularly pneumococcal pneumonia. Similarly, there is an increased risk of fulminant hepatitis due to hepatitis A and B viruses. The Ministry of Health updated specific vaccination recommendations for this group in 2018.

Dental anxiety and oral health-related quality of life before and after non-surgical periodontal treatment.

OBJECTIVES: To (1) investigate dental anxiety (DA) and oral health-related quality of life (OHRQOL) before and after non-surgical periodontal treatment (NSPT) and (2) determine correlations between these patient-reported measures. MATERIALS AND METHODS: Demographics, smoking habits, dental pain, Modified Corah's Dental Anxiety Scale (MDAS), and Oral Health Impact Profile (OHIP-14) were assessed in eighty-two participants. RESULTS: Mean age was 48.3 years ± 11.5. At baseline, 8.5% reported being active smokers. Of non-smokers, 11% reported being an ex-smoker. After NSPT, 11.0% reported smoking. Patients' maximal pain in the last month decreased after therapy. Before treatment, participants reported higher DA. Extreme DA was observed in 8.5% of participants before therapy. Afterwards, 2.4% of participants reported extreme DA. Fear of having a foreign object in the mouth decreased after NSPT. All OHIP-14 scores, except functional limitation, improved post-treatment. Higher DA was associated with worse OHRQoL before treatment. After treatment, total MDAS score was associated with OHIP-14 global score, physical pain, psychological disability, and social disability. Worse MDAS sub-scores were associated with a higher OHIP-14 global score. Individuals with "normal/slight anxiety" had a significant improvement in OHRQoL, whereas people in the "moderate and extreme anxiety" group did not report a significant improvement. Patients diagnosed with generalized periodontitis (GP) stage III grade B and GP stage IV grade B reported less anxiety after NSPT. CONCLUSIONS: Associations of MDAS subcategories with OHIP-14 domain scores were found before and after therapy. DA decreases and OHRQoL enhances after NSPT in patients with "normal/slight" anxiety to dental treatment. Dental practitioners should plan strategies to cope with anxiety to dental treatment and prevent decreases in OHRQoL. CLINICAL RELEVANCE: Within the limitations of this study, DA and OHRQoL were positively correlated in patients with periodontitis, before and after NSPT, using the MDAS and OHIP-14 questionnaires. The results of our study suggest that treatment is effective in terms of alleviating DA and improving oral health, along with quality of life, in patients that report "normal/slight" anxiety to dental treatment. Nonetheless, results must be interpreted with caution since patients are generally anxious before any type of dental treatment. DA may not just be confined to NSPT per se. According to our results, evaluation of both outcomes should be an integral part of routine periodontal clinical evaluation and periodontal reevaluation of initial therapy. It is important that clinicians learn to identify patients that suffer from anxiety and take time to explain the treatment procedures to the patient, to strive for patient's emotional well-being before, during, and after dental care services. The use of specific questionnaires for both DA and OHRQoL may be more appropriate to demonstrate the psychological and quality of life differences due to periodontal disease and NSPT.

Upper gastrointestinal bleeding and Rigler triad.

Gallstone ileus is a rare complication of cholelithiasis, characterized by mechanical bowel obstruction due to a biliary calculus originating from a bilioenteric fistula. The Rigler triad, consisting of aerobilia, ectopic gallstone, and intestinal obstruction, is rarely observed in its complete form. We present the case of a 92-year-old male with a history of acute lithiasic cholecystitis who presented to the Emergency department with acute epigastric pain. Initial evaluation revealed gallbladder dilatation, gallstones, and gallbladder wall thickening suggestive of acute cholecystitis. During hospitalization, the patient experienced an episode of hematemesis, leading to the diagnosis of a cholecystoduodenal fistula and a large blood clot in the duodenal bulb. Further imaging showed an ectopic gallstone causing small bowel obstruction. The patient underwent urgent surgery for stone extraction, followed by endoscopic intervention for the bleeding vessel identified at a subsequent gastroscopy. Unfortunately, the patient had a poor postoperative course and passed away seven days later. This case report highlights the exceptional occurrence of both the Rigler triad and upper gastrointestinal bleeding in a patient with gallstone ileus. Surgical intervention is crucial for the initial resolution of intestinal obstruction, followed by cholecystectomy and repair of the bilioenteric fistula. Awareness of these rare presentations is important for timely diagnosis and appropriate management of this uncommon complication of cholelithiasis.

Hydration in Deep Eutectic Solvents Induces Non-monotonic Changes in the Conformation and Stability of Proteins.

The preservation of labile biomolecules presents a major challenge in chemistry, and deep eutectic solvents (DESs) have emerged as suitable environments for this purpose. However, how the hydration of DESs impacts the behavior of proteins is often neglected. Here, we demonstrate that the amino acid environment and secondary structure of two proteins (bovine serum albumin and lysozyme) and an antibody (immunoglobulin G) in 1:2 choline chloride:glycerol and 1:2 choline chloride:urea follow a re-entrant behavior with solvent hydration. A dome-shaped transition is observed with a folded or partially folded structure at very low (<10 wt % H2O) and high (>40 wt % H2O) DES hydration, while protein unfolding increases between those regimes. Hydration also affects protein conformation and stability, as demonstrated for bovine serum albumin in hydrated 1:2 choline chloride:glycerol. In the neat DES, bovine serum albumin remains partially folded and unexpectedly undergoes unfolding and oligomerization at low water content. At intermediate hydration, the protein begins to refold and gradually retrieves the native monomer-dimer equilibrium. However, ca. 36 wt % H2O is required to recover the native folding fully. The half-denaturation temperature of the protein increases with decreasing hydration, but even the dilute DESs significantly enhance the thermal stability of bovine serum albumin. Also, protein unfolding can be reversed by rehydrating the sample to the high hydration regime, also recovering protein function. This correlation provides a new perspective to understanding protein behavior in hydrated DESs, where quantifying the DES hydration becomes imperative to identifying the folding and stability of proteins.

Topological Dynamics of Micelles Formed by Geometrically Varied Surfactants.

The molecular architecture of sugar-based surfactants strongly affects their self-assembled structure, i.e., the type of micelles they form, which in turn controls both the dynamics and rheological properties of the system. Here, we report the segmental and mesoscopic structure and dynamics of a series of C16 maltosides with differences in the anomeric configuration and degree of tail unsaturation. Neutron spin-echo measurements showed that the segmental dynamics can be modeled as a one-dimensional array of segments where the dynamics increase with inefficient monomer packing. The network dynamics as characterized by dynamic light scattering show different relaxation modes that can be associated with the micelle structure. Hindered dynamics are observed for arrested networks of worm-like micelles, connected to their shear-thinning rheology, while nonentangled diffusing rods relate to Newtonian rheological behavior. While the design of novel surfactants with controlled properties poses a challenge for synthetic chemistry, we demonstrate how simple variations in the monomer structure can significantly influence the behavior of surfactants.

Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models.

Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24-72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.

Large bowel obstruction secondary to a simple renal cyst: an exceptional complication.

We report the case of an 81-year-old female with large bowel obstruction secondary to a giant simple renal cyst (16 cm), which was producing a compression of the descending colon against the abdominal wall. Percutaneous drainage of the renal cyst was performed by a urologist. The follow-up CT scan revealed a collapsed cyst with resolution of the bowel obstruction. The patient showed resolution of the symptoms with an improvement in blood test results.

McKittrick-Wheelock syndrome: rectal villous adenoma as a cause of acute renal failure.

We report the case of a 67-year-old male with a history of arterial hypertension and atrial fibrillation, who was admitted for acute renal failure (creatinine: 4.41 mg/dl) and hypotension. He also presented hyponatremia (129 mmol/L) and hypokalemia (2.7 mmol/L). The patient referred profuse diarrhea during the previous two months as a possible triggering cause. Physical examination showed signs of dehydration and palpation of a polypoid mass in the rectal ampulla.

Long-Range Electrostatic Colloidal Interactions and Specific Ion Effects in Deep Eutectic Solvents.

While the traditional consensus dictates that high ion concentrations lead to negligible long-range electrostatic interactions, we demonstrate that electrostatic correlations prevail in deep eutectic solvents where intrinsic ion concentrations often surpass 2.5 M. Here we present an investigation of intermicellar interactions in 1:2 choline chloride:glycerol and 1:2 choline bromide:glycerol using small-angle neutron scattering. Our results show that long-range electrostatic repulsions between charged colloidal particles occur in these solvents. Interestingly, micelle morphology and electrostatic interactions are modulated by specific counterion condensation at the micelle interface despite the exceedingly high concentration of the native halide from the solvent. This modulation follows the trends described by the Hofmeister series for specific ion effects. The results are rationalized in terms of predominant ion-ion correlations, which explain the reduction in the effective ionic strength of the continuum and the observed specific ion effects.

Introducing ATR-FTIR Spectroscopy through Analysis of Acetaminophen Drugs: Practical Lessons for Interdisciplinary and Progressive Learning for Undergraduate Students.

Infrared (IR) spectroscopy is a vibrational spectroscopic technique useful in chemical, pharmaceutical, and forensic sciences. It is essential to identify chemicals for reasons spanning from scientific research and academic practices to quality control in companies. However, in some university degrees, graduate students do not get the proficiency to optimize the experimental parameters to obtain the best IR spectra; to correlate the IR spectral bands with the molecular vibrations (chemical elucidation); to have some criteria for any substance identification (especially relevant in quality control to recognize counterfeit); and to apply chemometrics for comparing, visualizing, and classifying the IR spectra. This work presents an experimental laboratory practice for an introductory teaching of the IR instrumental conditions in the identification of substances based on visual spectra comparison and statistical analysis and matching. Then, the selected IR conditions are applied to different commercial drugs, in the solid state or in solution, mostly composed of acetaminophen. Finally, the students apply chemometrics analysis to the IR data. This practice was designed for the training in a chemistry subject for undergraduate students of the chemistry, pharmacy, or forensics degrees, among others related to science, medical, food, or technological sciences.

[18F]-FMISO PET/MRI Imaging Shows Ischemic Tissue around Hematoma in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH), being the most severe cerebrovascular disease, accounts for 10-15% of all strokes. Hematoma expansion is one of the most important factors associated with poor outcome in intracerebral hemorrhage (ICH). Several studies have suggested that an "ischemic penumbra" might arise when the hematoma has a large expansion, but clinical studies are inconclusive. We performed a preclinical study to demonstrate the presence of hypoxic-ischemic tissue around the hematoma by means of longitudinal [18F]-fluoromisonidazole ([18F]-FMISO) PET/MRI studies over time in an experimental ICH model. Our results showed that all [18F]-FMISO PET/MRI images exhibited hypoxic-ischemic tissue around the hematoma area. A significant increase of [18F]-FMISO uptake was found at 18-24 h post-ICH when the maximum of hematoma volume is achieved and this increase disappeared before 42 h. These results demonstrate the presence of hypoxic tissue around the hematoma and open the possibility of new therapies aimed to reduce ischemic damage associated with ICH.

Effect of the Anomeric Configuration on the Micellization of Hexadecylmaltoside Surfactants.

The self-assembly of the two anomeric forms of n-hexadecyl-d-maltopyranoside (denoted α-C16G2 and ß-C16G2) has been studied in dilute aqueous solution by means of surface tension measurements, scattering methods (dynamic light scattering, static light scattering, and small-angle X-ray and neutron scattering), and cryo-transmission electron microscopy at different surfactant concentrations and temperatures. Surface tension measurements demonstrate differences in the surfactant adsorption at the air-water interface, where α-C16G2 shows a lower CMC than ß-C16G2. Similarly, micelle morphology was found to profoundly depend on anomerism. ß-C16G2 preferentially forms very elongated micelles with large persistence lengths, whereas α-C16G2 assembles into smaller micelles for which the structure varies with concentration and temperature. The differences between the two surfactant anomers in terms of self-assembly can be attributed to the interaction between neighboring headgroups. Specifically, ß-C16G2 allows for a closer packing in the palisade layer, hence reducing the micelle curvature and promoting the formation of more elongated micelles. Strong intermolecular headgroup interactions may also account for the observed rigidity of the micelles.

The effectiveness of vaccination to prevent the papillomavirus infection: a systematic review and meta-analysis.

Our purpose was to determine the effectiveness and harms of vaccination in patients with any sexual history to prevent the prevalence of papillomavirus infection. A search strategy was conducted in the MEDLINE, CENTRAL, EMBASE and LILACS databases. Searches were also conducted in other databases and unpublished literature. The risk of bias was evaluated with the Cochrane Collaboration's tool. Analysis of fixed effects was conducted. The primary outcome was the infection by any and each human papillomavirus (HPV) genotype, serious adverse effects and short-term adverse effects. The measure of the effect was the risk difference (RD) with a 95% confidence interval (CI). The planned interventions were bivalent vaccine/tetravalent/nonavalent vs. placebo/no intervention/other vaccines. We included 29 studies described in 35 publications. Bivalent HPV vaccine offers protection against HPV16 (RD -0.05, 95% CI -0.098 to -0.0032), HPV18 (RD -0.03, 95% CI -0.062 to -0.0004) and HPV16/18 genotypes (RD of -0.1, 95% CI -0.16 to -0.04). On the other side, tetravalent HPV vaccine offered protection against HPV6 (RD of -0.0500, 95% CI -0.0963 to -0.0230), HPV11 (RD -0.0198, 95% CI -0.0310 to -0.0085). Also, against HPV16 (RD of -0.0608, 95% CI -0.1126 to -0.0091) and HPV18 (RD of -0.0200, 95% CI -0.0408 to -0.0123). There was a reduction in the prevalence of HPV16, 18 and 16/18 genotypes when applying the bivalent vaccine, with no increase in adverse effects. Regarding the tetravalent vaccine, we found a reduction in the prevalence of HPV6, 11, 16 and 18 genotypes, with no increase in adverse effects.

Bayesian determination of the effect of a deep eutectic solvent on the structure of lipid monolayers.

In this work, we present the first example of the self-assembly of phospholipid monolayers at the interface between air and an ionic solvent. Deep eutectic solvents are a novel class of environmentally friendly, non-aqueous, room temperature liquids with tunable properties, that have wide-ranging potential applications and are capable of promoting the self-assembly of surfactant molecules. We use a chemically-consistent Bayesian modelling of X-ray and neutron reflectometry measurements to show that these monolayers broadly behave as they do on water. This method allows for the monolayer structure to be determined, alongside the molecular volumes of the individual monolayer components, without the need for water-specific constraints to be introduced. Furthermore, using this method we are able to better understand the correlations present between parameters in the analytical model. This example of a non-aqueous phospholipid monolayer has important implications for the potential uses of these solvents and for our understanding of how biomolecules behave in the absence of water.

Freeze-Damage Detection in Lemons Using Electrochemical Impedance Spectroscopy.

Lemon is the most sensitive citrus fruit to cold. Therefore, it is of capital importance to detect and avoid temperatures that could damage the fruit both when it is still in the tree and in its subsequent commercialization. In order to rapidly identify frost damage in this fruit, a system based on the electrochemical impedance spectroscopy technique (EIS) was used. This system consists of a signal generator device associated with a personal computer (PC) to control the system and a double-needle stainless steel electrode. Tests with a set of fruits both natural and subsequently frozen-thawed allowed us to differentiate the behavior of the impedance value depending on whether the sample had been previously frozen or not by means of a single principal components analysis (PCA) and a partial least squares discriminant analysis (PLS-DA). Artificial neural networks (ANNs) were used to generate a prediction model able to identify the damaged fruits just 24 hours after the cold phenomenon occurred, with sufficient robustness and reliability (CCR = 100%).

Vision-Based Multirotor Following Using Synthetic Learning Techniques.

Deep- and reinforcement-learning techniques have increasingly required large sets of real data to achieve stable convergence and generalization, in the context of image-recognition, object-detection or motion-control strategies. On this subject, the research community lacks robust approaches to overcome unavailable real-world extensive data by means of realistic synthetic-information and domain-adaptation techniques. In this work, synthetic-learning strategies have been used for the vision-based autonomous following of a noncooperative multirotor. The complete maneuver was learned with synthetic images and high-dimensional low-level continuous robot states, with deep- and reinforcement-learning techniques for object detection and motion control, respectively. A novel motion-control strategy for object following is introduced where the camera gimbal movement is coupled with the multirotor motion during the multirotor following. Results confirm that our present framework can be used to deploy a vision-based task in real flight using synthetic data. It was extensively validated in both simulated and real-flight scenarios, providing proper results (following a multirotor up to 1.3 m/s in simulation and 0.3 m/s in real flights).

Pilot Study of the Safety and Efficacy of Gallbladder Cryoablation in a Porcine Model: Midterm Results.

PURPOSE: To investigate the midterm safety and efficacy of computed tomography (CT)-guided percutaneous gallbladder cryoablation in swine. MATERIALS AND METHODS: Three swine underwent gallbladder cryoablation. Cryoprobes were positioned percutaneously at the gallbladder margins or within the gallbladder lumen under CT guidance. Two freeze/thaw cycles were performed. One animal was euthanized on postprocedure day 4 as a result of hematemesis unrelated to the ablation. The other 2 animals were euthanized at postprocedure days 30 and 48, respectively. The gallbladder and bile ducts were resected and examined microscopically. RESULTS: Gallbladder cryoablation was completed with freeze/thaw cycle durations of 7.5-10 minutes (mean, 9.4 min ± 1.3) and ablation margins of 5.8-11.5 mm (mean, 7.8 mm ± 1.9). No nontarget ablation was observed. Laboratory values at postprocedure day 4 and the time of euthanasia were within normal limits. Two of 3 animals thrived and exhibited appropriate activity and weight gain. Contrast-enhanced CT immediately before euthanasia demonstrated delayed linear enhancement of the gallbladder wall. Gross inspection at autopsy revealed fibrotic-appearing gallbladders. Cholecystography revealed no communication to the biliary tree. Histologic examination demonstrated complete gallbladder wall fibrosis. Autopsy of the animal euthanized on day 4 revealed a gastric mucosal ulcer distant from the ablation site with no gastric serosal injury. CONCLUSIONS: Gallbladder cryoablation is a promising alternative to surgical cholecystectomy, with complete transmural gallbladder wall fibrosis and cystic duct occlusion seen at 30 and 48 days in swine. Further studies are required to establish procedural safety and long-term efficacy.

Surfactant-Solvent Interaction Effects on the Micellization of Cationic Surfactants in a Carboxylic Acid-Based Deep Eutectic Solvent.

Deep eutectic solvents have been demonstrated to support amphiphile self-assembly, providing potential alternatives as structure-directing agents in the synthesis of nanostructures, and drug delivery. Here we have expanded on this recent research to investigate the self-assembly of alkyltrimethylammonium bromide surfactants in choline chloride:malonic acid deep eutectic solvent and mixtures of the solvent with water. Surface tension and small-angle neutron scattering were used to determine the behavior of the amphiphiles. Surfactants were found to remain active in the solvent, and surface tension measurements revealed changes in the behavior of the surfactants with different levels of hydration. Small-angle neutron scattering shows that in this solvent the micelle shape depends on the surfactant chain length, varying from globular micelles (aspect ratio ∼2) for short chain surfactants to elongated micelles (aspect ratio ∼14) for long chain surfactants even at low surfactant concentration. We suggest that the formation of elongated micelles can be explained through the interaction of the solvent with the surfactant headgroup, since ion-ion interactions between surfactant headgroups and solvent may modify the morphology of the micelles. The presence of water in the deep eutectic solvents promotes an increase in the charge density at the micelle interface and therefore the formation of less elongated, globular micelles.