Effectiveness and safety of a 1L polyethylene glycol and ascorbic acid preparation for colonoscopy in routine clinical practice in Spain.

BACKGROUND AND AIMS: Large clinical trials and small real-world studies show that a 1L polyethylene glycol and ascorbic acid solution (1L PEG-ASC) is an effective and safe bowel preparation for colonoscopy. Here, the effectiveness and safety of 1L PEG-ASC was evaluated in a large cohort of patients in routine clinical practice in Spain. METHODS: A sub-analysis was performed in an observational, multicenter, retrospective study assessing the effectiveness and safety of 1L PEG-ASC in adult patients undergoing a colonoscopy at 10 centers in Spain. Cleansing quality was assessed with the Boston Bowel Preparation Scale, scores ≥6 with all segmental scores ≥2 was considered adequate colon cleansing, high-quality was considered as cleansing ≥8 or =3 in the right colon. Polyp and adenoma detection rates, and adverse events were also assessed. RESULTS: Data was collected from 7160 patients: 48.3% males; mean age 58.0, 33.6% ≥65 years old. Adequate overall bowel cleansing was achieved in 95.6% of patients (95% CI 95.1%-96.0%), high quality cleansing in 74.4% (95% CI 73.4%-75.4%) and high-quality right colon cleansing in 66.0% (95% CI 64.9-67.1). The adequate overall cleansing rate was 97.0% with a split-dose and 94.0% with same-day regimen (P<0.0001), and high-quality right colon cleansing was 69.0% and 62.5% (P<0.0001), respectively. Colonoscopy was completed in 97.2% of cases. A multivariate regression analysis revealed that an overnight split-dose regimen and age <65 years were independent predictors of adequate bowel cleansing of the overall colon, age <65 years and female gender were independent predictors of HQ cleansing of the overall colon, and the three covariates were independent predictors of HQ cleansing of the right colon. At least one adverse event was experienced by 3.3% of participants, with nausea (1.5%) and vomiting (1.2%) being the most frequent. CONCLUSION: This sub-analysis confirmed 1L PEG-ASC to be an effective and safe bowel cleansing preparation in a real world setting in Spain.

Rapid liver self-recovery: A challenge for rat models of tissue damage.

Animal models, mainly murine, stay as a fundamental resource in diverse research pursuits, notably contributing to significant strides in discovering novel treatments for therapeutic applications. Preclinical assays must consider the existence of self-recovery mechanisms in the murine species to achieve a well-designed control group. This study focuses on unveiling the innate rapid regenerative capacity of rat liver by utilizing the thioacetamide-induced sub-chronic liver injury model. Employing histopathological, biochemical, and molecular liver function tests, we assessed the recovery of liver tissue functionality. Moreover, animals were housed with voluntary running wheels and locomotory activity was recorded and employed as an indirect index of overall animal recuperation. Remarkably, basal locomotory activity reestablished to normal levels only two weeks post-thioacetamide exposure. Our results raise vital considerations about the importance of temporal synchronicity in comparative assays to validate the real action of treatments, emphasizing the role of the rapid rat liver endogenous self-recovery.

Scoring story recall for individual differences research: Central details, peripheral details, and automated scoring.

Story recall is an episodic memory paradigm that is popular among researchers interested in the effects of aging, disease, and/or injury on memory functioning; it is less popular among individual-differences researchers studying neurotypical young adults. One reason differential psychologists may favor other episodic memory paradigms is that the prospect of scoring story recall is daunting, as it typically requires manually scoring hundreds or thousands of freely recalled narratives. In this study, I investigated two questions related to scoring story recall for individual differences research. First, whether there is anything to gain by scoring story recall for memory of central and peripheral details or if a single score is sufficient. Second, I investigated whether scoring can be automated using computational methods - namely, BERTScore and GPT-4. A total of 235 individuals participated in this study. At the latent variable level, central and peripheral factors were highly correlated (r = .99), and the two factors correlated with external factors (viz., fluid intelligence, crystallized intelligence, and working memory capacity) similarly. Regarding automated scoring, both BERTScore and GPT-4 derived scores were strongly correlated with manually derived scores (r ≥ .97); additionally, factors estimated from the various scoring methods all showed a similar pattern of correlations with the external factors. Thus, differential psychologists may be able to streamline scoring by disregarding detail type and by using automated approaches. Further research is needed, particularly of the automated approaches, as both BERTScore and GPT-4 derived scores were occasionally leptokurtic while manual scores were not.

Mechanisms of RNA Polymerase II Termination at the 3'-End of Genes.

RNA polymerase II (RNAPII) is responsible for the synthesis of a diverse set of RNA molecules, including protein-coding messenger RNAs (mRNAs) and many short non-coding RNAs (ncRNAs). For this purpose, RNAPII relies on a multitude of factors that regulate the transcription cycle, from initiation and promoter-proximal pausing, through elongation and finally termination. RNAPII transcription termination at the end of genes ensures the release of RNAPII from the DNA template and its efficient recycling for further rounds of transcription. Termination of RNAPII is tightly coupled to 3'-end mRNA processing, which constitutes an important trigger for the subsequent transcription termination event. In this review, we discuss the current understanding of RNAPII termination mechanisms, focusing on 'canonical' termination at the 3'-end of genes. We also integrate the allosteric and 'torpedo' models into a unified model of termination, and describe the different termination factors that have been identified to date, paying special attention to the human factors and their mechanism of action at the molecular level. Indeed, in recent years the development of novel approaches in structural biology, biochemistry and cell biology have together led to a more detailed comprehension of the different mechanisms of RNAPII termination, and a better understanding of their importance in regulating gene expression, especially under cellular stress and pathological situations.

Electromagnetic Characterization of EAC-1A and JSC-2A Lunar Regolith Simulants.

The development of devices for the in situ resource utilization (ISRU) of lunar surface powder (regolith) by means of microwaves needs regolith simulants with electromagnetic properties similar to the lunar regolith. This document deals with the measurement of complex permittivity and dielectric loss tangent of the aforementioned simulants at ambient temperature from 400 MHz to 20 GHz, performing measurements using two lunar dust simulants, EAC-1A and JSC-2A, resulting, on the one hand, in permittivity values of ε'=-0.0432f+4.0397 for the EAC-1A lunar dust simulant and ε'=-0.0432f+4.0397 for the JSC-2A simulant, and on the other hand, in loss tangent values of tanδe=-0.0015f+0.0659 for the EAC-1A powder and tanδe=-0.0039f+0.1429 for the JSC-2A powder. In addition, further studies are carried out taking into account the humidity of the samples and their densities at room temperature. The obtained results are applicable for comparing the measured values of EAC-1A and JSC-2A between them and with other previously measured simulants and real samples. The measurements are carried out by applying two different nonresonant techniques: Open-Ended Coaxial Probe (OECP) and transmission line. For this purpose, the DAK and EpsiMu commercial kits are used, respectively.

Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins.

Recently, targeted degradation has emerged as a powerful therapeutic modality. Relying on "event-driven" pharmacology, proteolysis targeting chimeras (PROTACs) can degrade targets and are superior to conventional inhibitors against undruggable proteins. Unfortunately, PROTAC discovery is limited by warhead scarcity and laborious optimization campaigns. To address these shortcomings, analogous protein-based heterobifunctional degraders, known as bioPROTACs, have been developed. Compared to small-molecule PROTACs, bioPROTACs have higher success rates and are subject to fewer design constraints. However, the membrane impermeability of proteins severely restricts bioPROTAC deployment as a generalized therapeutic modality. Here, we present an engineered bioPROTAC template able to complex with cationic and ionizable lipids via electrostatic interactions for cytosolic delivery. When delivered by biocompatible lipid nanoparticles, these modified bioPROTACs can rapidly degrade intracellular proteins, exhibiting near-complete elimination (up to 95% clearance) of targets within hours of treatment. Our bioPROTAC format can degrade proteins localized to various subcellular compartments including the mitochondria, nucleus, cytosol, and membrane. Moreover, substrate specificity can be easily reprogrammed, allowing modular design and targeting of clinically-relevant proteins such as Ras, Jnk, and Erk. In summary, this work introduces an inexpensive, flexible, and scalable platform for efficient intracellular degradation of proteins that may elude chemical inhibition.

Annular papulovesicular lesions with a purpuric center in a female inpatient.

Epidermal multinucleated keratinocytes, or epidermal grape cells, in the absence of any viral infection, are an important histological finding and a clue for the diagnosis of dermatoses induced by external irritation or aggression, dermatitis artefacta, and facticial dermatitis. Thermal damage such as cryogenic injury is part of the spectrum of causes to be evoked in case of their presence.

Transcutaneous cervical vagus nerve stimulation enhances second-language vocabulary acquisition while simultaneously mitigating fatigue and promoting focus.

Transcutaneous vagus nerve stimulation (tVNS) is a promising technique for enhancing cognitive performance and skill acquisition. Yet, its efficacy for enhancing learning rate and long-term retention in an ecologically valid learning environment has not been demonstrated. We conducted two double-blind sham-controlled experiments examining the efficacy of auricular tVNS (taVNS: Experiment (1) and cervical tVNS (tcVNS: Experiment (2), on a 5 day second-language vocabulary acquisition protocol among highly selected career linguists at the US Department of Defense's premier language school. tcVNS produced accelerated recall performance during training (Day 2-4), benefits of which were maintained across a 24 h retention interval with no stimulation at the final test. Consistent with prior work, tcVNS also produced fatigue-mitigating and focus-promoting effects as measured by the Air Force Research Laboratory Mood Questionnaire. Based on the current and the previous findings supporting tVNS' efficacy on performance, training enhancement, and fatigue mitigation, we believe tcVNS to be an effective learning acceleration tool that can be utilized at language-teaching and other institutions focused on intensive training of cognitive skills.

Latent Space Representations for Marker-Less Realtime Hand-Eye Calibration.

Marker-less hand-eye calibration permits the acquisition of an accurate transformation between an optical sensor and a robot in unstructured environments. Single monocular cameras, despite their low cost and modest computation requirements, present difficulties for this purpose due to their incomplete correspondence of projected coordinates. In this work, we introduce a hand-eye calibration procedure based on the rotation representations inferred by an augmented autoencoder neural network. Learning-based models that attempt to directly regress the spatial transform of objects such as the links of robotic manipulators perform poorly in the orientation domain, but this can be overcome through the analysis of the latent space vectors constructed in the autoencoding process. This technique is computationally inexpensive and can be run in real time in markedly varied lighting and occlusion conditions. To evaluate the procedure, we use a color-depth camera and perform a registration step between the predicted and the captured point clouds to measure translation and orientation errors and compare the results to a baseline based on traditional checkerboard markers.

A new topical biotechnological phytocomplex for truncal mild-moderate acne restores skin microbiota balance.

BACKGROUND: The disruption of the microbial community or dysbiosis alters the functional composition, metabolic activity, and local distribution of the microbiota leading the development of acne. The aim of this study is to evaluate the effect of a lotion containing a biotechnological phytocomplex, niacinamide, and succinic acid in the bacterial diversity of subjects with truncal mild-moderate acne and its clinical benefits due to microbiota changes. MATERIALS AND METHODS: Open, clinical study in 43 subjects with truncal mild-moderate acne treated with a lotion for 8 weeks. Bacterial diversity was analyzed by 16S rRNA gene sequencing of skin samples. Clinical effects were evaluated through IGA acne severity scale, biometric measurements, and safety. RESULTS: After 56 days of product's use, an increase in richness alpha diversity was found (p = 0.005), with a decrease in Cutibacterium acnes relative abundance (66.43% vs. 58.11%, p = 0.009). The clinical results showed a decrease in IGA score (27.59% decrease; p = 0.001), the inflammatory lesions (52.12% decrease, p = 0.006) and erythema (18.33% decrease, p = 0.007), and desquamation index (63.83% decrease, p = 0.02). The responder analysis of the IGA score showed that 60.47% of patients improved by at least one point at day 56. The product was well tolerated along the study. CONCLUSION: The use of the lotion on acneic skin was effective on rebalancing the microbiota, inhibiting biofilm formation and other virulence factors, reducing erythema and desquamation, and improving acne's severity.

Evaluating the Safety of the Intragastric Balloon: Spanish Multicenter Experience in 20,680 Cases and with 12 Different Balloon Models.

INTRODUCTION: Intragastric balloon (IGB) is a minimally invasive and reversible option for obesity treatment. There is a worldwide growing number of different IGB models. The efficacy and safety profile for each model must be demonstrated. We aim to evaluate IGB safety profile according to the experience of the Spanish Bariatric Endoscopy Group (GETTEMO). METHODS: A survey of 37 IGBs safety-related questions was sent to all GETTEMO members, to retrospectively collect a multicenter Spanish registry. Incidence, causes, and resolution of both major and minor complications and adverse events (AEs), including legal consequences, differentiated for each balloon model were evaluated. Secondary outcome was weight loss data to confirm efficacy. RESULTS: Twenty-one Spanish hospitals experienced in IGBs responded. The overall data encompassed 20,680 IGBs, including 12 different models. Mean %TBWL of 17.66 ± 2.5% was observed. Early removal rate due to intolerance was 3.62%. Mean major complications rate was 0.70% (> 1% in Spatz2, HB, and Spatz3 models), mainly complicated gastric ulcer. Minor AEs rate was 6.37%, mainly esophagitis. Nine cases (0.04%) required surgery. A single case of mortality (0.0048%) occurred. Seven lawsuits (0.0034%) were received, all with favorable resolution. CONCLUSIONS: In the Spanish experience accumulating 20,680 IGBs and including 12 different balloon models, a low incidence rate of major complications and minor AEs are observed (0.70% and 6.37%, respectively), mostly resolved with medical/endoscopic management. IGB shows good tolerance and efficacy profile. These safety data are within the accepted quality standards.

SARS-CoV-2-related bat viruses evade human intrinsic immunity but lack efficient transmission capacity.

Circulating bat coronaviruses represent a pandemic threat. However, our understanding of bat coronavirus pathogenesis and transmission potential is limited by the lack of phenotypically characterized strains. We created molecular clones for the two closest known relatives of SARS-CoV-2, BANAL-52 and BANAL-236. We demonstrated that BANAL-CoVs and SARS-CoV-2 have similar replication kinetics in human bronchial epithelial cells. However, BANAL-CoVs have impaired replication in human nasal epithelial cells and in the upper airway of mice. We also observed reduced pathogenesis in mice and diminished transmission in hamsters. Further, we observed that diverse bat coronaviruses evade interferon and downregulate major histocompatibility complex class I. Collectively, our study demonstrates that despite high genetic similarity across bat coronaviruses, prediction of pandemic potential of a virus necessitates functional characterization. Finally, the restriction of bat coronavirus replication in the upper airway highlights that transmission potential and innate immune restriction can be uncoupled in this high-risk family of emerging viruses.

Exploring structural and computational contrasts in Myoglobins: Implications for thermal treatment-induced Sulfmyoglobin formation.

Greening of tuna metmyoglobin (MetMb) by thermal treatment (TT) and free cysteine is associated with sulfmyoglobin (SulfMb) production. This greening reaction (GR) was once thought to occur only in tuna species. However, recent research has revealed that not all tuna species exhibit this behavior, and it can also occur in horse MetMb. Thus, the present study aimed to compare the GR-reactive (Katsuwonus pelamis and Equus caballus) and GR-unreactive (Sarda chiliensis and Euthynnus lineatus) MetMb using UV-vis spectrometry during TT (60 °C/30 min and free cysteine) to monitor the GR. We used molecular dynamics (MD) simulation to assess the stability of the heme group during TT. We discovered that using GR-unreactive MetMb resulted in an incomplete GR without producing SulfMb. Additionally, our MD simulations indicated that Met85 presence in the heme cavity from GR-unreactive is responsible for the heme group instability and displacement of distal His during TT.

Longitudinal outcome over four decades of allogeneic stem cell transplantation: a single center experience.

This 45-year study (1978-2022) at a single institution evaluated HSCT outcomes and complications, emphasizing recent advances, with to provide insights into HSCT's evolving field and ongoing efforts to enhance patient outcomes. Involving 1707 patients, the study revealed an initial phase (1978-1987) with a limited activity that yielded modest outcomes, a nearly three-decade span (1988-2016) with a substantial increase in transplant activity, emphasizing umbilical cord blood transplantation (UCBT) for patients lacking a suitable matched sibling donor. In addition to a gradual increase in recipient age, significant improvement in outcomes emerged in the recent period (2017-2022), marked by UCBT replacement with haploidentical transplants, introduction of PTCY-based GVHD prophylaxis for all type of transplants, and increased use of conditioning regimens with thiotepa, busulfan, and fludarabine. In this period, reductions in GVHD, non-relapse mortality, and relapse rates significantly contributed to improved overall survival, event-free survival, and GVHD-free/relapse-free survival. The study identified specific factors, including GVHD prophylaxis and donor selection changes, associated with these positive trends. This four-decade study provides a unique perspective on allogeneic HSCT, showcasing the dynamic evolution of transplantation practices and their impact on outcomes, offering valuable insights for personalized treatment approaches and emphasizing continual innovation in this critical therapeutic modality.

The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses.

Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV-related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (Mpro) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.

Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.

Childhood-Onset Non-Infectious Uveitis in the "Biologic Era". Results From Spanish Multicenter Multidisciplinary Real-World Clinical Settings.

OBJECTIVE: To characterize and describe clinical experience with childhood-onset non-infectious uveitis. STUDY DESIGN: A multicenter retrospective multidisciplinary national web-based registry of 507 patients from 21 hospitals was analyzed. Cases were grouped as immune disease-associated (IMDu), idiopathic (IDIu) or ophthalmologically distinct. Characteristics of juvenile idiopathic arthritis-associated (non-HLA-B27-related) uveitis (JIAu), IDIu, and pars planitis (PP) were compared. RESULTS: IMDu (62.3%) and JIAu (51.9%) predominated in young females; and IDIu (22.7%) and PP (13.6%) in older children, without sex imbalance. Ocular complications occurred in 45.3% of cases (posterior synechiae [28%], cataracts [16%], band keratopathy [14%], ocular hypertension [11%] and cystoid macular edema [10%]) and were associated with synthetic (86%) and biologic (65%) disease-modifying antirheumatic drug (DMARD) use. Subgroups were significantly associated (p < 0.05) with different characteristics. JIAu was typically anterior (98%), insidious (75%), in ANA-positive (69%), young females (82%) with fewer complications (31%), better visual outcomes, and later use of uveitis-effective biologics. In contrast, IDIu was characteristically anterior (87%) or panuveitic (12.1%), with acute onset (60%) and more complications at onset (59%: synechiae [31%] and cataracts [9.6%]) and less DMARD use, while PP is intermediate, and was mostly bilateral (72.5%), persistent (86.5%) and chronic (86.8%), with more complications (70%; mainly posterior segment and cataracts at last visit), impaired visual acuity at onset, and greater systemic (81.2%), subtenon (29.1%) and intravitreal (10.1%) steroid use. CONCLUSION: Prognosis of childhood uveitis has improved in the "biologic era," particularly in JIAu. Early referral and DMARD therapy may reduce steroid use and improve outcomes, especially in PP and IDIu.

Enhancing reclaimed water distribution network resilience with cost-effective meshing.

Water Distribution Networks (WDNs) are critical infrastructures that ensure a continuous supply of safe water to homes. In the face of challenges, like water scarcity, establishing resilient networks is imperative, especially in regions vulnerable to water crises. This study evaluates the resilience of network designs through graph theory, including its hydraulic feasibility using EPANET software, an aspect often overlooked. Novel mathematical algorithms, including Resilience by Design (RbD) and Resilience-strengthening (RS) algorithms, provide cost-effective and resilient network designs, even with budget constraints. A novel metric, Water Availability (WA), is introduced to offer a comprehensive measure of network resilience, thereby addressing ongoing discrepancies in resilience evaluation methods. Practical benefits are illustrated through a case study in which a resilient-by-design reclaimed water network is created, and an existing equivalent non-resilient network is improved. The resilient-by-design network demonstrates remarkably better results compared to the equivalent non-resilient design, including up to a 36 % reduction in the probability of service disruptions and a nearly 65 % decrease in the annual average unserved water due to service disruptions. These findings underscore the enormous advantages of a resilience-focused network design approach. When compared to the equivalent non-resilient design, the resilient-by-design network generated effectively safeguards up to a significant 91,700m3 of water from the impacts of water disruption events over a 50-year operational period. In addition, the resilient-by-design WDN solution incurs a subtle decrease in overall costs compared to consuming tap water from the drinking WDN baseline over a 50-year operational period. These findings highlight the cost-effectiveness of the approach, even offering financial benefits. This paper builds on our previous research by expanding its scope to include resilience considerations, providing algorithms that can be easily adapted from reclaimed to drinking WDNs. Ultimately, we contribute to the enhancement of water resource management and infrastructure planning in ever-evolving urban environments.