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BackgroundThe International Myeloma Working Group recommends the use of 18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for treatment response evaluation, as it is superior to magnetic resonance imaging (MRI). However, at initial staging, the sensitivity of FDG-PET remains inferior to that of MRI. Therefore, there is a need for an imaging technique that could have a sensitivity equal to that of MRI at diagnosis and could serve to evaluate therapy. 18F-choline has shown increased sensitivity when compared with 18-FDG, with about 75% more lesions detected in patients with relapsed or progressive multiple myeloma (MM). ObjectiveOur primary objective is to prospectively compare the detection rate of bone lesions by 18F-choline PET/CT (FCH-PET) and FDG-PET in newly diagnosed MM. Our secondary objectives are to assess the accuracy of both PET modalities for the detection of bone lesions and the diagnosis of diffuse disease, to assess the detection rate of extramedullary lesions. MethodsWe will prospectively include 30 patients in a paired comparative accuracy study. Patients with de novo MM will undergo FCH-PET, FDG-PET, and whole-body MRI (WB-MRI) within a 3-week period. WB-MRI will be composed of conventional sequences on the spine and pelvis and of whole-body diffusion axial sequences. The following 6 skeletal areas will be defined: skull, sternum/costal grid, spine, pelvis, superior limbs, and inferior limbs. The number of focal lesions, their respective localization, and intensity of uptake will be retrieved for each skeletal area. Readings will be performed blinded from other imaging techniques. The reference standard will be WB-MRI. Focal lesions present on PET/CT but not on WB-MRI will require a decision made with a consensus of experts based on clinical and imaging data. The number of bone lesions and number of extramedullary lesions will be compared using the Wilcoxon test. The accuracy of FCH-PET and FDG-PET will be compared using the McNemar test. ResultsThe study started in September 2019, and enrollment is ongoing. As of June 2020, 8 participants have been included. Data collection is expected to be completed in June 2021, and the results are expected to be available in December 2021. ConclusionsThis study will assess if FCH-PET is superior to FDG-PET for the evaluation of MM tumor burden. This will pave the way for future prospective evaluations of the prognostic value of 18-FCH for treatment response evaluation in MM patients. Additionally, this work may provide new perspectives for better assessment of the risk of smoldering MM progressing to MM. Trial RegistrationClinicalTrials.gov NCT03891914; https://clinicaltrials.gov/ct2/show/NCT03891914 International Registered Report Identifier (IRRID)DERR1-10.2196/17850

Phylogenetic analyses showed that the virus responsible for a May 2024 Oropouche fever outbreak in Cuba was closely related to viruses from Brazil in 2023. Pools of Ceratopogonidae spp. biting midges and Culex quinquefasciatus mosquitoes were positive for Oropouche viral RNA. No cases were severe. Virus extension to new areas may increase case numbers and severity.

Abstract To investigate the effect of physical activity (PA) (both general and its type) on self-esteem during and after cancer treatment. A systematic search was conducted across PubMed, Web of Science, Scopus, SPORTDiscuss, and PsycINFO from their inception to February 2024. The systematic review included 32 studies, with 15 studies (13 RCT and 2 quasi-experimental) and 3604 participants (66.7% female) included in the meta-analysis involving controlled trials using a control group and at least one PA intervention group. The study was registered in PROSPERO (CRD42022309771). Risk of bias for RCTs was assessed using the Cochrane Collaboration’s tool for assessing risk of bias (RoB2), and quasi-experimental studies with the Joanna Briggs Institute critical appraisal tool. PA significantly improved self-esteem during and after cancer treatment (pooled SMD = 0.32, p

Abstract Reliable description of stacking interaction of aromatic molecules is important for the understanding structure, stability, and functions of biopolymers. The caffeine molecule is an ideal object for this study as the stacking interactions are the preferential ones for self-associations of this hydrophobic molecule without H-bond donor groups. The analysis of anhydrous caffeine crystal structures revealed five types of caffeine stacking dimers. Geometry optimization of these dimers was performed using two molecular mechanics force fields, ab-initio method Møller Plesset of the second order (MP2), and density functional theory (DFT) with different functionals. The comparison of geometric parameters of the caffeine dimers obtained using different theoretical methods with those in crystals enables us to suggest the methods providing the most reliable stacking characteristics. These methods are: the MP2 with Basis Set Superposition Error correction (MP2/CP), Poltev force field, along with PBE0-DH, SCAN and PBE-D3 functionals of DFT. For the methods, which give the dimer interaction energy close to that obtained by MP2/CP method, the evaluated sublimation enthalpy values are shown to be close to the experimental data. Additionally, MP2/CP, Poltev FF and PBE0-DH functional showed to be the methods that describe well both the energy and geometry of the caffeine stacking dimer.

Abstract This study is an investigation of the impact of volatile phenols (VPs) released from burning wood during wildfires on grape composition and the resulting wines. Baseline levels of VPs in grapes and sensory differences between smoke-impacted wines and non-smoke-impacted wines were determined. The differences were related to different levels of smoke taint marker compounds in different wine matrices, using modified descriptive analysis (DA), multivariate statistics, gas chromatography mass spectrometry (GC-MS) and liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS) of the free and total VPs, and individual bound glycosides, respectively. Across two DA panels, Cabernet Sauvignon, Cabernet Franc, Petite Verdot, Merlot, Syrah, Malbec, and Zinfandel wines made from grape originating from different areas in California were evaluated. The results show sensory differences between highly smoke-impacted and non-impacted wines with wines made from highly smoke-impacted grapes characterized as smoky, barbeque, medicinal, and having a retro-nasal ashtray character. Low smoke-impact wines based on free and total VP concentrations were not significantly different from the non-impacted wines when rated through descriptive analysis. The amount of smoke exposure was the largest contributor to smoke impact determined by sensory evaluation, but the different wine matrices from different locations and varietals also played an important role in determining the level of perceived smoke impact. The results of this study will contribute to our understanding of smoke impact and how it influences wine characteristics by relating smoke marker indicator compounds to wine sensory attributes.

Abstract Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway.

Abstract In this work, we design and implement a new bifocal diffractive spiral lens within an optical tweezers system. The proposed diffractive optical element coined Kolokaski Kinoform Spiral Lens (KKSL), generates twin optical vortices along the propagation direction. The axial positions, as well as the diameters of the generated vortex beams, are correlated with the Kolakoski aperiodic sequence introduced in the design of the diffractive lens. The unique properties of KKSLs make it ideal for optical trapping applications, allowing independent multiple trapping and particle displacement within each optical vortex beam. We present both the focusing properties of KKSL and the experimental results of its integration into the optical tweezer setup.

Abstract Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/ ) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.

In early 2024, explosive outbreaks of Oropouche virus (OROV) linked to a novel lineage were documented in the Amazon Region of Brazil. We report the introduction of this lineage into Colombia and its co-circulation with another OROV lineage. Continued surveillance is needed to prevent further spread of OROV in the Americas.

Highly pathogenic avian influenza A(H5N1) detected in dairy cows raises concerns about milk safety. The effects of pasteurization-like temperatures on influenza viruses in retail and unpasteurized milk revealed virus resilience under certain conditions. Although pasteurization contributes to viral inactivation, influenza A virus, regardless of strain, displayed remarkable stability in pasteurized milk.

Abstract Remote sensing technologies have the potential to support monitoring of floating plastic litter in aquatic environments. An experimental campaign was carried out in a large-scale hydrodynamic test facility to explore the detectability of floating plastics in ocean waves, comparing and contrasting different microwave and optical remote sensing technologies. The extensive experiments revealed that detection of plastics was feasible with microwave measurement techniques using X and Ku-bands with VV polarization at a plastic threshold concentration of 1 item/m2 or 1–10 g/m2. The optical measurements further revealed that spectral and polarization properties in the visible and infrared spectrum had diagnostic information unique to the floating plastics. This assessment presents a crucial step towards enabling the detection of aquatic plastics using advanced remote sensing technologies. We demonstrate that remote sensing has the potential for global targeting of plastic litter hotspots, which is needed for supporting effective clean-up efforts and scientific evidence-based policy making.

Abstract Pesticide use is crucial in global agriculture to control pests and increase crop yields. In Ecuador, the use of pesticides, including fungicides and insecticides, is common in crops such as potatoes and tomatoes. However, the indiscriminate use of these products has proven to have negative consequences for human health and the environment. This study investigates these risks in Ecuadorian agriculture, specifically in the Paute canton, where inadequate data exacerbates these issues. Employing a descriptive research design, data were collected through validated surveys administered to 30 farmers (9 women and 21 men) residing in various rural communities. The study also included observational methods to complement survey data. Findings reveal that farmer, predominantly with primary education, face health risks from inappropriate pesticide use. Symptoms reported include eye irritation, headaches, and nasal irritation, which vary based on education level and safety practices. The research highlights the urgent need for improved pesticide management through targeted training and sustainable practices. This study’s insights into the extent of health issues and variability in safety measures provide a basis for developing effective interventions to mitigate the health and environmental impacts of pesticide use in Paute and similar regions.

Abstract Illness perceptions (IPs) encompass opinions regarding the nature, severity and curability of a disease. The aim of this cross-sectional study was to investigate the association between alexithymia and IPs among persons with multiple sclerosis (PwMS) and their partners, as well as within the dyads composed of PwMS and partners. PwMS referred to the Multiple Sclerosis Center of the University Hospital “Policlinico-San Marco” from 11th August 2021 to 7th January 2022 and their partners completed a battery of questionnaires, including the Toronto Alexithymia Scale-20 and the Illness Perception Questionnaire Revised. A dyadic data analysis (Actor-Partner Interdependence Model) was performed to test the effect of alexithymic traits both on a person’s own illness perceptions (actor effect) and on the partner’s illness perceptions (partner effect). 100 PwMS (71 women; mean age 47.6 ± 10.4 years) and 100 partners (29 women; mean age 49.1 ± 10.8 years), with a mean partnership duration of 20.1 ± 11.7 years, were enrolled. At the dyadic analysis, statistically significant small-to-moderate actor and partner effects were found considering alexithymia (total score and alexithymic facets) and IPs, whereby higher alexithymic traits related to higher negative perceptions (i.e. consequences, emotional representations) and lower positive ones (i.e. coherence, treatment control). Our findings support the relationship between alexithymia and negative illness appraisals. This data may inform therapeutic interventions aimed at reducing alexithymic traits, which in turn may reduce negative, and potentially dysfunctional, illness perceptions.

Abstract Graphene quantum dots (GQDs) have garnered significant attention across numerous fields due to their ultrasmall size and exceptional properties. However, their extensive applications may lead to environmental exposure and subsequent uptake by humans. Yet, conflicting reports exist regarding the potential toxicity of GQDs based on experimental investigations. Therefore, a comprehensive understanding of GQD biosafety requires further microscopic and molecular-level investigations. In this study, we employed molecular dynamics (MD) simulations to explore the interactions between GQDs and graphene oxide quantum dots (GOQDs) with a protein model, the human intestinal fatty acid binding protein (HIFABP), that plays a crucial role in mediating the carrier of fatty acids in the intestine. Our MD simulation results reveal that GQDs can be adsorbed on the opening of HIFABP, which serves as an entrance for the fatty acid molecules into the protein’s interior cavity. This adsorption has the potential to obstruct the opening of HIFABP, leading to the loss of its normal biological function and ultimately resulting in toxicity. The adsorption of GQDs is driven by a combination of van der Waals (vdW), π-π stacking, cation-π, and hydrophobic interactions. Similarly, GOQDs also exhibit the ability to block the opening of HIFABP, thereby potentially causing toxicity. The blockage of GOQDs to HIFABP is guided by a combination of vdW, Coulomb, π-π stacking, and hydrophobic interactions. These findings not only highlight the potential harmful effects of GQDs on HIFABP but also elucidate the underlying molecular mechanism, which provides crucial insights into GQD toxicology.

Abstract As clinical trials for psychedelics move into phase III in the USA, Europe must address its lag in integrating professional education around psychedelic-assisted therapy (PAT) and supporting psychedelic drug research. This paper evaluates the necessary frameworks for implementing PAT in Germany, emphasizing the nation’s potential leadership role within the European Union. With Australia having already approved MDMA and psilocybin for mental health indications, the Ukrainian government exploring MDMA treatment for war-related PTSD, and initial clinical trials involving MDMA and LSD with patients in Switzerland which restarted the restricted medical use of these substances around 2014, the medical authorization of psychedelics in these countries establishes precedent showcasing both the promise and challenges of researching and implementing PAT in nations where the substances were formally scheduled as illicit substances. Key challenges include establishing rigorous standards for practitioner training, accessibility, and defining regulatory oversight. This paper focuses on the development of robust infrastructure in Germany, which will support the roll out of PAT, and details ethical considerations, training protocols, and governmental roles in the formulation of treatment frameworks. This approach aims not only to guide Germany in adopting PAT but also to influence broader European policy, ensuring that patients receive ethically sound and proficient care. The findings suggest pathways for Europe to reclaim its historical lead in psychiatric and therapeutic innovation.

Abstract In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiological responses to stress and fear conditioning. These differences may be attributable to variations in hormone levels, brain structure, and neural circuitry, particularly in regions such as the prefrontal cortex (PFC). In the present study, we explored sex differences in prelimbic cortex (PL) calcium activity in animals submitted to immobilization stress (IMO), fear conditioning (FC), and fear extinction (FE). While no significant sex differences were found in behavioral responses, we did observe differences in several PL calcium activity parameters. To determine whether these results were related to behaviors beyond stress and fear memory, we conducted correlation studies between the movement of the animals and PL activity during IMO and freezing behavior during FC and FE. Our findings revealed a clear correlation between PL calcium activity with movement during stress exposure and freezing behavior, with no sex differences observed in these correlations. These results suggest a significant role for the PL in movement and locomotion, in addition to its involvement in fear-related processes. The inclusion of both female and male subjects is crucial for studies like this to fully understand the role of the PFC and other brain areas in stress and fear responses. Recognizing sex differences enhances our comprehension of brain function and can lead to more personalized and effective approaches in the study and treatment of stress and fear-related conditions.

Abstract Recent advances in artificial intelligence (AI) created powerful tools for research, particularly for extracting meaningful insights from extremely large data sets. These developments increase research benefits of big data and risks posed to individual privacy, forcing a re-examination of ethics in research which is of particular importance to the Military Health System. To advance discussion of research ethics in this context, the Forum on Health and National Security: Ethical Use of Big Data for Healthy Communities and a Strong Nation was held in December 2018. The workshop was designed to identify ethical questions relevant to population and health research studies using difficult to access, health-related data in the Department of Defense (DoD). Discussions explored researchers’ ethical obligations to research subjects, particularly in the areas of privacy, trust, and consent, as well as potential methods to improve researchers’ ability to collect, access, and share data while protecting privacy and potential risks to national security. These include creating risk management frameworks and data governance policies, improving education and workplace training, and increasing community involvement in research design and practice. While the workshop was conducted in 2018, the discussion of data ethics is still relevant today. The research agenda of the nation is best served by building ethics into the research ecosystem. There are substantial challenges to fully realizing this goal including commitments of time and funding to address the ethical complexities, train others to understand them, and create appropriate ethical frameworks before research begins.

Abstract Particle tracking (PT) is a popular technique in microscopy, microfluidics and colloidal transport studies, where image analysis is used to reconstruct trajectories from bright spots in a video. The performance of many PT algorithms has been rigorously tested for directed and Brownian motion in open media. However, PT is frequently used to track particles in porous media where complex geometries and viscous flows generate particles with high velocity variability over time. Here, we present an evaluation of four PT algorithms for a simulated dispersion of particles in porous media across a range of particle speeds and densities. Of special note, we introduce a new velocity-based PT linking algorithm (V-TrackMat) that achieves high accuracy relative to the other PT algorithms. Our findings underscore that traditional statistics, which revolve around detection and linking proficiency, fall short in providing a holistic comparison of PT codes because they tend to underpenalize aggressive linking techniques. We further elucidate that all codes analyzed show a decrease in performance due to high speeds, particle densities, and trajectory noise. However, linking algorithms designed to harness velocity data show superior performance, especially in the case of high-speed advective motion. Lastly, we emphasize how PT error can influence transport analysis.

Abstract Neoadjuvant endocrine therapy (NET) for hormone receptor-positive (HR+) breast cancer might be as effective as chemotherapy, with a better toxicity profile. Blocking a crucial process such as angiogenesis with sunitinib may have a synergistic effect with NET. We aimed to assess the efficacy and safety of neoadjuvant sunitinib plus exemestane in early-stage HR+/HER2-negative breast cancer. In this phase I/II study, postmenopausal women with HR+/HER2− stage II-III breast cancer received neoadjuvant exemestane at conventional dose of 25mg plus sunitinib in a 3 + 3 design at 25mg (3/1weeks scheme) or 37.5mg continuous dose, for 6 months. Coprimary endpoints were the recommended dose of sunitinib combined with exemestane and objective response. Secondary endpoints included safety and biomarkers of early response. For 15 months, 18 patients were enrolled, 15 at sunitinib 25mg and 3 at 37.5mg. Median age was 73, 77% of patients had T2 tumors and 67% node-positive disease. The most common grade 2 toxicity was asthenia (44%), as was hypertension (22%) for grade 3. No grade 4–5 were reported. Twelve patients (66%) achieved an objective response. VEGFR-2 levels significantly decreased after one month of treatment. Differential gene expression analysis showed downregulation of ESR1, PGR and NAT1 in post-treatment samples and upregulation of EGFR, MYC, SFRP1, and FOXC1. PAM50 analysis on 83% of patients showed a prevalence of luminal A subtype, both in pre-treatment (63.6%) and post-treatment tumors (54.5%). Sunitinib plus exemestane was associated with substantial yet reversible toxicities, providing safety, efficacy and biological impact insights of combining an antiangiogenic drug with hormone therapy in early-stage breast cancer. Trial registration: Registered with ClinicalTrials.gov, NCT00931450. 02/07/2009

We identified 3 clades of dengue virus serotype 3 belonging to genotype III isolated during 2019–2020 in Jamaica by using whole-genome sequencing and phylogenomic and phylogeographic analyses. The viruses likely originated from Asia in 2014. Newly expanded molecular surveillance efforts in Jamaica will guide appropriate public health responses.

Abstract Background Long-term deterioration in the mental health of healthcare workers (HCWs) has been reported during and after the COVID-19 pandemic. Determining the impact of COVID-19 incidence and mortality rates on the mental health of HCWs is essential to prepare for potential new pandemics. This study aimed to investigate the association of COVID-19 incidence and mortality rates with depressive symptoms over 2 years among HCWs in 20 countries during and after the COVID-19 pandemic. Methods This was a multi-country serial cross-sectional study using data from the first and second survey waves of the COVID-19 HEalth caRe wOrkErS (HEROES) global study. The HEROES study prospectively collected data from HCWs at various health facilities. The target population included HCWs with both clinical and non-clinical roles. In most countries, healthcare centers were recruited based on convenience sampling. As an independent variable, daily COVID-19 incidence and mortality rates were calculated using confirmed cases and deaths reported by Johns Hopkins University. These rates represent the average for the 7 days preceding the participants’ response date. The primary outcome was depressive symptoms, assessed by the Patient Health Questionnaire-9. A multilevel linear mixed model (LMM) was conducted to investigate the association of depressive symptoms with the average incidence and mortality rates. Results A total of 32,223 responses from the participants who responded to all measures used in this study on either the first or second survey, and on both the first and second surveys in 20 countries were included in the analysis. The mean age was 40.1 (SD = 11.1), and 23,619 responses (73.3%) were from females. The 9323 responses (28.9%) were nurses and 9119 (28.3%) were physicians. LMM showed that the incidence rate was significantly and positively associated with depressive symptoms (coefficient = 0.008, standard error 0.003, p = 0.003). The mortality rate was significantly and positively associated with depressive symptoms (coefficient = 0.049, se = 0.020, p = 0.017). Conclusions This is the first study to show an association between COVID-19 incidence and mortality rates with depressive symptoms among HCWs during the first 2 years of the outbreak in multiple countries. This study’s findings indicate that additional mental health support for HCWs was needed when the COVID-19 incidence and mortality rates increase during and after the early phase of the pandemic, and these findings may apply to future pandemics. Trial registration Clinicaltrials.gov, NCT04352634.

Abstract Background Helicobacter pylori colonizes the human stomach and may affect the inflammatory response, hormone production related to energy regulation, and gastrointestinal microbiota composition. Previous studies have explored a potential association between H. pylori infection and pediatric obesity with varying results. Considering the immunomodulatory effects of early-life infection with H. pylori that can confer beneficial effects, we hypothesized that we would find an inverse relationship between H. pylori seropositivity and obesity among Danish children and adolescents. Methods We assessed H. pylori seroprevalence in 713 subjects from an obesity clinic cohort and 990 subjects from a population-based cohort, aged 6 to 19 years, and examined its association with obesity and other cardiometabolic risk factors. Results No association was found between H. pylori and body mass index standard deviation score (BMI SDS). H. pylori seropositivity was, however, significantly associated with higher fasting plasma glucose levels and the prevalence of hyperglycemia. Conclusion While we did not find an association between H. pylori seropositivity and BMI SDS, we observed a significant association with higher fasting plasma glucose levels and increased prevalence of hyperglycemia, suggesting that H. pylori infection may contribute to impaired glucose regulation in Danish children and adolescents. Graphical abstract

Abstract Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases.

Abstract The present study aims to investigate the low-energy consumption and high-efficiency removal of arsenic from aqueous solutions. The designed adsorbent Fe/TBC was synthesized by impregnating iron on torrefaction henequen fibers. Isothermal adsorption experiments indicated maximum adsorption capacities of 7.30 mg/g and 8.98 mg/g for arsenic(V) at 25.0 °C and 40.0 °C, respectively. The interference testing showed that elevated levels of pH, HCO3 − concentration, and humic acid content in the solution could inhibit the adsorption of arsenic by Fe/TBC. Characterization of the adsorbent before and after adsorption using FTIR and SEM–EDS techniques confirmed arsenic adsorption mechanisms, including pore filling, electrostatic interaction, surface complexation, and H-bond adhesion. Column experiments were conducted to treat arsenic-spiked water and natural groundwater, with effective treatment volumes of 550 mL and 8792 mL, respectively. Lastly, the life cycle assessment (LCA) using OpenLCA 2.0.3 software was performed to treat 1 m3 of natural groundwater as the functional unit. The results indicated relatively significant environmental impacts during the Fe/TBC synthesis stage. The global warming potential resulting from the entire life cycle process was determined to be 0.8 kg CO2-eq. The results from batch and column experiments, regeneration studies, and LCA analysis indicate that Fe/TBC could be a promising adsorbent for arsenic(V).

Abstract Background The number of people with palliative care needs is projected to increase globally. Chile has recently introduced legislation for universal access to palliative care services for patients with severe and terminal illnesses, including non-cancer conditions. We aimed to estimate the number of people affected by serious health-related suffering and need for palliative care in Chile to 2050. Methods We used data on all deaths registered in Chile between 1997-2019 and population estimates for 1997–2050. We used Poisson regression to model past trends in causes of death adjusted by age, sex and population estimates, to project the number of deaths for each cause from 2021 to 2050. We applied the Lancet Commission on Palliative Care and Pain Relief weights to these projections to identify decedents and non-decedents with palliative care needs. Results Population palliative care needs in Chile are projected to increase from 117 (95% CI 114 to 120) thousand people in 2021 to 209 (95% CI 198 to 223) thousand people in 2050, a 79% increase (IRR 1.79; 95% CI 1.78–1.80). This increase will be driven by non-cancer conditions, particularly dementia (IRR 2.9, 95% CI 2.85–2.95) and cardiovascular conditions (IRR 1.86, 95% CI 1.83–1.89). By 2050, 50% of those estimated to need palliative care will be non-decedents (not expected to die within a year). Conclusions Chile will experience a large increase in palliative care needs, particularly for people with dementia and other non-cancer conditions. Improved availability of high-quality services, expanded clinician training and new sustainable models of care are urgently required to ensure universal access to palliative care.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

BackgroundComprehensive antenatal care (ANC) must prioritize competent, evidence-based medical attention to ensure a positive experience and value for its users. Unfortunately, there is scarce evidence of implementing this holistic approach to ANC in low- and middle-income countries, leading to gaps in quality and accountability. This study assessed care competence, women's experiences during the first ANC visit, and the factors associated with these care attributes.Methods and findingsThe study analyzed cross-sectional baseline data from the maternal eCohort study conducted in Mexico from August to December 2023. The study adapted the Quality Evidence for Health System Transformation (QuEST) network questionnaires to the Mexican context and validated them through expert group and cognitive interviews with women. Pregnant women aged 18 to 49 who had their first ANC visit with a family physician were enrolled in 48 primary clinics of the Instituto Mexicano del Seguro Social across 8 states. Care competence and women's experiences with care were the primary outcomes. The statistical analysis comprised descriptive statistics, multivariable linear and Poisson regressions. A total of 1,390 pregnant women were included in the study. During their first ANC visit, women received only 67.7% of necessary clinical actions on average, and 52% rated their ANC experience as fair or poor. Women with previous pregnancies (adjusted regression coefficient [aCoef.] -3.55; (95% confidence intervals [95% CIs]): -4.88, -2.22, p < 0.001), at risk of depression (aCoef. -3.02; 95% CIs: -5.61, -0.43, p = 0.023), those with warning signs (aCoef. -2.84; 95% CIs: -4.65, -1.03, p = 0.003), common pregnancy discomforts (aCoef. -1.91; 95% CIs: -3.81, -0.02, p = 0.048), or those who had a visit duration of less than 20 minutes (ConclusionsWe found important gaps in adherence to ANC standards and that care competence during the first ANC visit is an important predictor of positive user experience. To inform quality improvement efforts, IMSS should institutionalize the routine monitoring of ANC competencies and ANC user experience. This will help identify poorly performing facilities and providers and address gaps in the provision of evidence-based and women-centered care.

Abstract Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

Abstract Introduction Herlyn–Werner–Wunderlich syndrome , a rare Müllerian ducts congenital disease, is characterized by a diphtheritic uterus, blind hemivagina, and ipsilateral renal agenesis. Diagnosis is at young age by ultrasound and magnetic resonance imaging, and the prognosis is good. Usually, complications evolve endometriosis and secondary pelvic inflammation. Case report A 40-year-old female patient, Brazilian, white, primigravida, diagnosed at 30 years with a didelphic uterus on ultrasound, and 4 years later, with a left ovarian endometrioma, multiple ovarian cysts, and left renal agenesis on magnetic resonance imaging. Subsequently, due to dyspareunia and a feeling of swelling, the patient underwent transvaginal ultrasound with bowel preparation, and a hematocolpos was found and Herlyn–Werner–Wunderlich syndrome was suspected; 10 years after the diagnosis she had a planned pregnancy. She presented frequent contractions following the 15th week of pregnancy and fortunately there were no complications or premature labor. Labor was inducted at 40 weeks and 6 days without progress and a cesarean section was indicated and performed without complications. Herlyn–Werner–Wunderlich syndrome often goes unnoticed, leading to inadequate treatment. Individuals with Herlyn–Werner–Wunderlich syndrome commonly face fertility issues, such as high miscarriage rate (21–33%), and obstetric complications, such as spontaneous abortions (40% risk), intrauterine growth restriction, postpartum hemorrhage, increased fetal mortality, preterm delivery (21–29%), and elevated rates of cesarean sections. In addition, there is higher susceptibility of developing endometriosis, especially with hemivaginal obstruction, and pelvic adhesions. Conclusion Early diagnosis enables timely treatment and, consequently, fewer complications. Still, when these factors are absent, vaginal birth may still be possible. The true prevalence and incidence of complications related to Herlyn–Werner–Wunderlich syndrome are still unknown.

Introduction: Medical cannabis (MC) is available upon certification for one of several qualifying conditions in Florida, USA. Previous studies suggested that some people seek cannabis for medical conditions/symptoms beyond those legally permitted. However, data remain limited on patient motives for seeking MC and their experiences around its impact on their health. We aimed to compare reported qualifying conditions for MC certification with the most frequently self-reported reasons for using MC while assessing the alignment between the two and understanding the perceived impacts of MC on self-reported conditions and symptoms. Methods: We conducted a cross-sectional study using survey data from the Medical Marijuana and Me (M3) Data Bank of individuals receiving MC in Florida, USA, in 2022. Participants were recruited via convenience sampling from nine MC clinics/clinic networks across Florida and were asked to fill out an online survey. The study measures included sociodemographic variables, self-reported health conditions, self-reported main reasons for using MC, self-reported qualifying conditions for MC certification, and self-reported perceived impact of MC on health conditions. We cross-tabulated reported qualifying conditions and reasons for MC use and reported the perceived impact per condition. Results: A total of 632 participants completed the survey, of whom 396 (62.66%) were female and 471 (74.53%) were non-Hispanic white. The median (IQR) age was 45 (35, 58). The most frequently reported qualifying conditions were post-traumatic stress disorder (PTSD) (n = 187, 29.59%), a condition not on the qualifying conditions list (n = 175, 27.69%), medical conditions of the same kind/comparable to those listed (n = 140, 22.15%), and chronic nonmalignant pain (n = 62, 25.63%). The top ten most frequently reported reasons for using MC were anxiety (n = 383, 60.60%), chronic pain (n = 278, 43.99%), depression (n = 252, 39.87%), PTSD (n = 220, 34.81%), headaches/migraine (n = 134, 21.20%), fibromyalgia (n = 67, 10.60%), attention-deficit hyperactivity disorder (ADHD) (n = 59, 9.34%), bipolar disorder (n = 53, 8.39%), high blood pressure (n = 41, 6.49%), and cancer (n = 18,2.85%). Of respondents, 70–90% with each qualifying condition reported it as one of the main reasons for using MC. Most respondents reported improvement of anxiety (n = 430/451, 95.34%), depression (n = 381/392, 97.20%), chronic pain (n = 305/310, 98.39%), insomnia/sleeping problems (n = 225/295, 86.44%), PTSD (n = 247/270, 91.48%), headaches/migraine (n = 172/218, 78.90%), ADHD (n = 82/123, 66.67%), bipolar disorder (n = 79/89, 88.76%), and fibromyalgia (n = 77/82, 93.90%). Most respondents were unsure/reported no change in blood pressure (n = 93/162, 57.41%). A small percentage reported perceived worsening impacts on their conditions. Conclusion: Qualifying conditions and self-reported reasons for using MC aligned for most respondents. Yet, a notable proportion of respondents sought MC for broader treatment effects beyond those delineated by the officially recognized qualifying conditions in Florida, USA. Most patients perceived positive effects, including those with limited available evidence on efficacy.

Abstract The first therapeutical goal followed by neurooncological surgeons dealing with prefrontal gliomas is attempting supramarginal tumor resection preserving relevant neurological function. Therefore, advanced knowledge of the frontal aslant tract (FAT) functional neuroanatomy in high-order cognitive domains beyond language and speech processing would help refine neurosurgeries, predicting possible relevant cognitive adverse events and maximizing the surgical efficacy. To this aim we performed the recently developed correlational tractography analyses to evaluate the possible relationship between FAT’s microstructural properties and cognitive functions in 27 healthy subjects having ultra-high-field (7-Tesla) diffusion MRI. We independently assessed FAT segments innervating the dorsolateral prefrontal cortices (dlPFC-FAT) and the supplementary motor area (SMA-FAT). FAT microstructural robustness, measured by the tract’s quantitative anisotropy (QA), was associated with a better performance in episodic memory, visuospatial orientation, cognitive processing speed and fluid intelligence but not sustained selective attention tests. Overall, the percentual tract volume showing an association between QA-index and improved cognitive scores (pQACV) was higher in the SMA-FAT compared to the dlPFC-FAT segment. This effect was right-lateralized for verbal episodic memory and fluid intelligence and bilateralized for visuospatial orientation and cognitive processing speed. Our results provide novel evidence for a functional specialization of the FAT beyond the known in language and speech processing, particularly its involvement in several higher-order cognitive domains. In light of these findings, further research should be encouraged to focus on neurocognitive deficits and their impact on patient outcomes after FAT damage, especially in the context of glioma surgery.

Abstract The excessive accumulation and malfunctioning of visceral adipose tissue (VAT) is a major determinant of increased risk of obesity-related comorbidities. Thus, risk stratification of people living with obesity according to their amount of VAT is of clinical interest. Currently, the most common VAT measurement methods include mathematical formulae based on anthropometric dimensions, often biased by human measurement errors, bio-impedance, and image techniques such as X-ray absorptiometry (DXA) analysis, which requires specialized equipment. However, previous studies showed the possibility of classifying people living with obesity according to their VAT through blood chemical concentrations by applying machine learning techniques. In addition, most of the efforts were spent on men living with obesity while little was done for women. Therefore, this study aims to compare the performance of the multilinear regression model (MLR) in estimating VAT and six different supervised machine learning classifiers, including logistic regression (LR), support vector machine and decision tree-based models, to categorize 149 women living with obesity. For clustering, the study population was categorized into classes 0, 1, and 2 according to their VAT and the accuracy of each MLR and classification model was evaluated using DXA-data (DXAdata), blood chemical concentrations (BLDdata), and both DXAdata and BLDdata together (ALLdata). Estimation error and $$\hbox {R}^{2}$$ R 2 were computed for MLR, while receiver operating characteristic (ROC) and precision-recall curves (PR) area under the curve (AUC) were used to assess the performance of every classification model. MLR models showed a poor ability to estimate VAT with mean absolute error $$\ge 401.40$$ ≥ 401.40 and $$\hbox {R}^{2} \le 0.62$$ R 2 ≤ 0.62 in all the datasets. The highest accuracy was found for LR with values of 0.57, 0.63, and 0.53 for ALLdata, DXAdata, and BLDdata, respectively. The ROC AUC showed a poor ability of both ALLdata and DXAdata to distinguish class 1 from classes 0 and 2 (AUC = 0.31, 0.71, and 0.85, respectively) as also confirmed by PR (AUC = 0.24, 0.57, and 0.73, respectively). However, improved performances were obtained when applying LR model to BLDdata (ROC AUC $$\ge $$ ≥ 0.61 and PR AUC $$\ge $$ ≥ 0.42), especially for class 1. These results seem to suggest that, while a direct and reliable estimation of VAT was not possible in our cohort, blood sample-derived information can robustly classify women living with obesity by machine learning-based classifiers, a fact that could benefit the clinical practice, especially in those health centres where medical imaging devices are not available. Nonetheless, these promising findings should be further validated over a larger population.

Abstract Background Unintentional injuries are a leading cause of death among children aged 1–19 years worldwide. Systematic reviews assessing various risk factors for different childhood injuries have been published previously. However, most of the related literature does not distinguish minor from severe or fatal injuries. This study aims to describe and summarize the current knowledge on the determinants of severe and fatal childhood unintentional injuries and to discuss the differences between risk factors for all injuries (including minor injuries) and severe and fatal injuries. The study also aims to quantify the reduction in childhood injuries associated with a reduction in exposure to some of the identified risk factors in the Canadian population. Methods A systematic review and meta-analysis will be conducted by searching MEDLINE, Embase, CINAHL, and Web of Science. Observational and experimental cohort studies assessing children and adolescents aged ≤ 19 years old and determinants of severe and fatal unintentional injury, such as personal behaviors, family and environmental characteristics, and socioeconomic and geographic context, will be eligible. The main outcome will be a composite of any severe or fatal unintentional injuries (including burns, drowning, transport-related injuries, and falls). Any severity measurement scale will be accepted as long as severe cases require at least one hospital admission. Two authors will independently screen for inclusion, extract data, and assess the quality of the data using the Cochrane ROBINS-E tool. Meta-analysis will be performed using random effects models. Subgroup analyses will examine age subgroups and high- vs low-income countries. Sensitivity analysis will be conducted after restricting analyses to studies with a low risk of bias. Attributable fractions will be computed to assess the burden of identified risk factors in the Canadian population. Discussion Given the numerous determinants of childhood injuries and the challenges that may be involved in identifying which individuals should be prioritized for injury prevention efforts, this evidence may help to inform the identification of high-risk children and prevention interventions, considering the disproportionate consequences of severe and fatal injuries. This evidence may also help pediatric healthcare providers prioritize counseling messaging. Systematic review registration PROSPERO CRD42023493322.

Abstract Monometallic and bimetallic Cu:Ni catalysts with different Cu:Ni molar ratios (3:1, 2:1, 1:1, 1:2, 1:3) were synthesized by wetness impregnation on activated carbon and characterized by TPR (temperature programmed reduction), XRD (X-ray diffraction) and XPS (X-ray photoelectron spectroscopy). The synthesized catalysts were evaluated in the gas phase production of diethyl carbonate from ethanol and carbon dioxide. The largest catalytic activity was obtained over the bimetallic catalyst with a Cu:Ni molar ratio of 3:1. Its improved activity was attributed to the formation of a Cu–Ni alloy on the surface of the catalyst, evidenced by XPS and in agreement with a previous assignment based on Vegard law and TPR analysis. During the reaction rate experiments, it observed the presence of a maximum of the reaction rate as a function of temperature, a tendency also reported for other carbon dioxide–alcohol reactions. It showed that the reaction rate-temperature data can be adjusted with a reversible rate equation. The initial rate as a function of reactant partial pressure data was satisfactorily adjusted using the forward power law rate equation and it was found that the reaction rate is first order in CO2 and second order in ethanol.

Abstract Although asexuality became a growing research subject over the last decade, data on the mental health of individuals identifying as asexual is still rare. The key objective of the present study was to examine depressive symptoms among individuals identifying as asexual. Data of LGBTQIA+ (Lesbian, Gay, Bi-sexual, Trans*, Queer, Inter*, Asexual and/or + indicating others within the community) and cisgender heterosexual individuals was collected through an online survey during the COVID-19 lockdowns in Germany. The survey included questions about sexual and gender identity, depressive symptoms, and asexual identity. An analysis of N = 6601 participants was conducted. A total of n = 445 individuals identified as asexual. Regression results indicated identifying as asexual being significantly associated with higher depressive symptoms. Results suggest that individuals identifying as asexual represent a vulnerable group within the group of sexual minorities, one that fundamentally requires special psychosocial support, especially in times of pandemics.

Abstract Age-related changes in emotional processing are complex, with a bias toward positive information. However, the impact of aging on emotional responses in positive everyday situations remains unclear. Virtual Reality (VR) has emerged as a promising tool for investigating emotional processing, offering a unique balance between ecological validity and experimental control. Yet, limited evidence exists regarding its efficacy to elicit positive emotions in older adults. Our study aimed to explore age-related differences in positive emotional responses to immersion in both social and nonsocial virtual emotional environments. We exposed 34 younger adults and 24 older adults to natural and social 360-degree video content through a low immersive computer screen and a highly immersive Head-Mounted Display, while recording participants' physiological reactions. Participants also provided self-report of their emotions and sense of presence. The findings support VR’s efficacy in eliciting positive emotions in both younger and older adults, with age-related differences in emotional responses influenced by the specific video content rather than immersion level. These findings underscore the potential of VR as a valuable tool for examining age-related differences in emotional responses and developing VR applications to enhance emotional wellbeing across diverse user populations.

Abstract Diabetes mellitus (DM) is a risk factor for the development of ulnar nerve entrapment (UNE). Differences in surgical outcomes for UNE between patients with and without DM have been reported, but studies on presurgical management are scarce. This study aimed to evaluate the presurgical management of UNE in patients with (DM diagnosis

Abstract Background DNA methylation may have a regulatory role in monogenic sensorineural hearing loss and complex, polygenic phenotypic forms of hearing loss, including age-related hearing impairment or Meniere disease. The purpose of this systematic review is to critically assess the evidence supporting a functional role of DNA methylation in phenotypes associated with hearing loss. Results The search strategy yielded a total of 661 articles. After quality assessment, 25 records were selected (12 human DNA methylation studies, 5 experimental animal studies and 8 studies reporting mutations in the DNMT1 gene). Although some methylation studies reported significant differences in CpG methylation in diverse gene promoters associated with complex hearing loss phenotypes (ARHI, otosclerosis, MD), only one study included a replication cohort that supported a regulatory role for CpG methylation in the genes TCF25 and POLE in ARHI. Conversely, several studies have independently confirmed pathogenic mutations within exon 21 of the DNMT1 gene, which encodes the DNA (cytosine-5)-methyltransferase 1 enzyme. This methylation enzyme is strongly associated with a rare disease defined by autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Of note, rare variants in DNMT1 and DNMT3A genes have also been reported in noise-induced hearing loss. Conclusions Evidence supporting a functional role for DNA methylation in hearing loss is limited to few genes in complex disorders such as ARHI. Mutations in the DNMT1 gene are associated with ADCA-DN, suggesting the CpG methylation in hearing loss genes deserves further attention in hearing research.

Objetives. Bacterial resistance to antibiotics is a public health problem, however, few studies are performed in natural water ecosystems in middle-low-income countries. The objective of this study was to evaluate the presence and sensitivity to antimicrobials of Escherichia coli strains isolated from 24 irrigation water samples from the Rimac River in eastern Lima. Materials and methods. E.coli were identified by PCR. Antibiotic susceptibility was determined by disk diffusion method. The extended-spectrum beta-lactamase (ESBL), quinolones and virulence involved genes were determined by PCR. Results. All samples exceeded the permissible limits established in the Environmental Quality Standards for vegetable irrigation. Of the 94 strains, 72.3% showed resistance to at least one antibiotic, 24.5% were multidrug-resistant (MDR), and 2.1% were extremely drug resistant. The highest percentages of resistance were observed against nalidixic acid (50%), trimethoprim-sulfamethoxazole (35.5%) and ciprofloxacin (20.4%). Among the isolates, 3.2% presented ESBL phenotype related to blaCTX-M-15 gene. The transferable mechanisms of resistance to quinolones, qnrB were more frequent (20.4%), and 2.04% had the qnrS. It was determined that 5.3% were diarrheagenic E. coli and of these, 60% were enterotoxigenic E. coli, 20% were enteropathogenic E. coli and 20% were enteroaggregative E. coli. Conclusions. Our results show the existence diarrheagenic pathotypes in water used to irrigate fresh produce and highlights the presence of ESBL-producers and MDR E. coli, demonstrating the role that irrigation water plays in disseminating resistance genes in Peru.

Abstract Background Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. Main body By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. Conclusion The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Abstract No-take marine protected areas (MPAs) can mitigate the effects of overfishing, climate change and habitat degradation, which are leading causes of an unprecedented global biodiversity crisis. However, assessing the effectiveness of MPAs, especially in remote oceanic islands, can be logistically challenging and often restricted to relatively shallow and accessible environments. Here, we used a long-term dataset (2010–2019) collected by the DeepSee submersible of the Undersea Hunter Group that operates in Isla del Coco National Park, Costa Rica, to (1) determine the frequency of occurrence of elasmobranch species at two depth intervals (50–100 m; 300–400 m), and (2) investigate temporal trends in the occurrence of common elasmobranch species between 2010 and 2019, as well as potential drivers of the observed changes. Overall, we observed 17 elasmobranch species, 15 of which were recorded on shallow dives (50–100 m) and 11 on deep dives (300–400 m). We found a decreasing trend in the probability of occurrence of Carcharhinus falciformis over time (2010–2019), while other species (e.g. Taeniurops meyeni, Sphyrna lewini, Carcharhinus galapagensis, Triaenodon obesus, and Galeocerdo cuvier) showed an increasing trend. Our study suggests that some species like S. lewini may be shifting their distributions towards deeper waters in response to ocean warming but may also be sensitive to low oxygen levels at greater depths. These findings highlight the need for regional 3D environmental information and long-term deepwater surveys to understand the extent of shark and ray population declines in the ETP and other regions, as most fishery-independent surveys from data-poor countries have been limited to relatively shallow waters.

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet the mechanisms underlying this synergy differ between IDP families.

Hospital at Home (HaH) provides hospital-level care within patients’ homes. With services expanding, a London HaH service embedded new junior doctor posts. Currently, gaps exist in the under- and postgraduate curriculum to develop clinical skills required to deliver care in this context. HaH simulation (HaH-SIM) was developed, through a multi-cycle QIP, to improve early-career doctors’ confidence in providing care in this unfamiliar environment. Surveys before and after HaH-SIM assessed confidence in practical, clinical and communication skills; ranked concerns; rated sessions and gained qualitative feedback. 41 doctors participated over 2 years. It currently includes six low-fidelity stations and three high-fidelity stations. Confidence improved, particularly in managing end of life, decision-making around hospital admission and administering intravenous medications/fluids. High-fidelity scenarios, practical skills and prescribing stations were most highly rated. As HaH services expand, HaH-SIM is a feasible, effective and transferable way of improving early-career doctors’ confidence and skills to provide care in patients’ homes.

BackgroundClinical practice guidelines (CPGs) are designed to assist health care professionals in medical decision-making, but they often lack effective integration of shared decision-making (SDM) principles to reflect patient values and preferences, particularly in the context of preference-sensitive CPG recommendations. To address this shortcoming and foster SDM through CPGs, the integration of patient decision aids (PDAs) into CPGs has been proposed as an important strategy. However, methods for systematically identifying and prioritizing CPG recommendations relevant to SDM and related decision support tools are currently lacking. ObjectiveThe aim of the project is to develop (1) a tool for systematically identifying and prioritizing CPG recommendations for which SDM is considered particularly relevant and (2) a platform for PDAs to support practical SDM implementation. MethodsThe project consists of 6 work packages (WPs). It is embedded in the German health care context but has an international focus. In WP 1, we will conduct a scoping review in bibliographic databases and gray literature sources to identify methods used to foster SDM via PDAs in the context of CPGs. In WP 2, we will conduct semistructured interviews with CPG experts to better understand the concepts of preference sensitivity and identify strategies for fostering SDM through CPGs. WP 3, a modified Delphi study including surveys and focus groups with SDM experts, aims to define and operationalize preference sensitivity. Based on the results of the Delphi study, we will develop a methodology for prioritizing key questions in CPGs. In WP 4, the tool will be developed. A list of relevant items to identify CPG recommendations for which SDM is most relevant will be created, tested, and iteratively refined, accompanied by the development of a user manual. In WP 5, a platform for creating and digitizing German-language PDAs will be developed to support the practical application of SDM during clinical encounters. WP 6 will conclude the project by testing the tool with newly developed and revised CPGs. ResultsThe Brandenburg Medical School Ethics Committee approved the project (165122023-ANF). An international multidisciplinary advisory board is involved to guide the tool development on CPGs and SDM. Patient partners are involved throughout the project, considering the essential role of the patient perspective in SDM. As of February 20, 2024, we are currently assessing literature references to determine eligibility for inclusion in the scoping review (WP 1). We expect the project to be completed by December 31, 2026. ConclusionsThe tool will enable CPG developers to systematically incorporate aspects of SDM into CPG development, thereby providing guideline-based support for the patient-practitioner interaction. Together, the tool for CPGs and the platform for PDAs will create a systematic link between CPGs, SDM, and PDAs, which may facilitate SDM in clinical practice. International Registered Report Identifier (IRRID)DERR1-10.2196/57611

Introducción: El cáncer de pulmón es un problema de salud en el mundo. En el carcinoma de pulmón de células no pequeñas se han identificado la presencia de una serie de alteraciones moleculares entre ellas, la mutación del receptor del factor de crecimiento epidérmico. Objetivo: Describir el desarrollo y evolución de la terapia con inhibidores tirosina quinasa para el tratamiento de pacientes con carcinoma de pulmón con mutación del receptor del factor de crecimiento epidérmico. Métodos: Se consultaron las bases de datos, EMBASE, Cochrane y Scopus, así como la plataforma PubMed. Se emplearon términos del Medical Subject Headings (MeSH), se tuvieron en cuenta: Artículos publicados entre el 2014 y el 2023, en idioma español e inglés. Se revisaron un total de 183 artículos y se seleccionaron 52: Artículos de revisión (16) y artículos originales (36), libros de texto (2) y guía de diagnóstico y tratamiento (2). Desarrollo: El descubrimiento de este gen fue seguido del desarrollo de fármacos inhibidores de la tirosina quinasa, que han permitido evidenciar una mayor eficacia en los pacientes portadores de dicha mutación, en comparación con la quimioterapia, lo cual inició una nueva era en el tratamiento del cáncer de pulmón. A pesar de las excelentes tasas de respuestas y supervivencia la mayoría de los pacientes, desarrollan resistencia adquirida, después de una mediana de supervivencia de 12 meses de iniciado el tratamiento. Conclusiones: El desarrollo de terapias dirigidas a la mutación del receptor del factor de crecimiento epidérmico, cambió el estándar de tratamiento de los pacientes con cáncer de pulmón de células no pequeñas, que expresan dicha mutación.

In cardiomyocytes, the KCNQ1/KCNE1 channel complex mediates the slow delayed-rectifier current (IKs), pivotal during the repolarization phase of the ventricular action potential. Mutations in IKs cause long QT syndrome (LQTS), a syndrome with a prolonged QT interval on the ECG, which increases the risk of ventricular arrhythmia and sudden cardiac death. One potential therapeutical intervention for LQTS is based on targeting IKs channels to restore channel function and/or the physiological QT interval. Polyunsaturated fatty acids (PUFAs) are potent activators of KCNQ1 channels and activate IKs channels by binding to two different sites, one in the voltage sensor domain – which shifts the voltage dependence to more negative voltages – and the other in the pore domain – which increases the maximal conductance of the channels (Gmax). However, the mechanism by which PUFAs increase the Gmax of the IKs channels is still poorly understood. In addition, it is unclear why IKs channels have a very small single-channel conductance and a low open probability or whether PUFAs affect any of these properties of IKs channels. Our results suggest that the selectivity filter in KCNQ1 is normally unstable, contributing to the low open probability, and that the PUFA-induced increase in Gmax is caused by a stabilization of the selectivity filter in an open-conductive state.

The diversity of cognitive skills across primates remains both a fascinating and a controversial issue. Recent comparative studies provided conflicting results regarding the contribution of social vs ecological constraints to the evolution of cognition. Here, we used an interdisciplinary approach combining comparative cognitive neurosciences and behavioral ecology. Using brain imaging data from 16 primate species, we measured the size of two prefrontal brain regions, the frontal pole (FP) and the dorso-lateral prefrontal cortex (DLPFC), respectively, involved in metacognition and working memory, and examined their relation to a combination of socio-ecological variables. The size of these prefrontal regions, as well as the whole brain, was best explained by three variables: body mass, daily traveled distance (an index of ecological constraints), and population density (an index of social constraints). The strong influence of ecological constraints on FP and DLPFC volumes suggests that both metacognition and working memory are critical for foraging in primates. Interestingly, FP volume was much more sensitive to social constraints than DLPFC volume, in line with laboratory studies showing an implication of FP in complex social interactions. Thus, our data highlights the relative weight of social vs ecological constraints on the evolution of specific prefrontal brain regions and their associated cognitive operations in primates.

IntroductionExtraction of Doppler-based measurements from feto-placental Doppler images is crucial in identifying vulnerable new-borns prenatally. However, this process is time-consuming, operator dependent, and prone to errors.MethodsTo address this, our study introduces an artificial intelligence (AI) enabled workflow for automating feto-placental Doppler measurements from four sites (i.e., Umbilical Artery (UA), Middle Cerebral Artery (MCA), Aortic Isthmus (AoI) and Left Ventricular Inflow and Outflow (LVIO)), involving classification and waveform delineation tasks. Derived from data from a low- and middle-income country, our approach's versatility was tested and validated using a dataset from a high-income country, showcasing its potential for standardized and accurate analysis across varied healthcare settings.ResultsThe classification of Doppler views was approached through three distinct blocks: (i) a Doppler velocity amplitude-based model with an accuracy of 94%, (ii) two Convolutional Neural Networks (CNN) with accuracies of 89.2% and 67.3%, and (iii) Doppler view- and dataset-dependent confidence models to detect misclassifications with an accuracy higher than 85%. The extraction of Doppler indices utilized Doppler-view dependent CNNs coupled with post-processing techniques. Results yielded a mean absolute percentage error of 6.1 ± 4.9% (n = 682), 1.8 ± 1.5% (n = 1,480), 4.7 ± 4.0% (n = 717), 3.5 ± 3.1% (n = 1,318) for the magnitude location of the systolic peak in LVIO, UA, AoI and MCA views, respectively.ConclusionsThe developed models proved to be highly accurate in classifying Doppler views and extracting essential measurements from Doppler images. The integration of this AI-enabled workflow holds significant promise in reducing the manual workload and enhancing the efficiency of feto-placental Doppler image analysis, even for non-trained readers.

Objectives Major trauma centres (MTCs) save lives but rehabilitation to support return-to-work (RTW) is lacking. This paper describes development of a vocational rehabilitation intervention (the ROWTATE intervention) to support RTW following traumatic injury.Design Sequential and iterative person-based approach in four stages—Stage 1: review of evidence about the efficacy and mechanisms of RTW interventions; Stage 2: interviews (n=38) and focus groups (n=25) with trauma survivors and service providers in five UK MTCs to identify the issues, and challenges faced postinjury; Stage 3: codesign workshops (n=43) with trauma stakeholders in MTCs to conceptually test and identify intervention delivery barriers/enablers; Stage 4: meetings (n=7) with intervention development working group (IDWG) to: (1) generate guiding principles, (2) identify key intervention features (process, components, mechanisms) to address unmet rehabilitation needs; (3) generate a logic model and programme theory to illustrate how the intervention works; and (4) develop a training package to support delivery.Results Trauma survivors described unmet needs relating to early advice about RTW; psychological support; pain management; hidden disabilities (eg, fatigue); estimating recovery; and community, amputee and musculoskeletal rehabilitation. Mechanisms of effective interventions identified in the review included early intervention, colocation, employer engagement, case coordination and work accommodations. Intervention features identified by IDWG members (n=13) from stages 1 and 2 were use of stepped-care approaches by occupational therapists (OTs) and clinical psychologists (CPs), OT/CP formulation for complex cases, assessment of mental health problems, individually tailored rehabilitation including vocational goal setting, cross-sector coordination/communication, employer engagement, phased RTW, education/advice for family/employers, exploration of work alternatives, ongoing review of physical and mental health needs, work stability monitoring. Conceptual testing ratified the logic model. Geography and long waiting lists were identified as potential delivery barriers.Conclusions Real-world testing of the intervention is underway in a randomised controlled trial.