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Abstract This study investigates a novel microfluidic mixing technique that uses the resonant oscillation of coalescent droplets. During the vertical contact-separation process, solutes are initially separated as a result of the combined effects of diffusion and gravity. We show that the application of alternating current (AC) voltage to microelectrodes below the droplets causes a resonant oscillation, which enhances the even distribution of the solute. The difference in concentration between the top and bottom droplets exhibits frequency dependence and indicates the existence of a particular AC frequency that results in a homogeneous concentration. This frequency corresponds to the resonance frequency of the droplet oscillation that is determined using particle tracking velocimetry. To understand the mixing process, a phenomenological model based on the equilibrium between surface tension, viscosity, and electrostatic force was developed. This model accurately predicted the resonance frequency of droplet flow and was consistent with the experimental results. These results suggest that the resonant oscillation of droplets driven by AC voltage significantly enhances the diffusion of solutes, which is an effective approach to microfluid mixing.

Abstract Objective Livestock droppings cause some environmental problems, but they have the potential to be used as effective biomass resources. The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), is suitable for efficiently processing such resources. By using BSF larvae for the disposal of livestock droppings, we can obtain two valuable products: protein resources and organic fertilizer. However, there is insufficient research on the digestive enzymes suitable for processing this waste. Here, we aimed to construct an efficient BSF processing system using livestock droppings, and we explored the digestive enzymes involved in this process. Results First, we investigated the characteristics of transcripts expressed in the midgut of BSF larvae and found that immune response-related genes were expressed in the midgut. Then, we investigated digestive enzymes and identified a novel serine protease, HiBrachyurin, whose mRNA was highly expressed in the posterior midgut when BSF larvae fed on horse droppings. Despite the low protein content of horse droppings, larvae that fed on horse droppings accumulated more protein than those in the other groups. Therefore, HiBrachyurin may contribute to digestibility in the early stage of protein degradation in BSF larvae fed on horse droppings.

Abstract Salmonella enterica and Escherichia coli are major food-borne human pathogens, and their genomes are routinely sequenced for clinical surveillance. Computational pipelines designed for analyzing pathogen genomes should both utilize the most current information from annotation databases and increase the coverage of these databases over time. We report the development of the GEA pipeline to analyze large batches of E. coli and S. enterica genomes. The GEA pipeline takes as input paired Illumina raw reads files which are then assembled followed by annotation. Alternatively, assemblies can be provided as input and directly annotated. The pipeline provides predictive genome annotations for E. coli and S. enterica with a focus on the Center for Genomic Epidemiology tools. Annotation results are provided as a tab delimited text file. The GEA pipeline is designed for large-scale E. coli and S. enterica genome assembly and characterization using the Center for Genomic Epidemiology command-line tools and high-performance computing. Large scale annotation is demonstrated by an analysis of more than 14,000 Salmonella genome assemblies. Testing the GEA pipeline on E. coli raw reads demonstrates reproducibility across multiple compute environments and computational usage is optimized on high performance computers.

Introduction Leveraging data science could significantly advance the understanding of the health impacts of climate change and air pollution to meet health systems’ needs and improve public health in Africa. This scoping review will aim to identify and synthesise evidence on the use of data science as an intervention to address climate change and air pollution-related health challenges in Africa.Methods and analysis The search strategy will be developed, and the search will be conducted in the Web of Science, Scopus, CAB Abstracts, MEDLINE and EMBASE electronic databases. We will also search the reference lists of eligible articles for additional records. We will screen titles, technical reports, abstracts and full texts and select studies reporting the use of data science in relation to the health effects and interventions associated with climate change and air pollution in Africa.Ethics and dissemination There are no formal ethics requirements as we are not collecting primary data. Results, once published, will be disseminated via conferences and shared with policy-makers and public health, air pollution and climate change key stakeholders in Africa.

Abstract An association between climatic conditions and asthma incidence has been widely assumed. However, it is unclear whether climatic variations have a fingerprint on asthma dynamics over long time intervals. The aim of this study is to detect a possible correlation of the Summer North Atlantic Oscillation (S-NAO) index and the self-calibrated palmer drought severity index (scPDSI) with asthma incidence over the period from 1957 to 2006 in Italy. To this aim, an analysis of non-stationary and non-linear signals was performed on the time series of the Italian databases on respiratory health (ISAYA and GEIRD) including 36,255 individuals overall, S-NAO, and scPDSI indices to search for characteristic periodicities. The ISAYA (Italian Study on Asthma in Young Adults) and GEIRD (Gene Environment Interactions in Respiratory Diseases) studies collected information on respiratory health in general population samples, born between 1925 and 1989 and aged 20–84 years at the time of the interview, from 13 Italian centres. We found that annual asthma total incidence shared the same periodicity throughout the 1957–2006 time interval. Asthma incidence turned out to be correlated with the dynamics of the scPDSI, modulated by the S-NAO, sharing the same averaged 6 year-periodicity. Since climate patterns appear to influence asthma incidence, future studies aimed at elucidating the complex relationships between climate and asthma incidence are warranted.

Objetivo: describir un paciente con isquemia miocárdica con múltiples causas. Caso Clínico: En este caso clínico se describe a un hombre de 58 años con antecedentes de hipertensión, dislipidemia, EPOC e infarto de miocardio (IAM) previo. Acudió a urgencias con dolor torácico y disnea. Los hallazgos incluyeron crepitantes bibasales, electrocardiograma con fibrosis anterior antigua, NT-ProBNP elevado y ecocardiograma con acinesia septoapical. Durante la hospitalización, experimentó taquiarritmia y deterioro hemodinámico, siendo sometido a cardioversión eléctrica (CVE). Se diagnosticó síndrome coronario agudo sin elevación del segmento ST (SCASEST) complicado con arritmia ventricular y edema pulmonar agudo. La angiografía coronaria reveló ectasias coronarias sin lesiones obstructivas, pero con estenosis leve en tres vasos. El paciente fue tratado con éxito mediante ventilación no invasiva, diuréticos, vasodilatadores y anticoagulación. Se otorgó el alta con el plan de profundizar estudios para optimizar y guiar tratamiento y finalmente se abordó al diagnóstico de Infarto de Miocardio con Arterias No Obstructivas (MINOCA) y la presencia de ectasias coronarias. Conclusión: es importante destacar las causas no isquémicas en MINOCA y la asociación entre ectasia coronaria y eventos cardiovasculares, por lo que subrayamos la necesidad de más estudios para comprender mejor la relación entre estos fenómenos.

The application of remote sensing data has been significant in modeling soil erosion. However, previous studies have fallen short in elucidating and lacked an understanding of the multifactor influencing erosion. This study addresses these limitations by employing the InVEST and the Geodetector models. Specifically, it aims (1) to delineate both spatial and temporal variations in soil erosion within the Citarum watershed from 2010 to 2020, (2) to identify the key drivers of soil erosion and unravel the underlying mechanisms, and (3) to identify the high-risk zones for soil erosion. Both models consider a range of natural predictors, including topography (slope factor), climate (precipitation factor), and vegetation cover (vegetation factor). In addition, they incorporate social parameters such as income per capita and population density, which interact with the watershed’s position in the downstream, middle, and upper streams. The results reveal that, over a decade, the average soil erosion increased by 15.50 × 106 tons, marking a 16.65% surge. The impact of factors varies significantly across different subwatershed areas. For example, fraction vegetation cover interactions influence upper- and middle-stream regions, while the downstream area is notably affected by precipitation interactions. The high-risk erosion areas in the watershed are primarily influenced by slope, precipitation, and fractional vegetation cover. In these areas, factors causing high erosion risks include slope, precipitation, and other environmental variables categorized into strata. The study highlights the varying influential factors in different watershed areas.

Abstract Background Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. Methods To further characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with a focus on associations between birth defects, drugs, and genes. Specifically, we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression changes in cell lines, known drug targets, genetic burden scores for human genes, and placental crossing scores for small molecules. Results Using ReproTox-KG and semi-supervised learning (SSL), we scored >30,000 preclinical small molecules for their potential to cross the placenta and induce birth defects, and identified >500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG can be accessed via a web-based user interface available at https://maayanlab.cloud/reprotox-kg . This site enables users to explore the associations between birth defects, approved and preclinical drugs, and all human genes. Conclusions ReproTox-KG provides a resource for exploring knowledge about the molecular mechanisms of birth defects with the potential of predicting the likelihood of genes and preclinical small molecules to induce birth defects.

Abstract In vertical contact control (VCC), a microdroplet array selectively contacts with an opposite microdroplet array. Generally, VCC is useful for the dispenser mechanism based on solute diffusion between microdroplet pairs. However, sedimentation due to gravity can cause an inhomogeneous distribution of solutes in microdroplets. Therefore, it is necessary to enhance solute diffusion to achieve the accurate dispensing of a large quantity of solute in the direction opposite to that of gravity. Herein, we applied a rotational magnetic field to the microrotors in microdroplets to enhance the solute diffusion in microdroplets. Driven by microrotors, the rotational flow can generate a homogeneous distribution of solutes in microdroplets. We analyzed the diffusion dynamics of solutes using a phenomenological model, and the results showed that the rotation of microrotors can increase the diffusion constant of solutes.

Abstract Background Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback. Results The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network ( https://www.equator-network.org/ ).

Abstract Transportation of magnetized particles (MPs) against gravity is possible by applying a magnetic field to the particles. This transport phenomenon of MPs in microdroplets can be quantitatively assessed by determining the contribution of individual forces acting on the MPs. We studied the selective transportation of MPs in microdroplets. MPs in microdroplets were transported in the opposite direction to gravity when we applied an external magnetic field larger than a threshold value. We modulated the intensity of the external magnetic field and selectively manipulated the MPs. As a result, MPs were separated into different microdroplets based on their magnetic properties. Our quantitative investigation of transport dynamics shows that the threshold magnetic field depends only on the magnetic susceptibility and the density of MPs. This is a universal criterion for the selective transport of magnetized targets such as magnetized cells in microdroplets.

A male rural worker with cutaneous leishmaniasis (CL) was initially treated with repeated cycles of Meglumine Antimoniate (Glucantime®) and two cycles of Amphotericin B deoxycholate during a three-year period. However, the patient remained with two active lesions. An experimental topical treatment with liposomal Miltefosine was tested. The efficacy was determined from the MD’s in-spection of the patient and analysis of the lesions’ photographic images, lesions samples culture, and anti-Leishmania antibodies quantification. The parasites from the patient were isolated. The parasites were typified as Leishmania braziliensis, and their susceptibility to Miltefosine, Meglu-mine Antimoniate, and Amphotericin B was measured. The wound healing was initially good with the topical treatment, but the clinical cure was achieved only with a combination of the topical lipo-somal Miltefosine and intravenous Amphotericin B. Of note, the treatment efficacy was strongly correlated with the degree of stress suffered by the patient. To our knowledge, this is the first report on using a topical Miltefosine formulation on a CL patient.

Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V–mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V–positive patients with PC.

Abstract The emergency room (ER) is the first gateway for patients with sepsis to inpatient units, and identifying best practices and benchmarks to be applied in this setting might crucially result in better patient’s outcomes. In this study, we want to evaluate the results in terms of decreased the in-hospital mortality of patients with sepsis of a Sepsis Project developed in the ER. All patients admitted to the ER of our Hospital from the 1st January, 2016 to the 31stJuly 2019 with suspect of sepsis (MEWS score ≥ of 3) and positive blood culture upon ER admission were included in this retrospective observational study. The study comprises of two periods: Period A: From the 1st Jan 2016 to the 31st Dec 2017, before the implementation of the Sepsis project. Period B: From the 1st Jan 2018 to the 31stJul 2019, after the implementation of the Sepsis project. To analyze the difference in mortality between the two periods, a univariate and multivariate logistic regression was used. The risk of in-hospital mortality was expressed as an odds ratio (OR) and a 95% confidence interval (95% CI). Overall, 722 patients admitted in ER had positive BC on admissions, 408 in period A and 314 in period B. In-hospital mortality was 18.9% in period A and 12.7% in period B (p = 0.03). At multivariable analysis, mortality was still reduced in period B compared to period A (OR 0.64, 95% CI 0.41–0.98; p = 0.045). Having an infection due to GP bacteria or polymicrobial was associated with an increased risk of death, as it was having a neoplasm or diabetes. A marked reduction in in-hospital mortality of patients with documented BSI associated with signs or symptoms of sepsis after the implementation of a sepsis project based on the application of sepsis bundles in the ER.

Abstract The spatial resolution of typical sensor probes is sufficient for measuring the average electric properties of microelectrical devices, but they are unable to measure the distribution with a spatial precision. Liquid crystal droplets (LCDs) are promising candidate for visualizing the distribution. When voltage is applied, the LCDs show rotational and translational behaviors which depend on the location of LCDs within the devices. We demonstrate that by comparing the experimental and numerical results, the electric field and electrostatic energy distribution are visualized by rotating and transporting LCDs, with a spatial resolution of 10 µm and a detection accuracy of 5 µV/µm. In addition, we produced an array of LCDs by designing periodic modulation of the electrostatic energy density in the model device. These findings show that the LCDs serve as a periodic modulator of the refractive index as well as a sensor for the observation of electric properties of microelectrical devices.

Abstract Severe/critical COVID-19 is associated with immune dysregulation and plasmatic SARS-CoV-2 detection (i.e. RNAemia). We detailed the association of SARS-CoV-2 RNAemia with immune responses in COVID-19 patients at the end of the first week of disease. We enrolled patients hospitalized in acute phase of ascertained SARS-CoV-2 pneumonia, and evaluated SARS-CoV-2 RNAemia, plasmatic cytokines, activated/pro-cytolytic T-cells phenotypes, SARS-CoV-2-specific cytokine-producing T-cells (IL-2, IFN-γ, TNF-α, IL-4, IL-17A), simultaneous Th1-cytokines production (polyfunctionality) and amount (iMFI). The humoral responses were assessed with anti-S1/S2 IgG, anti-RBD total-Ig, IgM, IgA, IgG1 and IgG3, neutralization and antibody-dependent cellular cytotoxicity (ADCC). Out of 54 patients, 27 had detectable viremia (viremic). Albeit comparable age and co-morbidities, viremic more frequently required ventilatory support, with a trend to higher death. Viremic displayed higher pro-inflammatory cytokines (IFN-α, IL-6), lower activated T-cells (HLA-DR+CD38+), lower functional SARS-CoV-2-specific T-cells (IFN-γ+CD4+, TNF-α+CD8+, IL-4+CD8+, IL-2+TNF-α+CD4+, and IL-2+TNF-α+CD4+ iMFI) and SARS-CoV-2-specific Abs (anti-S IgG, anti-RBD total-Ig, IgM, IgG1, IgG3; ID50, %ADCC). These data suggest a link between SARS-CoV-2 RNAemia at the end of the first stage of disease and immune dysregulation. Whether high ab initium viral burden and/or intrinsic host factors contribute to immune dysregulation in severe COVID-19 remains to be elucidated, to further inform strategies of targeted therapeutic interventions.

Abstract Background and objectives The identification of predictors of response to antiCGRP mAbs could favor tailored therapies and personalized treatment plans. This study is aimed at investigating predictors of ≥ 50%, ≥ 75% and 100% response at 24 weeks in patients with high-frequency episodic (HFEM: 8–14 days/month) or chronic migraine (CM). Methods This is a large, multicenter, cohort, real-life study. We considered all consecutive adult patients affected by HFEM or CM who were prescribed antiCGRP mAbs for ≥ 24 weeks in 20 headache centers. Patients were interviewed face-to-face using a shared semi-structured questionnaire carefully exploring socio-demographic and clinical characteristics. Patients received subcutaneous erenumab (70 mg or140 mg, monthly), galcanezumab (120 mg monthly, following a 240 mg loading dose), or fremanezumab (225 mg, monthly or 675 mg, quarterly) according to drug market availability, physician’s choice, or patient’s preference. The primary endpoint of the study was the assessment of ≥ 50% response predictors at 24 weeks. Secondary endpoints included ≥ 75% and 100% response predictors at 24 weeks. Results Eight hundred sixty-four migraine patients had been treated with antiCGRP mAbs for ≥ 24 weeks (erenumab: 639 pts; galcanezumab: 173 pts; fremanezumab: 55 pts). The ≥50% response (primary endpoint) in HFEM was positively associated with unilateral pain (UP) + unilateral cranial autonomic symptoms (UAs) (OR:4.23, 95%CI:1.57–11.4; p = 0.004), while in CM was positively associated with UAs (OR:1.49, 95%CI:1.05–2.11; p = 0.026), UP + UAs (OR:1.90, 95%CI:1.15–3.16; p = 0.012), UP + allodynia (OR:1.71, 95%CI:1.04–2.83; p = 0.034), and negatively associated with obesity (OR:0.21, 95%CI:0.07–0.64; p = 0.006). The 75% response (secondary endpoint) was positively associated with UP + UAs in HFEM (OR:3.44, 95%CI:1.42–8.31; p = 0.006) and with UP + UAs (OR:1.78, 95%CI:1.14–2.80; p = 0.012) and UP + allodynia (OR:1.92, 95%CI:1.22–3.06; p = 0.005) in CM. No predictor of 100% response emerged in patients with HFEM or CM. Conclusions A critical evaluation of headache characteristics indicating peripheral or central sensitization may help in predicting responsiveness to antiCGRP mAbs in HFEM and CM. A more precise pain profiling may represent a steppingstone for a mechanism-based approach and personalized treatment of migraine with compounds targeting specific molecular mechanisms.

Abstract In birds, sex is determined through cell-autonomous mechanisms and various factors, such as the dosage of DMRT1. While the sex-determination mechanism in gonads is well known, the mechanism in germ cells remains unclear. In this study, we explored the gene expression profiles of male and female primordial germ cells (PGCs) during embryogenesis in chickens to predict the mechanism underlying sex determination. Male and female PGCs were isolated from blood and gonads with a purity > 96% using flow cytometry and analyzed using RNA-seq. Prior to settlement in the gonads, female circulating PGCs (cPGCs) obtained from blood displayed sex-biased expression. Gonadal PGCs (gPGCs) also exhibited sex-biased expression, and the number of female-biased genes detected was higher than that of male-biased genes. The female-biased genes in gPGCs were enriched in some metabolic processes. To reveal the mechanisms underlying the transcriptional regulation of female-biased genes in gPGCs, we performed stimulation tests. Retinoic acid stimulation of cultured gPGCs derived from male embryos resulted in the upregulation of several female-biased genes. Overall, our results suggest that sex determination in avian PGCs involves aspects of both cell-autonomous and somatic-cell regulation. Moreover, it appears that sex determination occurs earlier in females than in males.

Abstract We proposed the detection mechanism of the micro-levels of temperature gradient in a micro-electromechanical system using the unidirectional rotation of cholesteric-liquid crystal (Ch-LC) droplets. Ch-LC droplets in the presence of an isotropic phase subjected to a heat flux rotate with a speed proportional to the magnitude of the temperature gradient. We further quantified the temperature gradient-to-torque conversion efficiency to apply the thermomechanical cross-correlation to the detection of temperature gradient. Then, we observed the rotational behavior of Ch-LC droplets after introducing them onto model devices containing patterned Au thin-film electrodes. Direct electric current applied to these Au electrodes results in unidirectional rotation of the Ch-LC droplets in response to heat flux generated from the Au electrodes. By evaluating the possible temperature gradient detection resolution using Ch-LC droplet rotation, we show that Ch-LC droplets can achieve both high spatial resolution (~ 10 µm) and high detection accuracy (~ 0.1 mK/µm).

Although botulinum toxin is widely considered an effective and safe treatment for a variety of neurological conditions (such as disabling spasticity), local or systemic adverse effects have often been reported. This study describes three cases of patients with severe acquired brain injury who were receiving speech therapy for recovering dysphagia and dysarthria but showed worsening of these symptoms after receiving BoNT treatment for motor spasticity. To increase clinicians’ knowledge of these adverse effects, we present our cases and explore their significance to avoid major complications such as aspiration pneumonia.

Abstract Background Chile was severely affected by COVID19 outbreaks but was also one of the first countries to start a nationwide program to vaccinate against the disease. Furthermore, Chile became one of the fastest countries to inoculate a high percentage of the target population and implemented homologous and heterologous booster schemes in late 2021 to prevent potential immunological waning. The aim of this study is to compare the immunogenicity and time course of the humoral response elicited by the CoronaVac vaccine in combination with homologous versus heterologous boosters. Methods We compared the immunogenicity of two doses of CoronaVac and BNT162b2 vaccines and one homologous or heterologous booster through an ELISA assay directed against the ancestral spike protein of SARS-CoV-2. Sera were collected from individuals during the vaccination schedule and throughout the implementation of homologous and heterologous booster programs in Chile. Results Our findings demonstrate that a two-dose vaccination scheme with CoronaVac induces lower levels of anti-SARS-CoV-2 spike antibodies than BNT162b2 in a broad age range (median age 42 years; interquartile range (IQR) 27-61). Furthermore, antibody production declines with time in individuals vaccinated with CoronaVac and less noticeably, with BNT162b2. Analysis of booster schemes revealed that individuals vaccinated with two doses of CoronaVac generate immunological memory against the SARS-CoV-2 ancestral strain, which can be re-activated with homologous or heterologous (BNT162b2 and ChAdOx1) boosters. Nevertheless, the magnitude of the antibody response with the heterologous booster regime was considerably higher (induction fold BNT162b2: 11.2x; ChAdoX1; 12.4x; CoronaVac: 6.0x) than the responses induced by the homologous scheme. Both homologous and heterologous boosters induced persistent humoral responses (median 122 days, IQR (108-133)), although heterologous boosters remained superior in activating a humoral response after 100 days. Conclusions Two doses of CoronaVac induces antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the BNT162b2 vaccine. However, the response induced by CoronaVac can be greatly potentiated with a heterologous booster scheme with BNT162b2 or ChAdOx1 vaccines. Furthermore, the heterologous and homologous booster regimes induce a durable antibody response which does not show signs of decay 3 months after the booster dose.

Abstract Background Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8–14 days/month) or CM. Methods This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9–12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals. Results Sixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p

Background Relatlimab plus nivolumab (anti–lymphocyte-activation gene 3 plus anti–programmed death 1 [anti–LAG-3+anti–PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.Methods We evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy–refractory patients with metastatic melanoma treated with anti–LAG-3+anti–PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαβ-Seq) combined with other multiomics profiling.Results The highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.Conclusion Anti–LAG-3+anti–PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registration ClinicalTrials.gov (NCT01968109)Funding Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.

MINOCA es un síndrome que abarca varias patologías y que ocurre en el contexto clínico de un Síndrome Coronario Agudo. Su incidencia varía de acuerdo con la población estudiada, métodos de diagnósticos utilizados y si han incluido a la Miocarditis y Síndrome de Takotsubo, los cuáles, fueron excluidos recientemente de la definición de MINOCA. Por esta razón, consideramos que la novedad de esta publicación es la no inclusión de estas dos patologías y, por lo tanto, el objetivo de la presente revisión es actualizar este síndrome de forma concisa. También se aborda el manejo de los tres tipos de MINOCA, cuyo diagnóstico se basa fundamentalmente en la utilización de imágenes complementarias específicas, ya que la coronariografia tiene sus limitaciones. El tratamiento será en general farmacológico de acuerdo con el mecanismo fisiopatológico involucrado.

Se analizan los resultados obtenidos en 19 pacientes operados por cáncer de colon izquierdo con variable grado de obstrucción. Diesisiete fueron operados por un cáncer de colon izquierdo obstructivo ubicados: cinco en el colon transverso distal, cinco en el ángulo esplénico y siete en el colon descendente proximal, tres de ellos con neoplasias sincrónicas derechas. Dos pacientes con un cáncer, tino localizado en el ángulo esplénico y otro en el descendente proximal fueron reintervenidos a las tres semanas de habérseles practicarlo una colostomía transversa por un cuadro oclusivo. No hubo mortalidad operatoria. Un paciente tuvo que ser reintervenido por el desarrollo de una peritonitis generalizada a partir de una fístula por disrrupción parcial de la anastomosis ileo- cólica termino- terminal. Se realizó la exteriorización de ambos extremos, con evolución favorable y posterior reanastomosis. También en un paciente con riii cáncer de ángulo esplénico exteriorizado hubo que drenar a los diez rijas rin absceso retroperitoneal por punción percutá nea y una lesión grado Lino del polo inferior del bazo fue resuelta con electrolulguración. Ningún paciente ha presentado diarrea invalidante y todos se han estabilizado en 2-3 deposiciones por día alrededor de los dos meses de la cirugía. La CDA, es 1.111d operación segura con una morbi-niortalidad operatoria baja y tiene un lugar privilegiado en el tratamiento de pacientes con neoplasias sincrónicas y/o carcinomas asociados a pólipos, sobre todo en aquellos casos con variable grado de obstrucción.

Introduction Early phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysis A methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and dissemination This project was approved by ICR’s Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration details SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

The hippocampus has been proposed to encode environments using a representation that contains predictive information about likely future states, called the successor representation. However, it is not clear how such a representation could be learned in the hippocampal circuit. Here, we propose a plasticity rule that can learn this predictive map of the environment using a spiking neural network. We connect this biologically plausible plasticity rule to reinforcement learning, mathematically and numerically showing that it implements the TD-lambda algorithm. By spanning these different levels, we show how our framework naturally encompasses behavioral activity and replays, smoothly moving from rate to temporal coding, and allows learning over behavioral timescales with a plasticity rule acting on a timescale of milliseconds. We discuss how biological parameters such as dwelling times at states, neuronal firing rates and neuromodulation relate to the delay discounting parameter of the TD algorithm, and how they influence the learned representation. We also find that, in agreement with psychological studies and contrary to reinforcement learning theory, the discount factor decreases hyperbolically with time. Finally, our framework suggests a role for replays, in both aiding learning in novel environments and finding shortcut trajectories that were not experienced during behavior, in agreement with experimental data.

Abstract Multiple sensors and actuators integrated in a small space, especially an elongated thin structure, require equivalent number of signal lines between microdevices, but there is limited space for signal wires. Thus, we propose a mechanism using a single microchannel where a liquid metal droplet moves and shuttles. A shuttling droplet switches multiple terminals of signal lines along a microchannel based on a traditional switching mechanism using a liquid metal droplet. Electrically conductive gallium alloy liquid metals (Galinstan) can flow in a microchannel due to their fluidity. The terminals consist of opposing electrode pairs in a microchannel. A change in a variable impedance connected to a terminal as a pseudo sensor can be read when a droplet flows in and connects electrode pairs. This paper presents switching and addressing objective terminals of chromium electrodes by a shuttling conductive droplet (500 µm in diameter and 10 mm long) in a microchannel (500 µm in diameter and 100 mm long). A demonstrated simple mechanism enables communication between multiple microdevices along a microchannel. We anticipate wide application of proposed mechanism toward a multiplexer, especially in microfluidic devices because of the advantages of utilizing microchannels as common microstructures for both microdevices and signal lines.

To characterize the immunogenicity of mRNA-1273 (Moderna, Cambridge, MA, USA) vaccine in HIV-positive hemophilic patients during the third COVID-19 wave in Italy and to investigate biomarkers of coagulation and endothelial perturbation before and after complete vaccination schedule, twenty-three consecutive adult HIV-positive patients with hemophilia were included. Blood was collected before and two weeks after vaccination. We measured anti-SARS-CoV-2 spike protein antibodies to assess immunogenicity; circulating biomarkers of coagulation (protein C and D-dimer), endothelial perturbation (von Willebrand factor (VWF)) and anti-Platelet Factor 4 (PF4) antibodies were analyzed. Flow-based analysis of thrombus formation was performed in nine patients using a flow-chamber device. Two weeks after completing the vaccination schedule, all patients had anti-spike antibodies values consistent with an effective immunization. Mean (±standard deviation) basal values of protein C and VWF (106 ± 21% and 171 ± 45%, respectively) were not significantly different from data obtained two weeks after the second dose (103 ± 20%, 162 ± 43%, respectively). D-dimer median values (interquartile range) were not significantly different at baseline (442 (603–142) ng/mL) and after the second dose (477 (654–262) ng/mL). Anti-PF4 antibodies were detected in three patients with no associated clinical manifestations. No significant differences were found in flow-based analysis of thrombus formation. Our data demonstrate that in HIV-positive patients with hemophilia, SARS-CoV-2 vaccination is effective and safe, with no effects on coagulation and endothelial perturbation.

Wilson disease (WD) is a rare copper metabolism disorder caused by mutations in the ATP7B gene. It usually affects young individuals and can produce hepatic and/or neurological involvement, potentially affecting health-related quality of life (HRQoL). We assessed HRQoL in a cohort of Spanish patients with WD and evaluated disease impact on several domains of patients’ lives, treatment adherence, drug preference and satisfaction, and healthcare resource utilisation in a cross-sectional, retrospective, multicentric, observational study. A total of 102 patients were included: 81.4% presented isolated liver involvement (group H) and 18.6% presented neurological or mixed involvement (group EH). Up to 30% of patients reported a deteriorated emotional status with anxiety and depression, which was greater in the EH subgroup; the use of neuropsychiatric drugs was high. Over 70% of the patients were satisfied with their current treatment but complained about taking too many pills, stating they would consider switching to another more patient-friendly treatment if available. The Simplified Medication Adherence Questionnaire revealed only 22.5% of patients were fully adherent to therapy, suggesting that alternative therapies are needed. This real-world study, even though is highly enriched with hepatic patients and mild disease, shows that WD impacts patients’ HRQoL, especially in the emotional domain.

El síndrome de Marfan es una enfermedad hereditaria autosómica dominante que compromete diversos sistemas que habitualmente requieren un enfoque multidisciplinario. La causa del síndrome de Marfan es desconocida, pero recientes estudios genéticos han relacionado esta enfermedad a un defecto microfibrilar extracelular localizado en el cromosoma 15q15-q21,3. Debido a la severidad de los signos y síntomas el diagnóstico suele ser a edad muy temprana. Reportamos un paciente con síndrome de Marfan extremo con todas las particulares que éste síndrome ofrece.

Introduction Novel therapies such as small protein molecule inhibitors and immunotherapies are tested in early phase trials before moving to later phase trials and ultimately standard practice. A key aim of these clinical trials is to define a toxicity profile, however, the emphasis is often on safety with measurements of organ toxicity. Other subjective side effects can be under-reported because they are not measured formally within the trial protocols. The concern from clinical practice is that cognitive toxicity is poorly studied and may be under-reported in this context. This could lead to toxicity profiles of new treatments not being fully described and patients with unmet need in terms of acknowledgement and support of symptoms. This protocol outlines a framework of an exploratory study with feasibility aspects to investigate the impact and experience of cognitive changes for patients on phase I trials.Methods and analysis This is a mixed-methods study, combining quantitative and qualitative approaches. The sample is 30 patients with advanced cancer who are participating in phase I trials of novel therapies in the early clinical trials unit of a specialist cancer centre. A test battery of validated cognitive assessments will be taken alongside patient reported outcome measures at three time points from baseline, day eight and day 28 post start of treatment. At day 28, a semi-structured interview will be conducted and the narrative thematically analysed. Results will be integrated to offer a comprehensive description of cognitive function in this patient group.Ethics and dissemination The study has received full HRA and ethical approval. It is the first study to introduce formal cognitive assessments in a cancer phase I trial context. The study has the potential to highlight previously unreported side effects and more importantly unmet need in terms of care for patients who are participating in the trials.

Purpose The NASCITA Study, a national-level, population-based, prospective cohort study, was set up to better understand the early health status of Italian children, comprising their physical, cognitive and psychological development, and how it is affected by social and health determinants, including nurturing care. NASCITA will also assess geographical differences and disparities in healthcare.Participants Participating family paediatricians from throughout Italy enrolled infants born during the enrolment period (April 2019–July 2020). The 5054 newborns seen by the 139 paediatricians for at least two visits, including the first well-child visit, and for whom parental consent was given, make up the baseline population.Findings to date Mothers had a mean age at delivery of 33.0 years and tended to have a high or medium level of education (42.5% university and 41.7% high school degrees) and to be employed (69.7%). One-third (36.1%) took folic acid supplementation appropriately, and 6.5% smoked or consumed alcohol (10.0%) during pregnancy. One-third (31.7%) of deliveries were caesarean deliveries. Concerning the newborns, 5.8% had a low birth weight and 6.2% were born prematurely. The majority (87.7%) slept in the supine position, and 63.6% were exclusively breast fed at 1 month, with a decreasing north to south prevalence (χ2t 52; p

Abstract Current classes of cancer therapeutics have negative side effects stemming from off-target cytotoxicity. One way to avoid this would be to use a drug delivery system decorated with targeting moieties, such as an aptamer, if a targeted aptamer is available. In this study, aptamers were selected against acute myeloid leukemia (AML) cells expressing the MLL-AF9 oncogene through systematic evolution of ligands by exponential enrichment (SELEX). Twelve rounds of SELEX, including two counter selections against fibroblast cells, were completed. Aptamer pools were sequenced, and three candidate sequences were identified. These sequences consisted of two 23-base primer regions flanking a 30-base central domain. Binding studies were performed using flow cytometry, and the lead sequence had a binding constant of 37.5 + / − 2.5 nM to AML cells, while displaying no binding to fibroblast or umbilical cord blood cells at 200 nM. A truncation study of the lead sequence was done using nine shortened sequences, and showed the 5′ primer was not important for binding. The lead sequence was tested against seven AML patient cultures, and five cultures showed binding at 200 nM. In summary, a DNA aptamer specific to AML cells was developed and characterized for future drug-aptamer conjugates.

Abstract Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

Abstract To ensure the safe operation of schools, workplaces, nursing homes, and other businesses during COVID-19 pandemic there is an urgent need to develop cost-effective public health strategies. Here we focus on the cruise industry which was hit early by the COVID-19 pandemic, with more than 40 cruise ships reporting COVID-19 infections. We apply mathematical modeling to assess the impact of testing strategies together with social distancing protocols on the spread of the novel coronavirus during ocean cruises using an individual-level stochastic model of the transmission dynamics of COVID-19. We model the contact network, the potential importation of cases arising during shore excursions, the temporal course of infectivity at the individual level, the effects of social distancing strategies, different testing scenarios characterized by the test’s sensitivity profile, and testing frequency. Our findings indicate that PCR testing at embarkation and daily testing of all individuals aboard, together with increased social distancing and other public health measures, should allow for rapid detection and isolation of COVID-19 infections and dramatically reducing the probability of onboard COVID-19 community spread. In contrast, relying only on PCR testing at embarkation would not be sufficient to avert outbreaks, even when implementing substantial levels of social distancing measures.

In this randomized, double-blind, placebo-controlled study, we evaluated the efficacy of an individualized technique of subcutaneous injection of botulinum toxin type A (BoNT-A) targeted (SjBoT) to the occipital or trigeminal skin area in non-responder patients with chronic migraine (CM). Patients who had not previously responded to at least two treatments of intramuscular injections of BoNT-A were randomly assigned (2:1) to receive two subcutaneous administrations of BoNT-A (up to 200 units) with the SjBoT injection paradigm or placebo. Following the skin area where the maximum pain began, treatment was given in the trigeminal or occipital region bilaterally. The primary endpoint changed in monthly headache days from baseline to the last 4 weeks. Among 139 randomized patients, 90 received BoNT-A and 49 received placebo, and 128 completed the double-blind phase. BoNT-A significantly reduced monthly headache days versus placebo (−13.2 versus −1.2; p < 0.0001) in the majority of patients who had cutaneous allodynia. Other secondary endpoints, including measures for disability (Migraine Disability Assessment questionnaire from baseline 21.96 to 7.59 after treatment, p = 0.028), also differed. Thus, in non-responder patients with CM, BoNT-A significantly reduced migraine days when administered according to the “follow the origin of maximum pain” approach using SjBoT injection paradigm.

Functional mitral regurgitation (FMR) and tricuspid regurgitation (FTR) occur due to cardiac remodeling in the presence of structurally normal valve apparatus. Two main mechanisms are involved, distinguishing an atrial functional form (when annulus dilatation is predominant) and a ventricular form (when ventricular remodeling and dysfunction predominate). Both affect the prognosis of patients with heart failure (HF) across the entire spectrum of left ventricle ejection fraction (LVEF), including preserved (HFpEF), mildly reduced (HFmrEF), or reduced (HFrEF). Currently, data on the management of functional valve regurgitation in the various HF phenotypes are limited. This review summarizes the epidemiology, pathophysiology, and treatment of FMR and FTR within the different patterns of HF, as defined by LVEF.

Abstract Background The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting. Methods This multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation. Results One hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p

Abstract Objective Insects are the most evolutionarily successful groups of organisms, and this success is largely due to their flight ability. Interestingly, some stick insects have lost their flight ability despite having wings. To elucidate the shift from wingless to flying forms during insect evolution, we compared the nutritional metabolism system among flight-winged, flightless-winged, and flightless-wingless stick insect groups. Results Here, we report RNA sequencing of midgut transcriptome of Entoria okinawaensis, a prominent Japanese flightless-wingless stick insect, and the comparative analysis of its transcriptome in publicly available midgut transcriptomes obtained from seven stick insect species. A gene enrichment analysis for differentially expressed genes, including those obtained from winged vs wingless and flight vs flightless genes comparisons, revealed that carbohydrate metabolic process-related genes were highly expressed in the winged stick insect group. We also found that the expression of the mitochondrial enolase superfamily member 1 transcript was significantly higher in the winged stick insect group than in the wingless stick insect group. Our findings could indicate that carbohydrate metabolic processes are related to the evolutionary process through which stick insects gain the ability of flight.

Abstract Formaldehyde (FA) is a human carcinogen used as formalin in hospital laboratories. We evaluated its association with human chromosomal aberrations (CAs) and the risk/protective role played by several genetic polymorphisms in this relationship, on a cohort of 57 exposed pathologists vs 48 controls. All subjects were assessed for CAs on peripheral blood lymphocytes and genotyped for the most common cancer-associated gene polymorphisms which could be related with the genotoxic outcome: CYP1A1 exon 7 (A>G), CYP1A1*2A (T>C), CYP2C19*2 (G>A), GSTT1 (Positive/Null), GSTM1 (Positive/null), GSTP1 (A>G), XRCC1 (G399A), XRCC1 (C194T), XRCC1 (A280G), XPD (A751C), XPC exon 15 (A939C), XPC exon 9 (C499T), TNFα − 308 (G>A), IL10 − 1082 (G>A), IL10 − 819 (C>T) and IL6 − 174 (G>C). Air-FA concentration was assessed through personal samplers. The comparison between pathologists and controls showed a significantly higher CAs frequency in pathologists. Significant positive correlations were found between CAs frequency and air-FA concentration while significant associations were found between variation in CAs frequency and the mutated allele for CYP1A1 exon 7 (A>G), CYP2C19*2 (G>A), GSTT1-positive, GSTM1-positive and XRCC1 (G399A). Our study confirms the role of FA as genotoxicity inductor, even in workers chronically exposed to low air-FA levels and reveals the role played by some genetic polymorphisms in this association, highlighting the importance of individual susceptibility biomarkers assessment in occupational health studies.

The bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.

Abstract Gallium alloy liquid metals (Galinstan) possessing fluidity, electric conductivity, and low toxicity are attractive for use in flexible devices and microfluidic devices. However, the oxide skin of Galinstan in the atmosphere adheres to the microchannel surface, preventing the transportation of Galinstan in the channel. To tackle the problem of the adhesion of Galinstan to microchannel, we introduced liquid with Galinstan into a channel with a diameter of 1000 μm. Then, we found that the cylindrical shape of the channel enabled smooth transportation of Galinstan independently of both the liquid and the channel material. The liquid introduced with Galinstan not only prevents adhesion but also improves the spatial controllability of Galinstan in the channel. We can control the position of Galinstan with 100 μm resolution using highly viscous (> 10 cSt) liquid. In addition, we combined the microchannel with patterned electrodes, fabricating a serially arranged capacitive device. The local capacitance detected by the patterned electrodes changed by more than 6% via the smooth transportation of Galinstan. The analysis results based on an equivalent circuit quantitatively agree with our experimental results. We can modulate the serially arranged capacitors using the smooth transportation of Galinstan in the channel.

Background: Cardiac computed tomography (CT) provides important insights into the geometrical configuration of the tricuspid valve (TV). The purpose of the present study was to assess the geometrical changes of TV in patients with functional tricuspid regurgitation (TR) using novel CT scan parameters and to correlate these findings with echocardiography. Methods: This single-center study enrolled 86 patients undergoing cardiac CT and divided them into two groups according to the presence or not of severe TR (43 patients with TR ≥ 3+ and 43 controls). The measurements collected were as follows: TV annulus area and perimeter, septal-lateral and antero-posterior annulus diameters, eccentricity, distance between commissures, segment between the geometrical centroid and commissures, and the angles of commissures. Results: We found a significant correlation between all annulus measurements and the grade of TR, except in regard to angles. TR ≥ 3+ patients had significantly larger TV annulus area and perimeter, larger septal-lateral, and antero-posterior annulus dimensions, as well as larger commissural distance and centroid-commissural distance. In patients with TR ≥ 3+ and controls, the eccentricity index predicted a circular shape and an oval shape of the annulus, respectively. Conclusions: These novel CT variables focusing on commissures increase the anatomical understanding of the TV apparatus and the TV geometrical changes in patients with severe functional TR.

Background: Climate change presents an unprecedented and urgent threat to human health and survival. South Africa’s health response will require a strong and effective intersectoral organisational effort. Aim: Exploratory interview outcomes are used to advance practice and policy recommendations, as well as for broad input in the development of a draft national framework for a health risk and vulnerability assessment (RVA) for national departments. Setting: Nationally in South Africa. Method: Twenty key expert interviews were conducted with South African experts in the field of climate change and health. Interview data was analysed by means of thematic content analysis. Results: Findings suggest that previously poor communities are most at risk to the impacts of climate change on health, as well as those with underlying medical conditions. Climate change may also serve as a catalyst for improving the healthcare system overall and should serve as the conduit to do so. A draft climate change and health RVA should take into account existing frameworks and should be implemented by local government. It is also critical that the health and health system impacts from climate change are well understood, especially in light of the plans to implement the (South African) National Health Insurance (NHI) scheme. Conclusion: Practice and policy initiatives should be holistic in nature. Consideration should be given to forming a South African National Department of Climate Change, or a similar coordinating body between the various national departments in South Africa, as health intercepts with all other domains within the climate change field.

Animals that lose one sensory modality often show augmented responses to other sensory inputs. The mechanisms underpinning this cross-modal plasticity are poorly understood. We probe such mechanisms by performing a forward genetic screen for mutants with enhanced O2 perception in Caenorhabditis elegans. Multiple mutants exhibiting increased O2 responsiveness concomitantly show defects in other sensory responses. One mutant, qui-1, defective in a conserved NACHT/WD40 protein, abolishes pheromone-evoked Ca2+ responses in the ADL pheromone-sensing neurons. At the same time, ADL responsiveness to pre-synaptic input from O2-sensing neurons is heightened in qui-1, and other sensory defective mutants, resulting in enhanced neurosecretion although not increased Ca2+ responses. Expressing qui-1 selectively in ADL rescues both the qui-1 ADL neurosecretory phenotype and enhanced escape from 21% O2. Profiling ADL neurons in qui-1 mutants highlights extensive changes in gene expression, notably of many neuropeptide receptors. We show that elevated ADL expression of the conserved neuropeptide receptor NPR-22 is necessary for enhanced ADL neurosecretion in qui-1 mutants, and is sufficient to confer increased ADL neurosecretion in control animals. Sensory loss can thus confer cross-modal plasticity by changing the peptidergic connectome.

Los tumores retroperitoneales primarios pueden ser neoplasias malignas o benignas, de las cuales el quiste mesentérico tiene presentación infrecuente. Su amplia variedad histológica incluye quistes linfáticos simples o linfangiomas, estos últimos congénitos o adquiridos, y de localización intraabdominal excepcional. Su presentación reconoce tres formas clínicas: incidental, inespecífica y aguda; cuyo abordaje terapéutico depende de las características imagenológicas, e implica el drenaje percutáneo preoperatorio en quistes gigantes, a fin de disminuir la volumetría tumoral y garantizar la quistectomía radical sin riesgo de recidiva. Se presentan 2 casos de síndrome de abdomen agudo secundario a masas quísticas retroperitoneales gigantes resueltos a través de abordaje mínimamente invasivo y revisión bibliográfica.