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Abstract Importation of malaria infections is a suspected driver of sustained malaria prevalence on areas of Bioko Island, Equatorial Guinea. Quantifying the impact of imported infections is difficult because of the dynamic nature of the disease and complexity of designing a randomized trial. We leverage a six-month travel moratorium in and out of Bioko Island during the initial COVID-19 pandemic response to evaluate the contribution of imported infections to malaria prevalence on Bioko Island. Using a difference in differences design and data from island wide household surveys conducted before (2019) and after (2020) the travel moratorium, we compare the change in prevalence between areas of low historical travel to those with high historical travel. Here, we report that in the absence of a travel moratorium, the prevalence of infection in high travel areas was expected to be 9% higher than observed, highlighting the importance of control measures that target imported infections.

Metastatic lung cancer remains a leading cause of death worldwide, with its intricate metastatic cascade posing significant challenges to researchers and clinicians. Despite substantial progress in understanding this cascade, many aspects remain elusive. Microfluidic-based vasculature-on-chip models have emerged as powerful tools in cancer research, enabling the simulation of specific stages of tumor progression. In this study, we investigate the extravasation behaviors of A549 lung cancer cell subpopulations, revealing distinct differences based on their phenotypes. Our results show that holoclones, which exhibit an epithelial phenotype, do not undergo extravasation. In contrast, paraclones, characterized by a mesenchymal phenotype, demonstrate a notable capacity for extravasation. Furthermore, we observed that paraclones migrate significantly faster than holoclones within the microfluidic model. Importantly, we found that the depletion of vascular endothelial growth factor (VEGF) effectively inhibits the extravasation of paraclones. These findings highlight the utility of microfluidic-based models in replicating key aspects of the metastatic cascade. The insights gained from this study underscore the potential of these models to advance precision medicine by facilitating the assessment of patient-specific cancer cell dynamics and drug responses. This approach could lead to improved strategies for predicting metastatic risk and tailoring personalized cancer therapies, potentially involving the sampling of cancer cells from patients during tumor resection or biopsies.

Abstract Background Indoor residual spraying (IRS) is a common vector control strategy in countries with high malaria burden. Historically, social norms have prevented women from working in IRS programmes. The Bioko Island Malaria Elimination Project has actively sought to reduce gender inequality in malaria control operations for many years by promoting women’s participation in IRS. Methods This study investigated the progress of female engagement and compared spray productivity by gender from 2010 to 2021, using inferential tests and multivariable regression. Spray productivity was measured by rooms sprayed by spray operator per day (RSOD), houses sprayed by spray operator per day (HSOD), and the daily productivity ratio (DPR), defined as the ratio of RSOD to HSOD, which standardized productivity by house size. Results The percentage of women participating in IRS has increased over time. The difference in DPR comparing male and female spray operators was only statistically significant (p

Abstract Contextual overgeneralization of emotional memory is a core aspect of anxiety disorders. Identifying methods to enhance contextual dependency of emotional memory is therefore of significant clinical interest. Animal research points to a promising approach: reexposure to the context in which fear is acquired reduces generalization to other contexts. However, the exact conditions for this effect are unknown, complicating translation to effective interventions. Most notably, exposure to a context that resembles—but is not identical to—the learning context may diminish contextual dependency of memory by integration of additional contextual cues. Here, we therefore assessed in a large-scale study (N = 180) whether context reexposure enhances contextual dependency of emotional episodic memory whereas exposure to a similar context impairs it. We also tested whether relatively strong memory retrieval during context (re)exposure amplifies these effects. We replicated prior research showing that correct recognition depends on context and contextual dependency is lower for emotional than neutral memories. However, exposure to the encoding context or a similar context did not affect contextual dependency of memory, and retrieval strength did not interact with such effects. Thorough insight into factors underlying the effects of context (re)exposure on contextual dependency seems key to eventually attain a memory recontextualization intervention.

Abstract Background Since 2004, malaria transmission on Bioko Island has declined significantly as a result of the scaling-up of control interventions. The aim of eliminating malaria from the Island remains elusive, however, underscoring the need to adapt control to the local context. Understanding the factors driving the risk of malaria infection is critical to inform optimal suits of interventions in this adaptive approach. Methods This study used individual and household-level data from the 2015 and 2018 annual malaria indicator surveys on Bioko Island, as well as remotely-sensed environmental data in multilevel logistic regression models to quantify the odds of malaria infection. The analyses were stratified by urban and rural settings and by survey year. Results Malaria prevalence was higher in 10–14-year-old children and similar between female and male individuals. After adjusting for demographic factors and other covariates, many of the variables investigated showed no significant association with malaria infection. The factor most strongly associated was history of travel to mainland Equatorial Guinea (mEG), which increased the odds significantly both in urban and rural settings (people who travelled had 4 times the odds of infection). Sleeping under a long-lasting insecticidal net decreased significantly the odds of malaria across urban and rural settings and survey years (net users had around 30% less odds of infection), highlighting their contribution to malaria control on the Island. Improved housing conditions indicated some protection, though this was not consistent across settings and survey year. Conclusions Malaria risk on Bioko Island is heterogeneous and determined by a combination of factors interacting with local mosquito ecology. These interactions grant further investigation in order to better adapt control according to need. The single most important risk factor identified was travel to mEG, in line with previous investigations, and represents a great challenge for the success of malaria control on the Island.

Abstract Despite it being widely acknowledged that the most important function of memory is to facilitate the prediction of significant events in a complex world, no studies to date have investigated how our ability to infer associations across distinct but overlapping experiences is affected by the inclusion of threat memories. To address this question, participants (n = 35) encoded neutral predictive associations (A → B). The following day these memories were reactivated by pairing B with a new aversive or neutral outcome (B → CTHREAT/NEUTRAL) while pupil dilation was measured as an index of emotional arousal. Then, again 1 day later, the accuracy of indirect associations (A → C?) was tested. Associative inferences involving a threat learning memory were impaired whereas the initial memories were retroactively strengthened, but these effects were not moderated by pupil dilation at encoding. These results imply that a healthy memory system may compartmentalize episodic information of threat, and so hinders its recall when cued only indirectly. Malfunctioning of this process may cause maladaptive linkage of negative events to distant and benign memories, and thereby contribute to the development of clinical intrusions and anxiety.

Chronic lung diseases result from alteration and/or destruction of lung tissue, inevitably causing decreased breathing capacity and quality of life for patients. While animal models have paved the way for our understanding of pathobiology and the development of therapeutic strategies for disease management, their translational capacity is limited. There is, therefore, a well-recognised need for innovative in vitro models to reflect chronic lung diseases, which will facilitate mechanism investigation and the advancement of new treatment strategies. In the last decades, lungs have been modelled in healthy and diseased conditions using precision-cut lung slices, organoids, extracellular matrix-derived hydrogels and lung-on-chip systems. These three-dimensional models together provide a wide spectrum of applicability and mimicry of the lung microenvironment. While each system has its own limitations, their advantages over traditional two-dimensional culture systems, or even over animal models, increases the value of in vitro models. Generating new and advanced models with increased translational capacity will not only benefit our understanding of the pathobiology of lung diseases but should also shorten the timelines required for discovery and generation of new therapeutics. This article summarises and provides an outline of the European Respiratory Society research seminar “Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research”, held in Lisbon, Portugal, in April 2022. Current in vitro models developed for recapitulating healthy and diseased lungs are outlined and discussed with respect to the challenges associated with them, efforts to develop best practices for model generation, characterisation and utilisation of models and state-of-the-art translational potential.

Viral and bacterial infections continue to pose significant challenges for numerous individuals globally. To develop novel therapies to combat infections, more insight into the actions of the human innate and adaptive immune system during infection is necessary. Human in vitro models, such as organs-on-chip (OOC) models, have proven to be a valuable addition to the tissue modeling toolbox. The incorporation of an immune component is needed to bring OOC models to the next level and enable them to mimic complex biological responses. The immune system affects many (patho)physiological processes in the human body, such as those taking place during an infection. This tutorial review introduces the reader to the building blocks of an OOC model of acute infection to investigate recruitment of circulating immune cells into the infected tissue. The multi-step extravasation cascade in vivo is described, followed by an in-depth guide on how to model this process on a chip. Next to chip design, creation of a chemotactic gradient and incorporation of endothelial, epithelial, and immune cells, the review focuses on the hydrogel extracellular matrix (ECM) to accurately model the interstitial space through which extravasated immune cells migrate towards the site of infection. Overall, this tutorial review is a practical guide for developing an OOC model of immune cell migration from the blood into the interstitial space during infection.

Prolonged exposure to environmental respirable toxicants can lead to the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and fibrosis. The limited number of FDA-approved inhaled drugs for these serious lung conditions has led to a shift from in vivo towards the use of alternative in vitro human-relevant models to better predict the toxicity of inhaled particles in preclinical research. While there are several inhalation exposure models for the upper airways, the fragile and dynamic nature of the alveolar microenvironment has limited the development of reproducible exposure models for the distal lung. Here, we present a mechanistic approach using a new generation of exposure systems, the Cloud α AX12. This novel in vitro inhalation tool consists of a cloud-based exposure chamber (VITROCELL) that integrates the breathing AXLung-on-chip system (AlveoliX). The ultrathin and porous membrane of the AX12 plate was used to create a complex multicellular model that enables key physiological culture conditions: the air-liquid interface (ALI) and the three-dimensional cyclic stretch (CS). Human-relevant cellular models were established for a) the distal alveolar-capillary interface using primary cell-derived immortalized alveolar epithelial cells (AXiAECs), macrophages (THP-1) and endothelial (HLMVEC) cells, and b) the upper-airways using Calu3 cells. Primary human alveolar epithelial cells (AXhAEpCs) were used to validate the toxicity results obtained from the immortalized cell lines. To mimic in vivo relevant aerosol exposures with the Cloud α AX12, three different models were established using: a) titanium dioxide (TiO2) and zinc oxide nanoparticles b) polyhexamethylene guanidine a toxic chemical and c) an anti-inflammatory inhaled corticosteroid, fluticasone propionate (FL). Our results suggest an important synergistic effect on the air-blood barrier sensitivity, cytotoxicity and inflammation, when air-liquid interface and cyclic stretch culture conditions are combined. To the best of our knowledge, this is the first time that an in vitro inhalation exposure system for the distal lung has been described with a breathing lung-on-chip technology. The Cloud α AX12 model thus represents a state-of-the-art pre-clinical tool to study inhalation toxicity risks, drug safety and efficacy.

Summary: The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC.

The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line (AXiAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment (AXlung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. AXiAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, AXiAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor β1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that AXiAECs cultured on the AXlung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm2) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics.

Zamprogno et al. report a lung-on-a-chip of the second generation that mimics an array of alveoli with in vivo-like dimensions, based on a thin, stretchable collagen-elastin membrane used to reproduce the air-blood barrier functions. The membrane is stable, can be cultured on both sides for weeks, is biodegradable and its elastic properties allow mimicking respiratory motions by mechanically stretching the cells.

Abstract Background Ultrasound-guided fascia iliaca compartment block (US-FICB) is not part of the learning curriculum of the emergency physicians (EP) and is usually performed by anesthesiologists. However, several studies promote EP to use this procedure. The goal of this study was to assess the feasibility of a training concept for non-anesthesiologists for the US-FICB on a simulator based on a validating learning path. Method This was a feasibility study. Emergency physicians and medical students received a 1-day training with a learning phase (theoretical and practical skills), followed by an assessment phase. The primary outcome at the assessment phase was the number of attempts before successfully completing the procedure. The secondary outcomes were the success rate at first attempt, the length of procedure (LOP), and the stability of the probe, corresponding to the visualization of the needle tip (and its tracking) throughout the procedure, evaluated on a Likert scale. Results A total of 25 participants were included. The median number of attempts was 2.0 for emergency physicians and 2.5 for medical students, and this difference was not significant (p = 0.140). Seven participants (28%) succeeded at the first attempt of the procedure; the difference between emergency physicians and medical students was not significant (37% versus 21%; p = 0.409). The average LOP was 19.7 min with a significant difference between emergency physicians and medical students (p = 0.001). There was no significant difference regarding the stability of the probe between the two groups. Conclusion Our 1-day training for non-anesthesiologists with or without previous skills in ultrasound seems to be feasible for learning the US-FICB procedure on a simulator.

In the lungs, vascular endothelial cells experience cyclic mechanical strain resulting from rhythmic breathing motions and intraluminal blood pressure. Mechanical stress creates evident physiological, morphological, biochemical, and gene expression changes in vascular endothelial cells. However, the exact mechanisms of the mechanical signal transduction into biological responses remain to be clarified. Besides, the level of mechanical stress is difficult to determine due to the complexity of the local distension patterns in the lungs and thus assumed to be the same as the one acting on the alveolar epithelium. Existing in vitro models used to investigate the effect of mechanical stretch on endothelial cells are usually limited to two-dimensional (2D) cell culture platforms, which poorly mimic the typical three-dimensional structure of the vessels. Therefore, the development of an advanced in vitro vasculature model that closely mimics the dynamic of the human lung vasculatures is highly needed. Here, we present the first study that investigates the interplay of the three-dimensional (3D) mechanical cyclic stretch and its magnitude with vascular endothelial growth factor (VEGF) stimulation on a 3D perfusable vasculature in vitro. We studied the effects of the cyclic strain on a perfusable 3D vasculature, made of either human lung microvascular endothelial cells or human umbilical vein endothelial cells embedded in a gel layer. The in vitro 3D vessels underwent both in vivo-like longitudinal and circumferential deformations, simultaneously. Our results showed that the responses of the human lung microvascular endothelial cells and human umbilical vein endothelial cells to cyclic stretch were in good agreement. Although our 3D model was in agreement with the 2D model in predicting a cytoskeletal remodeling in response to different magnitudes of cyclic stretch, however, we observed several phenomena in the 3D model that the 2D model was unable to predict. Angiogenic sprouting induced by VEGF decreased significantly in the presence of cyclic stretch. Similarly, while treatment with VEGF increased vascular permeability, the cyclic stretch restored vascular barrier tightness and significantly decreased vascular permeability. One of the major findings of this study was that a 3D microvasculature can be exposed to a much higher mechanical cyclic stress level than reported in the literature without any dysfunction of its barrier. For higher magnitudes of the cyclic stretch, the applied longitudinal strain level was 14% and the associated circumferential strain reached the equivalent of 63%. In sharp contrast to our findings, such strain typically leads to the disruption of the endothelial barrier in a 2D stretching assay and is considered pathological. This highlights the importance of 3D modeling to investigate mechanobiology effects rather than using a simple endothelial monolayer, which truly recapitulates the in vivo situation.

Abstract The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.

Abstract Background Plain abdominal radiography (PAR) is routinely performed in emergency departments (EDs). This study aimed to (1) identify the indications for PAR in EDs and compare them against international guidelines, (2) uncover predictors of non-compliance with guidelines, and (3) describe the use of additional radiological examinations in EDs. Methods Retrospective cohort study in the EDs of two hospitals in Geneva, Switzerland, including all adult patients who underwent PAR in the EDs. Indications were considered “appropriate” if complying with guidelines. Predictors of non-compliance were identified by univariate and multivariate analyses. Results Over 1 year, PAR was performed in 1997 patients (2.2% of all admissions). Their mean age was 59.7 years, with 53.1% of female patients. The most common indications were constipation (30.8%), suspected ileus (28.9%), and abdominal pain (15.3%). According to the French and American guidelines, only 11.8% of the PARs were indicated, while 46.2% of them complied with the Australian and British guidelines. On multivariate analysis, admission to the private hospital ED (odds ratio [OR] 3.88, 95% CI 1.78–8.45), female gender (OR 1.95, 95% CI 1.46–2.59), and an age > 65 years (OR 2.41, 95%CI 1.74–3.32) were associated with a higher risk of inappropriate PAR. Additional radiological examinations were performed in 73.7% of patients. Conclusions Most indications for PAR did not comply with guidelines and elderly women appeared particularly at risk of being exposed to inappropriate examination. PAR did not prevent the need for additional examinations. Local guidelines should be developed, and initiatives should be implemented to reduce unnecessary PARs. Trial registration ClinicalTrials.gov, identifier NCT02980081.

Abstract Background Acute abdominal pain accounts for about 10% of emergency department visits and has progressively become the primary indication for CT scanning in most centers. The goal of our study is to identify biological or clinical variables able to predict or rule out significant pathology (conditions requiring urgent medical or surgical treatment) on abdominal CT in patients presenting to an emergency department with acute abdominal pain. Methods This was a retrospective cohort study performed in the emergency department of an academic center with an annual census of 60′000 patients. One hundred and-nine consecutive patients presenting with an acute non-traumatic abdominal pain, not suspected of appendicitis or renal colic, during the first semester of 2013, who underwent an abdominal CT were included. Two medical students, completing their last year of medical school, extracted the data from patients’ electronic health record. Ambiguities in the formulations of clinical symptoms and signs in the patients’ records were solved by consulting a board certified emergency physician. Nine clinical and biological variables were extracted: shock index, peritonism, abnormal bowel sounds, fever (> 38 °C), intensity and duration of the pain, leukocytosis (white blood cell count >11G/L), relative lymphopenia (

BackgroundGeospatial datasets of population are becoming more common in models used for health policy. Publicly-available maps of human population make a consistent picture from inconsistent census data, and the techniques they use to impute data makes each population map unique. Each mapping model explains its methods, but it can be difficult to know which map is appropriate for which policy work. High quality census datasets, where available, are a unique opportunity to characterize maps by comparing them with truth.MethodsWe use census data from a bed-net mass-distribution campaign on Bioko Island, Equatorial Guinea, conducted by the Bioko Island Malaria Elimination Program as a gold standard to evaluate LandScan (LS), WorldPop Constrained (WP-C) and WorldPop Unconstrained (WP-U), Gridded Population of the World (GPW), and the High-Resolution Settlement Layer (HRSL). Each layer is compared to the gold-standard using statistical measures to evaluate distribution, error, and bias. We investigated how map choice affects burden estimates from a malaria prevalence model.ResultsSpecific population layers were able to match the gold-standard distribution at different population densities. LandScan was able to most accurately capture highly urban distribution, HRSL and WP-C matched best at all other lower population densities. GPW and WP-U performed poorly everywhere. Correctly capturing empty pixels is key, and smaller pixel sizes (100 m vs 1 km) improve this. Normalizing areas based on known district populations increased performance. The use of differing population layers in a malaria model showed a disparity in results around transition points between endemicity levels.DiscussionThe metrics in this paper, some of them novel in this context, characterize how these population maps differ from the gold standard census and from each other. We show that the metrics help understand the performance of a population map within a malaria model. The closest match to the census data would combine LandScan within urban areas and the HRSL for rural areas. Researchers should prefer particular maps if health calculations have a strong dependency on knowing where people are not, or if it is important to categorize variation in density within a city.

BACKGROUND Acute pain is the most common complaint of patients presenting to emergency departments (EDs). Effective pain management is a core ED mission, but numerous studies have pointed to insufficient pain treatment or oligoanalgesia. According to a 1997 national survey in Swiss EDs, a validated pain scale was used in only 14%, an analgesia protocol in

Two graphene-based nanofillers of different sizes were melt mixed with polylactide acid (PLA). Composite films based on graphite nanoplatelets (GNPs) with the largest lateral size showed superior electrical conductivity and a lower percolation threshold after melt-compounding and hot-pressing at room temperature. However, upon annealing in the melt, composites based on GNPs with the smallest lateral size displayed significantly improved electrical conductivity and a decrease in percolation threshold as a result of dynamic percolation while composites based on large GNPs showed hardly any change in conductivity and percolation threshold. Hybrid filler systems based on 5 wt% GNP with variable small/large GNP filler ratios displayed synergistic effects in the formation of a conductive network during thermal annealing, and an optimum filler ratio of 50/50 was found to achieve the highest conductivity after annealing. This annealing-induced increase in particle connectivity for composites based on 5 wt.% hybrid small/large GNPs was also reflected in rheological measurements by the manifestation of a plateau in the storage modulus at low frequencies after annealing while such phenomenon was not observed for nanocomposites solely based on either small or large GNPs at similar loadings.

Micro- and nanostructures found in nature can be adopted to new uses and materials in engineered composites. Here authors demonstrate large enhancements in toughness and electrical conductivity in a ceramic upon addition of graphene at low (1 volume %) levels.

OBJECTIVE:Overcrowding is common in most emergency departments (ED). Despite the use of validated triage systems, some patients are at risk of delayed medical evaluation. The objective of this study was to assess the impact of a patient-flow physician coordinator (PFPC) on the proportion of patients offered medical evaluation within time limits imposed by the Swiss Emergency Triage Scale (SETS) and on patient flow within the emergency department of a teaching urban hospital. METHODS:In this before-after retrospective cohort study, we compared the proportions of patients who received their first medical contact within SETS-imposed time limits, mean waiting times before first medical consultation, mean length of stay, and number of patients who left without being seen by a physician, between two periods before and after introducing a PFPC. The PFPC was a senior physician charged with quickly assessing in the waiting area patients who could not immediately be seen and managing patient flow within the department. RESULTS:Before introducing the PFPC position, 33,605 patients were admitted, versus 36,288 after. Introducing a PFPC enabled the department to increase the proportion of patients seen within the SETS-imposed time limits from 60.1% to 69.0% (p

AIMS OF THE STUDY: Profound hyponatremia (

BackgroundThe statistical plan of a phase II trial should balance minimizing the premature termination of potentially beneficial therapies (i.e. false negatives) and the further, costly testing of ineffective drugs (i.e. false positives). We sought to examine the methodology, reporting, and bias in the interpretation of outcomes of phase II oncology trials in recent years.Materials and methodsIn a retrospective cross-sectional analysis, we reviewed all full-length articles published on PubMed from 1 January 2021 to 20 June 2022. We searched for data regarding the sample size calculation (number, α value, power, and expected effect size), the primary and secondary outcomes and results, and the authors' conclusion of the study.ResultsAbout 5.4% of studies (n = 10) used a statistical power that was inferior to 80%, and 16.7% (n = 34) did not indicate the level of power for the sample size calculation. Approximately 16.7% (n = 31) of studies used a one-sided α level of ≤0.025; 17.7% (n = 33) of studies used a predefined threshold (no comparator effect size or difference between groups) to determine the sample size for efficacy. The percentage of studies with a positive authors' conclusion but not meeting the primary endpoint, or the endpoint was equivocal, was 27.4% (n = 51).ConclusionMany randomized phase II studies in oncology failed to report essential data for determining sample size calculations, many did not actually use a comparator to determine efficacy even though the studies were randomized, and many had positive conclusions even though the results were indeterminate or the primary endpoint was not met.

Stromal cells such as myofibroblasts influence tumor progression. The mechanisms are unclear but may involve effects on both tumor cells and recruitment of bone marrow-derived mesenchymal stromal cells (MSCs) which then colonize tumors. Using iTRAQ and LC-MS/MS we identified the adipokine, chemerin, as overexpressed in esophageal squamous cancer associated myofibroblasts (CAMs) compared with adjacent tissue myofibroblasts (ATMs). The chemerin receptor, ChemR23, is expressed by MSCs. Conditioned media (CM) from CAMs significantly increased MSC cell migration compared to ATM-CM; the action of CAM-CM was significantly reduced by chemerin-neutralising antibody, pretreatment of CAMs with chemerin siRNA, pretreatment of MSCs with ChemR23 siRNA, and by a ChemR23 receptor antagonist, CCX832. Stimulation of MSCs by chemerin increased phosphorylation of p42/44, p38 and JNK-II kinases and inhibitors of these kinases and PKC reversed chemerin-stimulated MSC migration. Chemerin stimulation of MSCs also induced expression and secretion of macrophage inhibitory factor (MIF) that tended to restrict migratory responses to low concentrations of chemerin but not higher concentrations. In a xenograft model consisting of OE21 esophageal cancer cells and CAMs, homing of MSCs administered i.v. was inhibited by CCX832. Thus, chemerin secreted from esophageal cancer myofibroblasts is a potential chemoattractant for MSCs and its inhibition may delay tumor progression.

BACKGROUND: In Switzerland, 30% of HIV-infected individuals are diagnosed late. To optimize HIV testing, the Swiss Federal Office of Public Health (FOPH) updated 'Provider Induced Counseling and Testing' (PICT) recommendations in 2010. These permit doctors to test patients if HIV infection is suspected, without explicit consent or pre-test counseling; patients should nonetheless be informed that testing will be performed. We examined awareness of these updated recommendations among emergency department (ED) doctors. METHODS: We conducted a questionnaire-based survey among 167 ED doctors at five teaching hospitals in French-Speaking Switzerland between 1(st) May and 31(st) July 2011. For 25 clinical scenarios, participants had to state whether HIV testing was indicated or whether patient consent or pre-test counseling was required. We asked how many HIV tests participants had requested in the previous month, and whether they were aware of the FOPH testing recommendations. RESULTS: 144/167 doctors (88%) returned the questionnaire. Median postgraduate experience was 6.5 years (interquartile range [IQR] 3; 12). Mean percentage of correct answers was 59 ± 11%, senior doctors scoring higher (P=0.001). Lowest-scoring questions pertained to acute HIV infection and scenarios where patient consent was not required. Median number of test requests was 1 (IQR 0-2, range 0-10). Only 26/144 (18%) of participants were aware of the updated FOPH recommendations. Those aware had higher scores (P=0.001) but did not perform more HIV tests. CONCLUSIONS: Swiss ED doctors are not aware of the national HIV testing recommendations and rarely perform HIV tests. Improved recommendation dissemination and adherence is required if ED doctors are to contribute to earlier HIV diagnoses.

BackgroundWhen a new drug comes to the market, the incentive for the sponsoring company is to maximize the treatment duration in order for the patient to reap the full therapeutic benefit of the product and achieve a positive trial result. We sought to enumerate instances when an already-approved oncology drug was used as a comparator for a newer drug seeking approval and compare the duration of treatment when it is used in the intervention arm to when it is used as a comparator.Patients and methodsIn a cross-sectional analysis, we searched drug approval announcements for advanced, metastatic, or unresectable cancers between 2009 and 2020. We included studies reporting on an approved drug and studies reporting on when the same drug was used as a comparator for other drugs seeking Food and Drug Administration (FDA) approval. We examined median progression-free survival and duration of treatment for when the drug was initially approved and for when the drug was used as a comparator for other drugs that were seeking approval.ResultsOf the 23 instances when an approved drug was later used as a comparator against a newer drug seeking FDA approval, we found 11 instances (47.8%) where the drug, when used as a comparator arm, had a shorter duration of treatment than when it was used in the intervention arm. The median duration of treatment in the study initially testing the drug was 6.0 months (range: 2.2-12.7 months), whereas the median duration of treatment when the same drug was used as a comparator was 4.9 months (range: 1.7-12.0 months).ConclusionsThese results suggest that there is bias in how long a patient receives a given therapy, and this bias favors the newer therapy. Clinical trialists should seek to utilize methodology that reduces bias so that the relative efficacy of newer drugs can be objectively assessed.

Recent contributions to the design, development, and fabrication of microtechnological devices for chemical analysis are summarized. The discussion includes microdisk-electrode arrays for voltammetric analysis of trace metals, and micro total-analysis systems for coulometric nanotitrations of different analytes.

The intrinsic properties of nanomaterials offer promise for technological revolutions in many fields, including transportation, soft robotics, and energy. Unfortunately, the exploitation of such properties in polymer nanocomposites is extremely challenging due to the lack of viable dispersion routes when the filler content is high. We usually face a dichotomy between the degree of nanofiller loading and the degree of dispersion (and, thus, performance) because dispersion quality decreases with loading. Here, we demonstrate a potentially scalable pressing-and-folding method (P & F), inspired by the art of croissant-making, to efficiently disperse ultrahigh loadings of nanofillers in polymer matrices. A desired nanofiller dispersion can be achieved simply by selecting a sufficient number of P & F cycles. Because of the fine microstructural control enabled by P & F, mechanical reinforcements close to the theoretical maximum and independent of nanofiller loading (up to 74 vol %) were obtained. We propose a universal model for the P & F dispersion process that is parametrized on an experimentally quantifiable " D factor". The model represents a general guideline for the optimization of nanocomposites with enhanced functionalities including sensing, heat management, and energy storage.