Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.

OBJECTIVE: To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies. DESIGN: We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies. RESULTS: Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); p = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); p < .001). No serious adverse events were documented. CONCLUSIONS: Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.

Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson's disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell-free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD. METHODS: We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fluid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease-free (non-converters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age-matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA. FINDINGS: Patients with IRBD, both converters and non-converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This finding was confirmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a significant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non-converters and converters. Conversely, a significant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder. INTERPRETATION: Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders. FUNDING: Funded by Michael J. Fox Foundation research grant MJFF-001111. Funded by MICIU/AEI/10.13039/501100011033 "ERDF A way of making Europe", grants PID2020-115091RB-I00 (RT) and PID2022-143279OB-I00 (ACo). Funded by Instituto de Salud Carlos III and European Union NextGenerationEU/PRTR, grant PMP22/00100 (RT and ACo). Funded by AGAUR/Generalitat de Catalunya, grant SGR00490 (RT and ACo). MP has an FPI fellowship, PRE2018-083297, funded by MICIU/AEI/10.13039/501100011033 "ESF Investing in your future".

Systemic inflammatory response syndrome triggered by blood-borne pathogens induces prolonged dendritic cell paralysis and immunosuppression.

Blood-borne pathogens can cause systemic inflammatory response syndrome (SIRS) followed by protracted, potentially lethal immunosuppression. The mechanisms responsible for impaired immunity post-SIRS remain unclear. We show that SIRS triggered by pathogen mimics or malaria infection leads to functional paralysis of conventional dendritic cells (cDCs). Paralysis affects several generations of cDCs and impairs immunity for 3-4 weeks. Paralyzed cDCs display distinct transcriptomic and phenotypic signatures and show impaired capacity to capture and present antigens in vivo. They also display altered cytokine production patterns upon stimulation. The paralysis program is not initiated in the bone marrow but during final cDC differentiation in peripheral tissues under the influence of local secondary signals that persist after resolution of SIRS. Vaccination with monoclonal antibodies that target cDC receptors or blockade of transforming growth factor ß partially overcomes paralysis and immunosuppression. This work provides insights into the mechanisms of paralysis and describes strategies to restore immunocompetence post-SIRS.

Experimental and numerical simulation dataset of a ferrocement wall subjected to fully-reversed cyclic load test.

The need for affordable housing in developing countries requires the development and use of new structural systems that allow easy, fast, and cheap construction while providing a sufficient seismic performance to protect the life and belongings of the population. In this regard, structural wall systems based on ferrocement have proved to be a feasible option to meet these criteria. Ferrocement is a construction system composed of mortar (i.e., cement, sand, and water) and thin and closely spaced steel reinforcement (i.e., small rebars, welded mesh, hexagonal wire mesh, metal fibers, etc.). This dataset corresponds to the hysteretic response of a ferrocement wall subjected to an increasing in-plane fully-reversed cyclic load test, following the loading protocol given by the ASTM Standard E2126-11. The dataset is composed of the forces and displacements read at the top section of the wall specimen. Finally, a nonlinear finite element model of the ferrocement wall, developed using SeismoStruct software, is also included along with the equivalent numerical simulation of the experimental test. This dataset can be potentially used for the calibration of hysteretic models with high pinching levels and the structural identification of ferrocement walls.

Neuronal excitability modulates developmental time of Drosophila melanogaster.

Developmental time is a fundamental life history trait that affects the reproductive success of animals. Developmental time is known to be regulated by many genes and environmental conditions, yet mechanistic understandings of how various cellular processes influence the developmental timing of an organism are lacking. The nervous system is known to control key processes that affect developmental time, including the release of hormones that signal transitions between developmental stages. Here we show that the excitability of neurons plays a crucial role in modulating developmental time. Genetic manipulation of neuronal excitability in Drosophila melanogaster alters developmental time, which is faster in animals with increased neuronal excitability. We find that selectively modulating the excitability of peptidergic neurons is sufficient to alter developmental time, suggesting the intriguing hypothesis that the impact of neuronal excitability on DT may be at least partially mediated by peptidergic regulation of hormone release. This effect of neuronal excitability on developmental time is seen during embryogenesis and later developmental stages. Observed phenotypic plasticity in the effect of genetically increasing neuronal excitability at different temperatures, a condition also known to modulate excitability, suggests there is an optimal level of neuronal excitability, in terms of shortening DT. Together, our data highlight a novel connection between neuronal excitability and developmental time, with broad implications related to organismal physiology and evolution.

The Adr1 transcription factor directs regulation of the ergosterol pathway and azole resistance in Candida albicans.

IMPORTANCE: Research often relies on well-studied orthologs within related species, with researchers using a well-studied gene or protein to allow prediction of the function of the ortholog. In the opportunistic pathogen Candida albicans, orthologs are usually compared with Saccharomyces cerevisiae, and this approach has been very fruitful. Many transcription factors (TFs) do similar jobs in the two species, but many do not, and typically changes in function are driven not by modifications in the structures of the TFs themselves but in the connections between the transcription factors and their regulated genes. This strategy of changing TF function has been termed transcription factor rewiring. In this study, we specifically looked for rewired transcription factors, or Candida-specific TFs, that might play a role in drug resistance. We investigated 30 transcription factors that were potentially rewired or were specific to the Candida clade. We found that the Adr1 transcription factor conferred resistance to drugs like fluconazole, amphotericin B, and terbinafine when activated. Adr1 is known for fatty acid and glycerol utilization in Saccharomyces, but our study reveals that it has been rewired and is connected to ergosterol biosynthesis in Candida albicans.

Technology Innovation and Guardrails in Elite Sport: The Future is Now.

A growing number of companies are developing or using wearable sensor technologies that can monitor, analyse and transmit data from humans in real time that can be used by the sporting, biomedical and media industries. To explore this phenomenon, we describe and review two high-profile sporting events where innovations in wearable technologies were trialled: the Tokyo 2020 Summer Olympic Games (Tokyo 2020, Japan) and the 2022 adidas Road to Records (Germany). These two major sporting events were the first time academic and industry partners came together to implement real-time wearable solutions during major competition, to protect the health of athletes competing in hot and humid environments, as well as to better understand how these metrics can be used moving forwards. Despite the undoubted benefits of such wearables, there are well-founded concerns regarding their use including: (1) limited evidence quantifying the potential beneficial effects of analysing specific parameters, (2) the quality of hardware and provided data, (3) information overload, (4) data security and (5) exaggerated marketing claims. Employment and sporting rules and regulations also need to evolve to facilitate the use of wearable devices. There is also the potential to obtain real-time data that will oblige medical personnel to make crucial decisions around whether their athletes should continue competing or withdraw for health reasons. To protect athletes, the urgent need is to overcome these ethical/data protection concerns and develop wearable technologies that are backed by quality science. The fields of sport and exercise science and medicine provide an excellent platform to understand the impact of wearable sensors on performance, wellness, health, and disease.

I Read, Therefore I Am: Examining Nonmedical Reading and Its Relationship to Empathy in Anesthesia Training.

Background: High levels of empathy among resident physicians are associated with improved patient outcomes. Empathy may be learned and practiced when reading nonmedical writing through narrative transportation, a process by which readers identify with characters and become emotionally involved in the plot. We hypothesized that residents and fellows who reported more nonmedical reading would have higher empathy levels and that empathy would decrease during training. Methods: An emailed survey was sent to program directors of Accreditation Council on Graduate Medical Education-accredited anesthesiology residency and fellowship programs, with a request to distribute the survey to trainees. The Toronto Empathy Questionnaire, reading volume, and demographics were included in the survey. Response data were analyzed using a multiple variable regression model. Results: Of 136 responses, 119 were included for data analysis. Seventeen partially completed surveys were excluded. Higher empathy scores were reported among women (P < .0001) and residents who worked 60 to 80 hours per week (P = .039). Age, postgraduate year of training, relationship status, time spent with family, and avid reading were not significantly associated with increased empathy. Conclusion: In this study, we examined whether nonmedical fiction reading would increase empathy in medical trainees. Our study was not able to find any significant association with time spent reading and increased empathy; however, we found that trainees who worked more hours, specifically 60 to 80 hours, had higher empathy scores. Limitations for this study included a smaller sample size. Further research should be done in this field to determine if there are other intangible factors that affect empathy in trainees.

Comparison of genomic-enabled cross selection criteria for the improvement of inbred line breeding populations.

A crucial step in inbred plant breeding is the choice of mating design to derive high-performing inbred varieties while also maintaining a competitive breeding population to secure sufficient genetic gain in future generations. In practice, the mating design usually relies on crosses involving the best parental inbred lines to ensure high mean progeny performance. This excludes crosses involving lower performing but more complementary parents in terms of favorable alleles. We predicted the ability of crosses to produce putative outstanding progenies (high mean and high variance progeny distribution) using genomic prediction models. This study compared the benefits and drawbacks of 7 genomic cross selection criteria (CSC) in terms of genetic gain for 1 trait and genetic diversity in the next generation. Six CSC were already published, and we propose an improved CSC that can estimate the proportion of progeny above a threshold defined for the whole mating plan. We simulated mating designs optimized using different CSC. The 835 elite parents came from a real breeding program and were evaluated between 2000 and 2016. We applied constraints on parental contributions and genetic similarities between selected parents according to usual breeder practices. Our results showed that CSC based on progeny variance estimation increased the genetic value of superior progenies by up to 5% in the next generation compared to CSC based on the progeny mean estimation (i.e. parental genetic values) alone. It also increased the genetic gain (up to 4%) and/or maintained more genetic diversity at QTLs (up to 4% more genic variance when the marker effects were perfectly estimated).

Outcomes and clinical characteristics of the compassionate use of plitidepsin for immunocompromised adult patients with COVID-19.

OBJECTIVES: To evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19. DESIGN: Retrospective observational study of data -collected from January 01, 2021 to April 30, 2022- from 35 immunocompromised adult patients with COVID-19 non-eligible for other available antiviral treatments. Main outcome measures were time to respiratory recovery (SpFi ≥ 315); COVID-19-related 30-day-cumulative mortality after first plitidepsin infusion; and time to undetectable levels of viral RNA. RESULTS: Thirty-three patients receiving a full course of plitidepsin (2.5 mg [n = 29] or 1.5 mg [n = 4]) were included. Most (69.7%) had a malignant hematologic disease and 27.3% had solid tumors. A total of 111 infusions were administered with lack of relevant safety events. Median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7-19). Median time to first negative reverse transcription-polymerase chain reaction for SARS-CoV-2 (cycle threshold >36) was 17 days (95% CI 13-25). Mortality rate was 16.3% (95% CI 3-37.3). CONCLUSION: These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients.

mRNA vaccine against malaria tailored for liver-resident memory T cells.

Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.

Terapia de estrógenos vaginales y riesgo de recurrencia en mujeres con antecedente de cáncer de mama

El cáncer de mama sigue siendo la neoplasia maligna más frecuente y una de las mortales en mujeres, considerándose un importante objetivo de la salud global y prioridad en salud pública. Con el uso de terapias innovadoras, ha mejorado la supervivencia, apareciendo condiciones asociadas, como el síndrome genitourinario menopaúsico. La terapia hormonal, se utiliza para el manejo de esta condición, mejorando sustancialmente la sintomatología, e incluso, siendo en algunos casos la única solución. La más utilizada, es la terapia de estrógenos vaginales. Sin embargo, se ha descrito un posible riesgo de recurrencia de cáncer de mama con su uso. En habla hispana, no existe evidencia que haya discutido este tópico. Se llevó a cabo una búsqueda en las bases PubMed, ScienceDirect y MEDLINE, utilizando los términos "Terapia de estrógenos vaginales", "Recurrencia" y "Cáncer de mama". Se encontró, que, de forma global, la terapia de estrógenos vaginales es una opción terapéutica eficaz y segura en el manejo del síndrome genitourinario menopaúsico en mujeres con antecedente de cáncer de mama, sin incrementar el riesgo de recurrencia, a excepción de aquellas tratadas con inhibidores de la aromatasa, en quienes se recomienda el uso de otras terapias para evitar acarrear este riesgo.

Breast cancer remains the most common malignant neoplasm and one of the leading causes of mortality in women, making it a significant target for global health efforts and a public health priority. Through the use of innovative therapies, survival rates have improved, leading to the emergence of associated conditions such as genitourinary menopausal syndrome. Hormonal therapy is employed for managing this condition, significantly alleviating its symptoms and, in some cases, serving as the sole solution. The most commonly utilized approach is vaginal estrogen therapy. Nevertheless, there have been reports of a potential risk of breast cancer recurrence associated with its use. In the Spanish-speaking context, there is limited evidence discussing this topic. A search was conducted across PubMed, ScienceDirect, and MEDLINE databases, using the terms "Vaginal Estrogen Therapy", "Recurrence" and "Breast Cancer." It was determined that, on a global scale, vaginal estrogen therapy is an effective and safe therapeutic option for managing genitourinary menopausal syndrome in women with a history of breast cancer. This therapy does not appear to increase the risk of recurrence, with the exception of those undergoing treatment with aromatase inhibitors. For these individuals, alternative therapies are recommended to mitigate this potential risk.

In Vitro Antiviral Activity of Nordihydroguaiaretic Acid against SARS-CoV-2.

The coronavirus infectious disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been spreading rapidly worldwide, creating a pandemic. This article describes the evaluation of the antiviral activity of nordihydroguaiaretic acid (NDGA), a molecule found in Creosote bush (Larrea tridentata) leaves, against SARS-CoV-2 in vitro. A 35 µM concentration of NDGA was not toxic to Vero cells and exhibited a remarkable inhibitory effect on the SARS-CoV-2 cytopathic effect, viral plaque formation, RNA replication, and expression of the SARS-CoV-2 spike glycoprotein. The 50% effective concentration for NDGA was as low as 16.97 µM. Our results show that NDGA could be a promising therapeutic candidate against SARS-CoV-2.

Synthesis and Anti-Mycobacterium tuberculosis Activity of Imidazo[2,1-b][1,3]oxazine Derivatives against Multidrug-Resistant Strains.

The emergence of multidrug-resistant strains of M. tuberculosis has raised concerns due to the greater difficulties in patient treatment and higher mortality rates. Herein, we revisited the 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine scaffold and identified potent new carbamate derivatives having MIC90 values of 0.18-1.63 µM against Mtb H37Rv. Compounds 47-49, 51-53, and 55 exhibited remarkable activity against a panel of clinical isolates, displaying MIC90 values below 0.5 µM. In Mtb-infected macrophages, several compounds demonstrated a 1-log greater reduction in mycobacterial burden than rifampicin and pretomanid. The compounds tested did not exhibit significant cytotoxicity against three cell lines or any toxicity to Galleria mellonella. Furthermore, the imidazo[2,1-b][1,3]oxazine derivatives did not show substantial activity against other bacteria or fungi. Finally, molecular docking studies revealed that the new compounds could interact with the deazaflavin-dependent nitroreductase (Ddn) in a similar manner to pretomanid. Collectively, our findings highlight the chemical universe of imidazo[2,1-b][1,3]oxazines and their promising potential against MDR-TB.

Electronic Structure and Core Spectroscopy of Scandium Fluoride Polymorphs.

Microscopic knowledge of the structural, energetic, and electronic properties of scandium fluoride is still incomplete despite the relevance of this material as an intermediate for the manufacturing of Al-Sc alloys. In a work based on first-principles calculations and X-ray spectroscopy, we assess the stability and electronic structure of six computationally predicted ScF3 polymorphs, two of which correspond to experimentally resolved single-crystal phases. In the theoretical analysis based on density functional theory (DFT), we identify similarities among the polymorphs based on their formation energies, charge-density distribution, and electronic properties (band gaps and density of states). We find striking analogies between the results obtained for the low- and high-temperature phases of the material, indirectly confirming that the transition occurring between them mainly consists of a rigid rotation of the lattice. With this knowledge, we examine the X-ray absorption spectra from the Sc and F K-edge contrasting first-principles results obtained from the solution of the Bethe-Salpeter equation on top of all-electron DFT with high-energy-resolution fluorescence detection measurements. Analysis of the computational results sheds light on the electronic origin of the absorption maxima and provides information on the prominent excitonic effects that characterize all spectra. A comparison with measurements confirms that the sample is mainly composed of the high- and low-temperature polymorphs of ScF3. However, some fine details in the experimental results suggest that the probed powder sample may contain defects and/or residual traces of metastable polymorphs.

Variability in Running Economy of Kenyan World-Class and European Amateur Male Runners with Advanced Footwear Running Technology: Experimental and Meta-analysis Results.

BACKGROUND: Advanced footwear technology improves average running economy compared with racing flats in sub-elite athletes. However, not all athletes benefit as performance changes vary from a 10% drawback to a 14% improvement. The main beneficiaries from such technologies, world-class athletes, have only been analyzed using race times. OBJECTIVE: The aim of this study was to measure running economy on a laboratory treadmill in advanced footwear technology compared to a traditional racing flat in world-class Kenyan (mean half-marathon time: 59:30 min:s) versus European amateur runners. METHODS: Seven world-class Kenyan and seven amateur European male runners completed a maximal oxygen uptake assessment and submaximal steady-state running economy trials in three different models of advanced footwear technology and a racing flat. To confirm our results and better understand the overall effect of new technology in running shoes, we conducted a systematic search and meta-analysis. RESULTS: Laboratory results revealed large variability in both world-class Kenyan road runners, which ranged from a 11.3% drawback to a 11.4% benefit, and amateur Europeans, which ranged from a 9.7% benefit to a 1.1% drawback in running economy of advanced footwear technology compared to a flat. The post-hoc meta-analysis revealed an overall significant medium benefit of advanced footwear technology on running economy compared with traditional flats. CONCLUSIONS: Variability of advanced footwear technology performance appears in both world-class and amateur runners, suggesting further testing should examine such variability to ensure validity of results and explain the cause as a more personalized approach to shoe selection might be necessary for optimal benefit.

Nonlinear Molecular Electronic Spectroscopy via MCTDH Quantum Dynamics: From Exact to Approximate Expressions.

We present an accurate and efficient approach to computing the linear and nonlinear optical spectroscopy of a closed quantum system subject to impulsive interactions with an incident electromagnetic field. It incorporates the effect of ultrafast nonadiabatic dynamics by means of explicit numerical propagation of the nuclear wave packet. The fundamental expressions for the evaluation of first- and higher-order response functions are recast in a general form that can be used with any quantum dynamics code capable of computing the overlap of nuclear wave packets evolving in different states. Here we present the evaluation of these expressions with the multiconfiguration time-dependent Hartree (MCTDH) method. Application is made to pyrene, excited to its lowest bright excited state S2 which exhibits a sub-100-fs nonadiabatic decay to a dark state S1. The system is described by a linear vibronic coupling Hamiltonian, parametrized with multiconfiguration electronic structure methods. We show that the ultrafast nonadiabatic dynamics can have a remarkable effect on the spectral line shapes that goes beyond simple lifetime broadening. Furthermore, a widely employed approximate expression based on the time scale separation of dephasing and population relaxation is recast in the same theoretical framework. Application to pyrene shows the range of validity of such approximations.

Al Coordination and Ga Interstitial Stability in a ß-(Al0.2Ga0.8)2O3 Thin Film.

Alloying Al2O3 with Ga2O3 to form ß-(AlxGa1-x)2O3 opens the door to a large number of new possibilities for the fabrication of devices with tunable properties in many high-performance applications such as optoelectronics, sensing systems, and high-power electronics. Often, the properties of these devices are impacted by defects induced during the growth process. In this work, we uncover the crystal structure of a ß-(Al0.2Ga0.8)2O3/ß-Ga2O3 interface grown by molecular beam epitaxy. In particular, we determine Al coordination and the stability of Al and Ga interstitials and their effect on the electronic structure of the material by means of scanning transmission electron microscopy combined with density functional theory. Al atoms can substitutionally occupy both octahedral and tetrahedral sites. The atomic structure of the ß-(Al0.2Ga0.8)2O3/ß-Ga2O3 interface additionally shows Al and Ga interstitials located between neighboring tetrahedrally coordinated cation sites, whose stability will depend on the number of surrounding Al atoms. The presence of Al atoms near interstitials leads to structural distortions in the lattice and creates interstitial-divacancy complexes that will eventually form deep-level states below the conduction band (Ec) at Ec -1.25 eV, Ec -1.68 eV, Ec -1.78 eV, Ec -1.83 eV, and Ec -1.86 eV for a Ga interstitial surrounded by zero, one, two, three, and four Al atoms, respectively. These findings bring new insight toward the fabrication of tunable ß-(AlxGa1-x)2O3 heterostructure-based devices with controlled electronic properties.

Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via γδ T cells and IL-17-promoted stress erythropoiesis.

Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vγ4+ γδ T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing γδ T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precursors could rescue mice from ECM. Modeling of γδ T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed individuals.

Primary and Community Care Transformation in Post-COVID Era: Nationwide General Practitioner Survey.

Introduction: The health emergency caused by COVID-19 has led to substantial changes in the usual working system of primary healthcare centers and in relations with users. The Catalan Society of Family and Community Medicine designed a survey that aimed to collect the opinions and facilitate the participation of its partners on what the future work model of general practitioners (GPs) should look like post-COVID-19. Methodology: Online survey of Family and Community Medicine members consisting of filiation data, 22 Likert-type multiple-choice questions grouped in five thematic axes, and a free text question. Results: The number of respondents to the questionnaire was 1051 (22.6% of all members): 83.2% said they spent excessive time on bureaucratic tasks; 91.8% were against call center systems; 66% believed that home care is the responsibility of every family doctor; 77.5% supported continuity of care as a fundamental value of patient-centered care; and >90% defended the contracting of complementary tests and first hospital visits from primary healthcare (PHC). Conclusions: The survey responses describe a strong consensus on the identity and competencies of the GP and on the needs of and the threats to the PHC system. The demand for an increase in health resources, greater professional leadership, elimination of bureaucracy, an increase in the number of health professionals, and greater management autonomy, are the axes towards which a new era in PHC should be directed.