In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma.

The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.

RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.

Selective KRASG12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRASG12C-mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients' biopsies identified a number of acquired KRAS mutations -both in cis and in trans- in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.

Cosmological analogies for geophysical flows, Lagrangians, and new analogue gravity systems.

Formal analogies between the ordinary differential equations describing geophysical flows and Friedmann cosmology are developed. As a result, one obtains Lagrangian and Hamiltonian formulations of these equations, while laboratory experiments aimed at testing geophysical flows are shown to constitute analogue gravity systems for cosmology.

When can we compute analytically lookback time, age of the universe, and luminosity distance?

In Friedmann-Lemaître-Robertson-Walker cosmology, it is sometimes possible to compute analytically lookback time, age of the universe, and luminosity distance versus redshift, expressing them in terms of a finite number of elementary functions. We classify these situations using the Chebyshev theorem of integration and providing examples.

Nosocomial Transmission of SARS-CoV-2 Involving Vaccinated Health Care Workers.

COVID-19 vaccination has proven to be effective at preventing symptomatic disease but there are scarce data to fully understand whether vaccinated individuals can still behave as SARS-CoV-2 transmission vectors. Based on viral genome sequencing and detailed epidemiological interviews, we report a nosocomial transmission event involving two vaccinated health care-workers (HCWs) and four patients, one of them with fatal outcome. Strict transmission control measures, as during the prevaccination period, must be kept between HCWs and HCWs-patients in nosocomial settings. IMPORTANCE COVID-19 vaccination has proven to be effective at preventing symptomatic disease. Although some transmission events involving vaccinated cases have also been reported, scarce information is still available to fully understand whether vaccinated individuals may still behave as vectors in SARS-CoV-2 transmission events. Here, we report a SARS-CoV-2 nosocomial transmission event, supported on whole genome sequencing, in early March 2021 involving two vaccinated HCWs and four patients in our institution. Strict transmission control measures between HCWs and HCWs - patients in nosocomial settings must not be relaxed, and should be kept as strictly as during the prevaccination period.

Overlapping of Independent SARS-CoV-2 Nosocomial Transmissions in a Complex Outbreak.

SARS-CoV-2 nosocomial outbreaks in the first COVID-19 wave were likely associated with a shortage of personal protective equipment and scarce indications on control measures. Having covered these limitations, updates on current SARS-CoV-2 nosocomial outbreaks are required. We carried out an in-depth analysis of a 27-day nosocomial outbreak in a gastroenterology ward in our hospital, potentially involving 15 patients and 3 health care workers. Patients had stayed in one of three neighboring rooms in the ward. The severity of the infections in six of the cases and a high fatality rate made the clinicians suspect the possible involvement of a single virulent strain persisting in those rooms. Whole-genome sequencing (WGS) of the strains from 12 patients and 1 health care worker revealed an unexpected complexity. Five different SARS-CoV-2 strains were identified, two infecting a single patient each, ruling out their relationship with the outbreak; the remaining three strains were involved in three independent, overlapping, limited transmission clusters with three, three, and five cases. Whole-genome sequencing was key to understand the complexity of this outbreak. IMPORTANCE We report a complex epidemiological scenario of a nosocomial COVID-19 outbreak in the second wave, based on WGS analysis. Initially, standard epidemiological findings led to the assumption of a homogeneous outbreak caused by a single SARS-CoV-2 strain. The discriminatory power of WGS offered a strikingly different perspective consisting of five introductions of different strains, with only half of them causing secondary cases in three independent overlapping clusters. Our study exemplifies how complex the SARS-CoV-2 transmission in the nosocomial setting during the second COVID-19 wave occurred and leads to extending the analysis of outbreaks beyond the initial epidemiological assumptions.

Point-of-care manufacturing: a single university hospital's initial experience.

BACKGROUND: The integration of 3D printing technology in hospitals is evolving toward production models such as point-of-care manufacturing. This study aims to present the results of the integration of 3D printing technology in a manufacturing university hospital. METHODS: Observational, descriptive, retrospective, and monocentric study of 907 instances of 3D printing from November 2015 to March 2020. Variables such as product type, utility, time, or manufacturing materials were analyzed. RESULTS: Orthopedic Surgery and Traumatology, Oral and Maxillofacial Surgery, and Gynecology and Obstetrics are the medical specialties that have manufactured the largest number of processes. Working and printing time, as well as the amount of printing material, is different for different types of products and input data. The most common printing material was polylactic acid, although biocompatible resin was introduced to produce surgical guides. In addition, the hospital has worked on the co-design of custom-made implants with manufacturing companies and has also participated in tissue bio-printing projects. CONCLUSIONS: The integration of 3D printing in a university hospital allows identifying the conceptual evolution to "point-of-care manufacturing."

Application of 3D printing and distributed manufacturing during the first-wave of COVID-19 pandemic. Our experience at a third-level university hospital.

BACKGROUND: 3D printing and distributed manufacturing represent a paradigm shift in the health system that is becoming critical during the COVID-19 pandemic. University hospitals are also taking on the role of manufacturers of custom-made solutions thanks to 3D printing technology. CASE PRESENTATION: We present a monocentric observational case study regarding the distributed manufacturing of three groups of products during the period of the COVID-19 pandemic from 14 March to 10 May 2020: personal protective equipment, ventilatory support, and diagnostic and consumable products. Networking during this period has enabled the delivery of a total of 17,276 units of products manufactured using 3D printing technology. The most manufactured product was the face shields and ear savers, while the one that achieved the greatest clinical impact was the mechanical ventilation adapters and swabs. The products were manufactured by individuals in 57.3% of the cases, and our hospital acted as the main delivery node in a hub with 10 other hospitals. The main advantage of this production model is the fast response to stock needs, being able to adapt almost in real time. CONCLUSIONS: The role of 3D printing in the hospital environment allows the reconciliation of in-house and distributed manufacturing with traditional production, providing custom-made adaptation of the specifications, as well as maximum efficiency in the working and availability of resources, which is of special importance at critical times for health systems such as the current COVID-19 pandemic.

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma.

Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.

Development of a customizable software application for medical imaging analysis and visualization.

Graphics technology has extended medical imaging tools to the hands of surgeons and doctors, beyond the radiology suite. However, a common issue in most medical imaging software is the added complexity for non-radiologists. This paper presents the development of a unique software toolset that is highly customizable and targeted at the general physicians as well as the medical specialists. The core functionality includes features such as viewing medical images in two-and three-dimensional representations, clipping, tissue windowing, and coloring. Additional features can be loaded in the form of 'plug-ins' such as tumor segmentation, tissue deformation, and surgical planning. This allows the software to be lightweight and easy to use while still giving the user the flexibility of adding the necessary features, thus catering to a wide range of user population.

Evaluación de la vía clínica de la colecistectomía laparoscópica en un servicio de cirugía general / Evaluation of a clinical pathway for laparoscopic cholecystectomy in a general surgery service

Objetivos: Evaluar la vía clínica (VC) de la colecistectomía laparoscópica (CL) tras un año de su implantación. Material y método: El 1 de febrero 2005 se implantó en nuestro servicio la VC de la colecistectomía laparoscópica. Se ha estudiado a todos los pacientes incluidos en la vía clínica desde su puesta en marcha. Los criterios de evaluación incluyen el grado de cumplimiento, los indicadores de efectividad en la atención clínica, el impacto económico y los indicadores de satisfacción basados en la encuesta. Los resultados se comparan con los de una serie de pacientes intervenidos durante el año anterior (2004) a la implantación de la VC. Resultados: Se ha revisado una serie de 170 pacientes intervenidos durante el año anterior a la puesta en marcha de la vía clínica, 136 mujeres y 34 varones con una media de edad de 51 años. La estancia media y el gasto medio del proceso de estos pacientes fueron de 1,29 días y 1.354 euros, respectivamente. Durante un año tras la implantación de la VC se realizaron 170 colecistectomías laparoscópicas, que se incluyeron en el estudio, a 133 mujeres y 37 varones con una media de edad de 50 años. La estancia media de estos pacientes fue de 1,28 días y el gasto medio por proceso, 1.334,7 euros. El grado de cumplimiento de la estancia fue del 85,3%. El grado de satisfacción fue del 96,8%. Conclusiones: El estudio muestra que la estancia media y el gasto medio por proceso han disminuido tras la implantación de la VC y con un alto grado de satisfacción de los pacientes

Objectives: To evaluate a clinical pathway for laparoscopic cholecystectomy 1 year after its introduction. Material and method: A clinical pathway for laparoscopic cholecystectomy was introduced in our service on 1st February, 2005. All patients included in the clinical pathway after its introduction were studied. The evaluation criteria included the degree of compliance, indicators of the effectiveness of clinical care, economic impact, and indicators of satisfaction based on a survey. The results were compared with those obtained in a series of patients who underwent surgery during the year before the introduction of the clinical pathway (2004). Results: A series of 170 patients who underwent surgery in the year prior to the introduction of the clinical pathway was evaluated (136 women and 43 men). The mean age was 51 years. In these patients, the mean length of hospital stay was 1.29 days and the mean cost of the process was 1,354 euros. In the first year after the introduction of the clinical pathway, 170 laparoscopic cholecystectomies were performed and included in this study. There were 133 women and 37 men. The mean age of these patients was 50 years. The mean length of hospital stay was 1.28 days and the mean cost in patients included in the clinical pathway was 1,334.7 euros. The degree of compliance with length of hospital stay was 85.3%. The degree of satisfaction was 96.8%. Conclusions: The mean length of hospital stay and the mean cost per process decreased after the creation of the clinical pathway. Patient satisfaction was high