Search

Background: Currently, mismatch repair deficient/microsatellite instable (dMMR/MSI) status constitutes a validated predictive marker of response to immune checkpoint inhibitors (ICIs) in patients with metastatic colorectal cancer (mCRC). Unfortunately, some of these patients do not benefit from ICIs. Very limited therapeutic options for patients with dMMR/MSI mCRC after progression on ICI(s) exist. These patients show poor outcomes with conventional chemotherapy. Inhibitors of tropomyosin receptor kinase (TRK) have shown promising activity against neurotrophic tropomyosin receptor kinase (NTRK) fusion-driven cancers. NTRK gene fusions are rare (

Background: Immune-checkpoint inhibitors (ICIs) are the standard of care for microsatellite instability (MSI) metastatic gastrointestinal cancer (mGIC) patients in first- and later-treatment lines. We compared tolerability and efficacy of ICIs in elderly (aged ≥75 years) versus non-elderly MSI mGIC patients and analyzed the correlation between immune-related adverse events (irAEs) and efficacy. Patients and methods: This single-center prospective cohort study included MSI mGIC patients treated with ICIs, excluding chemotherapy. Assessments covered grade ≥3 irAEs and ≥2 endocrine irAEs (E-irAEs). Results: Among 201 patients, 24 were elderly (mean age 75–90 years) and 177 non-elderly (mean age 22-74 years). In the overall population, grade ≥3 irAEs and E-irAEs incidence was 40% with the anti-programmed cell death protein 1 + anti-cytotoxic T lymphocyte-associated antigen 4 and 23% with anti-programmed cell death protein 1 monotherapy (P = 0.011). Treatment combination was administered to 29% of elderly and 40% of non-elderly patients. The incidence of grade ≥3 irAEs and E-irAEs was 37%/29% with monotherapy (P = 0.48) and 57%/39% with combination (P = 0.43) in elderly/non-elderly patients. No significant difference was observed in progression-free survival [hazard ratio (HR) = 1.15, 95% confidence interval (CI) 0.57-2.32, P = 0.7] and OS (HR = 1.61, 95% CI 0.75-3.43, P = 0.25) between elderly and non-elderly. Cox regression analysis with a time-dependent variable showed no survival difference between patients with/without grade ≥3 irAEs and E-irAEs (progression-free survival: HR = 1.19, 95% CI 0.64-2.19, P = 0.59; overall survival: HR = 0.91, 95% CI 0.44-1.92, P = 0.81). A positive association was found, however, between objective response rate and immune treatment-related adverse event occurrence [77%/59%, immune treatment-related adverse event patients/others (P = 0.0012)]. Conclusion: This study reveals comparable tolerability and efficacy of ICIs in elderly and non-elderly patients with MSI mGIC. Survival outcomes did not differ significantly between patients with and without grade ≥3 irAEs and E-irAEs.

Background: Programmed cell death protein 1 (PD-1) blockade improved the survival of patients with mismatch repair deficient (dMMR) and/or microsatellite instability-high (MSI-H) tumors, leading to tumor-agnostic approval of pembrolizumab in this population. Whether anti-programmed death (ligand)-1 [PD-(L)1] agents may achieve similar efficacy in dMMR/MSI-H metastatic gastric cancer (mGC) compared to metastatic colorectal cancer (mCRC) is unclear. Materials and methods: We conducted a multicenter cohort study to collect data on patients with dMMR/MSI-H mGC or mCRC treated with anti-PD-(L)1 monotherapy globally at 17 tertiary cancer centers. Clinical features were balanced according to tumor type through the inverse probability of treatment weighting (IPTW) method. The primary endpoint was overall survival (OS), as evaluated from the first anti-PD-(L)1 administration. Results: The cohort included 398 mCRC and 121 mGC patients, with a median follow-up of 34.6 and 25.1 months, respectively. The two populations differed for several baseline clinical features: patients with mCRC had younger age (60 versus 68 years, P < 0.001), better performance status (PS 0: 46% versus 34%, P = 0.062), higher frequency of primary tumor resection (82% versus 49%, P < 0.001) and liver metastases (38% versus 24%, P = 0.005), yet lower rates of distant nodal metastases (57% versus 83%, P < 0.001) and synchronous presentation (51% versus 76%, P < 0.001). After IPTW adjustment, patients with mGC showed no significant difference in progression-free survival (PFS) and OS compared to those with mCRC [PFS: hazard ratio (HR) 0.55, P = 0.077; OS: HR 0.65, P = 0.200]. Conclusions: Despite patients with dMMR/MSI-H mGC being enriched with poor prognostic factors as compared to the mCRC counterpart, anti-PD-(L)1 monotherapy’s efficacy appears similar in the two tumor types.

Sapos hembras de Mendoza (Bufo arenarum) recibieron exposiciones únicas a rayos X en todo el cuerpo. Los animales experimentados presentaron el mismo peso corporal que los controles, en las mismas condiciones ambientales. Las irradiaciones se realizaron en la Comisión Nacional de Energía Atómica, Buenos Aires, Departamento de Radiobiología, en los mismos períodos (mayo-agosto). Se distribuyó un rango de exposiciones de la siguiente manera: 12 sapos 1000 r; 12 sapos 2000 r; 8 sapos 3000 r; 10 sapos 4000 r; 10 sapos 6000 r; 10 sapos 8000 r. Se empleó la prueba de precipitación turbidimétrica por el procedimiento de Libby, a los 5 días después de la irradiación. Los resultados de las pruebas se trazaron en gráficos y su significación estadística se analizó mediante los métodos actuales. Exposiciones de 1000 r. no provocó alteraciones significativas en las propiedades serológicas del plasma de sapos. Las dosis de 2000 r y 3000-4000 r provocaron cambios significativos sobre todo en las globulinas. Exposiciones de 6000-8000 r inducen alteraciones cuantitativas de las propiedades serológicas plasmáticas de las globulinas y albúminas enteras. Se llevó a cabo una comparación con investigaciones análogas en otros vertebrados (aves).

Se compararon las especies argentinas del grupo Pachypus: Leptodactylus ocellatus, L. chaquensis, L. pentadactylus, L. laticeps. Las distancias serológicas mostradas por las pruebas de fotorrefletometría de precipitina, nos permiten establecer una relación relativamente antigua entre laticeps y pentadactylus y oceliatus-chaquensis respectivamente. En un sistema tridimensional estas dos especies crípticas, ya diferenciadas serológicamente, se colocarían juntas a la misma distancia de las otras dos especies, aunque todas ellas pertenecerían al mismo grupo en comparación con formas de cavicola por ejemplo. Las observaciones mediante electroforesis en gel, permiten subrayar la peculiaridad del patrón seroproteínico de L. laticeps confirmando así una diferenciación probablemente temprana e independiente de esta especie chaqueña.

Purpose: To determine if treatment with dextroamphetamine sulfate could ameliorate the symptoms of long-standing Menière’s disease in a menopausal woman with a past history of dysmenorrhea. Methods: Dextroamphetamine sulfate was started at 9.4 mg extended release tablets and eventually increased to 18.8 mg (Adzenys®). Results: The symptoms of constant ear fullness and severe tinnitus abated and have not returned for 2 years. In addition, the edema of the fingers and ankles have abated along with an 11 pound weight loss. Conclusions: Menière’s disease can be added to the long list of chronic treatment resistant conditions lumped together under the name of the increased cellular permeability syndrome. This syndrome may or may not be associated with pelvic pain. The common denominator is that these seemingly unrelated conditions affecting many organ systems all respond markedly well to amphetamine therapy. The hypothesis of the efficacy of dextroamphetamine sulfate is that it releases dopamine from sympathetic nerve fibers, which, in turn, diminishes cellular permeability.

Gas-phase atmospheric concentrations of peroxyacetyl nitrate (PAN), peroxypropionyl nitrate (PPN), and peroxymethacryloyl nitrate (MPAN) were measured on the ground using a gas chromatograph electron capture detector (GC-ECD) during the Southern Oxidants and Aerosols Study (SOAS) 2013 campaign (1 June to 15 July 2013) in Centreville, Alabama, in order to study biosphere–atmosphere interactions. Average levels of PAN, PPN, and MPAN were 169, 5, and 9 pptv, respectively, and the sum accounts for an average of 16 % of NOy during the daytime (10:00 to 16:00 local time). Higher concentrations were seen on average in air that came to the site from the urban NOx sources to the north. PAN levels were the lowest observed in ground measurements over the past two decades in the southeastern US. A multiple regression analysis indicates that biogenic volatile organic compounds (VOCs) account for 66 % of PAN formation during this study. Comparison of this value with a 0-D model simulation of peroxyacetyl radical production indicates that at least 50 % of PAN formation is due to isoprene oxidation. MPAN has a statistical correlation with isoprene hydroxynitrates (IN). Organic aerosol mass increases with gas-phase MPAN and IN concentrations, but the mass of organic nitrates in particles is largely unrelated to MPAN.

Purpose: To describe a case where a woman was ovulating with regular menses despite very low sera follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels. Case Report: Serum anti-Müllerian (AMH) was obtained because the woman was to be an egg donor for her identical twin sister. This 28-year-old woman responded fairly well to controlled ovarian hyperstimulation producing ten metaphase II eggs and eight fertilized and were cryopreserved on day 3. Her serum AMH level was subnormal at 0.6 ng/mL. Conclusions: This case suggests that FSH may be more biologically active in the presence of low AMH.

We show that the nonlinear interactions between x rays and longer wavelengths in crystals depend strongly on the band structure and related properties. Consequently, these types of interactions can be used as a powerful probe for fundamental properties of crystalline bulk materials. In contrast to previous work that highlighted that these types of nonlinear interactions can provide microscopic information on the valence electrons at the atomic scale resolution, we show that these interactions also contain information that is related to the periodic potential of the crystal. We explain how it is possible to distinguish between the two contributions. Our work indicates on the possibility for the development of novel multidimensional pump-probe metrology techniques that will provide spectroscopic information combined with structural information including ultrafast dynamics at the atomic scale.

Objectives We conducted an implementation science mental health treatment study in western Kenya, testing strategies for scale up of evidence-based mental health services for common adult disorders using a non-specialist workforce, integrated with existing primary care (Sequential Multiple, Assignment Randomized Trial of non-specialist-delivered psychotherapy (Interpersonal Psychotherapy) and/or medication (fluoxetine) for major depression and post-traumatic stress disorder (PTSD) (SMART DAPPER)). Because study launch coincided with the COVID-19 pandemic, participants were allowed to attend treatment visits via mHealth (audio-only mobile phone) or in-person. We conducted a secondary data analysis of the parent study to evaluate preference for mHealth or in-person treatment among our study participants, including rationale for choosing in-person or mHealth treatment modality, and comparison of baseline demographic and clinical characteristics.Design, setting, participants and interventions Participants were public sector primary care patients at Kisumu County Hospital in western Kenya with major depression and/or PTSD and were individually randomised to non-specialist delivery of evidence-based psychotherapy or medication (n=2162).Outcomes Treatment modality preference and rationale were ascertained before randomised assignment to treatment arm (psychotherapy or medication). The parent SMART DAPPER study baseline assessment included core demographic (age, gender, relationship status, income, clinic transport time and cost) and clinical data (eg, depression and PTSD symptoms, trauma exposures, medical comorbidities and history of mental healthcare). Given that this evaluation of mHealth treatment preference sought to identify the demographic and clinical characteristics of participants who chose in-person or mHealth treatment modality, we included most SMART DAPPER core measurement domains (not all subcategories).Results 649 (30.3%) SMART DAPPER participants preferred treatment via mHealth, rather than in person. The most cited rationales for choosing mHealth were affordability (18.5%) (eg, no transportation cost) and convenience (12.9%). On multivariate analysis, compared with those who preferred in-person treatment, participants who chose mHealth were younger and had higher constraints on receiving in-person treatment, including transport time 1.004 (1.00, 1.007) and finances 0.757 (0.612, 0.936). Higher PTSD symptoms 0.527 (0.395, 0.702) and higher disability 0.741 (0.559, 0.982) were associated with preference for in-person treatment.Conclusions To our knowledge, this is the first study of public sector mental healthcare delivered by non-specialists via mHealth for major depression and/or PTSD in Sub-Saharan Africa. Our finding that mHealth treatment is preferred by approximately one-third of participants, particularly younger individuals with barriers to in-person care, may inform future mHealth research to (1) address knowledge gaps in mental health service implementation and (2) improve mental healthcare access to evidence-based treatment.Trial registration number NCT03466346.

Aim. We aimed to analyze the diagnostic criteria proposed by the Bethesda System for Reporting Thyroid Cytopathology for follicular lesions of undetermined significance (FLUS), the risk of cancer and diagnostic improvement with use of immunocytochemistry. Methods. For each FLUS diagnosis, we analyzed the cytological criteria (9 Bethesda criteria), secondary fine-needle aspiration (FNA) results, surgical procedures, contribution of immunocytochemistry with the antibodies cytokeratin 19 (CK19) and monoclonal anti-human mesothelial cell (HBME1). Results. Among patients with 2,210 thyroid FNAs, 244 lesions (337 nodules) were classified as FLUS (11% of all thyroid FNAs). The 3 criteria most often applied were cytological atypia suggesting papillary carcinoma (36%), microfollicular architecture but sparse cellularity (23.1%), cytological atypia (21.5%). With secondary FNA, 48.8% of nodules were reclassified as benign. For about half of all cases (41.4% for the first FNA, 57.6% for the second FNA), immunocytochemistry helped establishing a diagnosis favoring malignant or benign. No benign immunocytochemistry results were associated with a malignant lesion. In all, 22.5% of the 39 removed nodules were malignant. Conclusion. The FLUS category is supported by well-described criteria. The risk of malignancy in our series was 22.5%. Because we had no false-negative immunocytochemistry results, immunocytochemistry could be helpful in FLUS management.

Objective. This prospective study evaluated laparoscopic sleeve gastrectomy for its safety and efficiency in excess weight loss (%EWL) in super superobese patients (BMI >60 Kg/m2). Results. Thirty patients (33 women and 7 men) were included, with mean age of 35 years (range 18 to 59). Mean preoperative BMI was 66 Kg/m2 (range 60 to 85). The study included one patient with complete situs inversus and 4 (14%) with previous restrictive gastric banding. The mean operative time was 120 minutes (range 80 to 220 min) and the mean hospital stay was 7.5 days (4 to 28 days). There was no postoperative mortality or need for a laparotomy conversion. Two subphrenic hematomas, one gastric fistula, and one pulmonary embolism, were the major complications. After 18 months 17 (77%) had sufficient weight loss and six had insufficient results, leading to either re-sleeve gastrectomy (3), or gastric bypass (2). Three years after the initial laparoscopic sleeve gastrectomy, the mean EWL was 51% (range 21 to 82). Conclusion. The laparoscopic sleeve gastrectomy is a safe and efficient operating procedure for treating super superobesity. In the case of insufficient weight loss, a second-stage operation like resleeve gastrectomy or gastric bypass can be proposed.

Agroecología: promoviendo una transición hacia la sostenibilidad. En este artículo se define agroecología como la aplicación de los conceptos y prinicipios ecológicos al diseño y manejo de los sistemas alimentarios sostenibles. Se presentan los argumentos principales que sostienen la validez, importancia y pertinencia del enfoque agroecológico, no solo para entender los procesos involucrados en la producción de alimentos, sino para proponer alternativas que conduzcan a esos procesos para operar en sistemas sostenibles. El concepto clave, que guía el razonamiento metodológico y epistemológico en este análisis, es el de sostenibilidad. Para alcanzar sostenibilidad la metodología agroecológica no solo se ancla en la Ecología, lo cual se describe en el trabajo, sino que percibe la producción de alimentos como un proceso que involucra a los productores y consumidores interactuando en forma dinámica.

The High Current Experiment at Lawrence Berkeley National Laboratory is part of the U.S. program to explore heavy-ion beam transport at a scale representative of the low-energy end of an induction linac driver for fusion energy production. The primary mission of this experiment is to investigate aperture fill factors acceptable for the transport of space-charge-dominated heavy-ion beams at high intensity (line charge density ∼0.2 μC/m) over long pulse durations (4 μs) in alternating gradient focusing lattices of electrostatic or magnetic quadrupoles. This experiment is testing transport issues resulting from nonlinear space-charge effects and collective modes, beam centroid alignment and steering, envelope matching, image charges and focusing field nonlinearities, halo, and electron and gas cloud effects. We present the results for a coasting 1 MeV K^{+} ion beam transported through ten electrostatic quadrupoles. The measurements cover two different fill factor studies (60% and 80% of the clear aperture radius) for which the transverse phase space of the beam was characterized in detail, along with beam energy measurements and the first halo measurements. Electrostatic quadrupole transport at high beam fill factor (≈80%) is achieved with acceptable emittance growth and beam loss, even though the initial beam distribution is not ideal (but the emittance is low) nor in thermal equilibrium. We achieved good envelope control, and rematching may only be needed every ten lattice periods (at 80% fill factor) in a longer lattice of similar design. We also show that understanding and controlling the time dependence of the envelope parameters is critical to achieving high fill factors, notably because of the injector and matching section dynamics.

We compare simulations to experiments measuring electron yield from heavy ions striking metal surfaces, in particular at grazing incidence, for 1.0 MeV potassium and 182.0 MeV gold ions striking stainless steel as measured in two recent experiments. We find the electron yield is proportional to within 3% for the potassium experiments and 13% for the gold experiments to the simulated energy deposited by the ions in a thin (≈20 Å) layer at the target surface. We discuss how nonequilibrium stopping and ion wake fields may account for the larger disagreement with the gold experiments. An analytic estimate based on specular reflection predicts the peak in simulated and measured electron yield as a function of angle to within a few percent.

Abstract Biomolecular condensates form via coupled associative and segregative phase transitions of multivalent associative macromolecules. Phase separation coupled to percolation is one example of such transitions. Here, we characterize molecular and mesoscale structural descriptions of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). These systems conform to sticker-and-spacers architectures. Stickers are cohesive motifs that drive associative interactions through reversible crosslinking and spacers affect the cooperativity of crosslinking and overall macromolecular solubility. Our computations reproduce experimentally measured sequence-specific phase behaviors of PLCDs. Within simulated condensates, networks of reversible inter-sticker crosslinks organize PLCDs into small-world topologies. The overall dimensions of PLCDs vary with spatial location, being most expanded at and preferring to be oriented perpendicular to the interface. Our results demonstrate that even simple condensates with one type of macromolecule feature inhomogeneous spatial organizations of molecules and interfacial features that likely prime them for biochemical activity.

Currently there is little doubt that the body mass index (BMI) is not an appropriate tool to grant access to metabolic surgery, especially in type 2 diabetics (T2D). Several studies are pointing towards other parameters that should go along with BMI in the treatment decision tree in non morbidly obese diabetics. Insulin resistance, fat distribution among others are considered good tools to predict favorable outcomes in medically non controlled diabetics if sent to surgery. The bottom line in good T2D control is to decrease cardiovascular mortality. Using adequate tools to screen patients to the appropriate surgical treatment may favor patients that are not under control after lifestyle changes and best medical treatment, thus decreasing longterm cardiovascular mortality secondary to type 2 diabetes.

The evolution of multicellular eukaryotes expresses two sorts of adaptations: local adaptations like fur or feathers, which characterize species in particular environments, and universal adaptations like microbiomes or sexual reproduction, which characterize most multicellulars in any environment. We reason that the mechanisms driving the universal adaptations of multicellulars should themselves be universal, and propose a mechanism based on properties of matter and systems: energy, entropy, and interaction. Energy from the sun, earth and beyond creates new arrangements and interactions. Metabolic networks channel some of this energy to form cooperating, interactive arrangements. Entropy, used here as a term for all forces that dismantle ordered structures (rather than as a physical quantity), acts as a selective force. Entropy selects for arrangements that resist it long enough to replicate, and dismantles those that do not. Interactions, energy-charged and dynamic, restrain entropy and enable survival and propagation of integrated living systems. This fosters survival-of-the-fitted – those entities that resist entropic destruction – and not only of the fittest – the entities with the greatest reproductive success. The “unit” of evolution is not a discrete entity, such as a gene, individual, or species; what evolves are collections of related interactions at multiple scales. Survival-of-the-fitted explains universal adaptations, including resident microbiomes, sexual reproduction, continuous diversification, programmed turnover, seemingly wasteful phenotypes, altruism, co-evolving environmental niches, and advancing complexity. Indeed survival-of-the-fittest may be a particular case of the survival-of-the-fitted mechanism, promoting local adaptations that express reproductive advantages in addition to resisting entropy. Survival-of-the-fitted accounts for phenomena that have been attributed to neutral evolution: in the face of entropy, there is no neutrality; all variations are challenged by ubiquitous energy and entropy, retaining those that are “fit enough”. We propose experiments to test predictions of the survival-of-the-fitted theory, and discuss implications for the wellbeing of humans and the biosphere.

The evolution of multicellular eukaryotes expresses two sorts of adaptations: local adaptations like fur or feathers, which characterize species in particular environments, and universal adaptations like microbiomes or sexual reproduction, which characterize most multicellulars in any environment. We reason that the mechanisms driving the universal adaptations of multicellulars should themselves be universal, and propose a mechanism based on properties of matter and systems: energy, entropy, and interaction. Energy from the sun, earth and beyond creates new arrangements and interactions. Metabolic networks channel some of this energy to form cooperating, interactive arrangements. Entropy, used here as a term for all forces that dismantle ordered structures (rather than as a physical quantity), acts as a selective force. Entropy selects for arrangements that resist it long enough to replicate, and dismantles those that do not. Interactions, energy-charged and dynamic, restrain entropy and enable survival and propagation of integrated living systems. This fosters survival-of-the-fitted – those entities that resist entropic destruction – and not only of the fittest – the entities with the greatest reproductive success. The “unit” of evolution is not a discrete entity, such as a gene, individual, or species; what evolves are collections of related interactions at multiple scales. Survival-of-the-fitted explains universal adaptations, including resident microbiomes, sexual reproduction, continuous diversification, programmed turnover, seemingly wasteful phenotypes, altruism, co-evolving environmental niches, and advancing complexity. Indeed survival-of-the-fittest may be a particular case of the survival-of-the-fitted mechanism, promoting local adaptations that express reproductive advantages in addition to resisting entropy. Survival-of-the-fitted accounts for phenomena that have been attributed to neutral evolution: in the face of entropy, there is no neutrality; all variations are challenged by ubiquitous energy and entropy, retaining those that are “fit enough”. We propose experiments to test predictions of the survival-of-the-fitted theory, and discuss implications for the wellbeing of humans and the biosphere.

The evolution of multicellular eukaryotes expresses two sorts of adaptations: local adaptations like fur or feathers, which characterize species in particular environments, and universal adaptations like microbiomes or sexual reproduction, which characterize most multicellulars in any environment. We reason that the mechanisms driving the universal adaptations of multicellulars should themselves be universal, and propose a mechanism based on properties of matter and systems: energy, entropy, and interaction. Energy from the sun, earth and beyond creates new arrangements and interactions. Metabolic networks channel some of this energy to form cooperating, interactive arrangements. Entropy, used here as a term for all forces that dismantle ordered structures (rather than as a physical quantity), acts as a selective force. Entropy selects for arrangements that resist it long enough to replicate, and dismantles those that do not. Interactions, energy-charged and dynamic, restrain entropy and enable survival and propagation of integrated living systems. This fosters survival-of-the-fitted – those entities that resist entropic destruction – and not only of the fittest – the entities with the greatest reproductive success. The “unit” of evolution is not a discrete entity, such as a gene, individual, or species; what evolves are collections of related interactions at multiple scales. Survival-of-the-fitted explains universal adaptations, including resident microbiomes, sexual reproduction, continuous diversification, programmed turnover, seemingly wasteful phenotypes, altruism, co-evolving environmental niches, and advancing complexity. Indeed survival-of-the-fittest may be a particular case of the survival-of-the-fitted mechanism, promoting local adaptations that express reproductive advantages in addition to resisting entropy. Survival-of-the-fitted accounts for phenomena that have been attributed to neutral evolution: in the face of entropy, there is no neutrality; all variations are challenged by ubiquitous energy and entropy, retaining those that are “fit enough”. We propose experiments to test predictions of the survival-of-the-fitted theory, and discuss implications for the wellbeing of humans and the biosphere.