Association of PD-L1 expression with driver gene mutations and clinicopathological characteristics in non-small cell lung cancer: A real-world study of 10 441 patients.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression is a well-known predictive biomarker of response to immune checkpoint blockade in non-small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD-L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. METHODS: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD-L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. RESULTS: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD-L1 expression was categorized as PD-L1 negative (45.1%), PD-L1 positive low-expression 1%-49% (32.3%), and PD-L1 positive high-expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD-L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non-adenocarcinoma histology had a significantly higher median PD-L1 expression (p < 0.001). Additionally, PD-L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14-2.25, p < 0.01]). In the multivariate analysis, EGFR-positive tumors were more commonly associated with PD-L1 low expression (OR 0.62 [95% CI: 0.51-0.75], p < 0.01), while ALK-positive tumors had a significant risk of being PD-L1 positive (OR 1.81 [95% CI: 1.30-2.52], p < 0.01). CONCLUSIONS: PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.

Analysis of the Rheological Properties of Natural Hydraulic Lime-Based Suspensions for Sustainable Construction and Heritage Conservation.

Natural hydraulic lime (NHL)-based binders play a crucial role in preserving cultural heritage structures, ensuring integrity and longevity. Beyond traditional uses, these binders exhibit potential for integration into both non-structural and structural components, being compatible with innovative manufacturing processes such as digital fabrication. Meticulously designed grouts, with applicability in their fresh and hardened states, are essential for heritage stability. This study explores the relationships between mineral additions, chemical admixtures, and lime for grout formulations, aiming to advance our understanding and inform the optimization of materials for heritage restoration. Key questions include the influence of natural volcanic pozzolan (NVP) and metakaolin (MK) on rheology and the impact of varying ratios of superplasticizer on NHL-based grout's rheological behavior. This systematic evaluation of rheological parameters aims to innovate mix designs, expanding NHL-based binders' applicability in construction and science. Our hypotheses suggest that well-designed lime grout formulations, incorporating NVP and MK, can enhance rheological properties, addressing challenges in sustainable construction and heritage conservation. This research provides valuable insights for optimizing lime-based materials, fostering advancements in heritage restoration, and promoting wider NHL-based binder adoption in diverse construction applications.

Blind date: female fossorial amphisbaenians prefer scent marks of large and healthy males.

Selecting a good mate is a decision with important fitness consequences. For this reason, mate choice has promoted the evolution of sexual ornaments signaling the quality of an individual. In fossorial animals, inhabiting visually restricted underground environments, chemical senses should be very important for mate choice. We examined whether sexual chemical signals (substrate scent marks) produced by males of the Iberian worm lizard, Blanus cinereus, a strictly fossorial blind amphisbaenian, provide information to females on morphological traits and health state. We administered corticosterone (CORT) to males simulating a continuous stressor affecting their health. Females preferred settling at sites scent-marked by males in comparison with similar sites with female scent or unmarked sites, but the attractiveness of males' scent differed between individuals. Females preferred scent marks of larger/older males and with a higher immune response, while their body condition and CORT treatment were unrelated to female preferences. Chemical analyses showed that proportions of some compounds in precloacal secretions of males (used to produce scent marks) were correlated with the morphological (body size) and health state (immune response and body condition, but not CORT treatment) of these males. These results suggest that females may make site-selection decisions based on assessing the chemical characteristics of males' scent marks, which were reliably related to some of the traits of the male that produced the scent. Therefore, females might use chemical senses to increase the opportunities to find and mate with males of high quality, coping with the restrictions of the subterranean environment.

Coping with drought? Effects of extended drought conditions on soil invertebrate prey and diet selection by a fossorial amphisbaenian reptile.

Arid climates are characterized by a summer drought period to which animals seem adapted. However, in some years, the drought can extend for unusually longer periods. Examining the effects of these current extreme weather events on biodiversity can help to understand the effects of climate change, as models predict an increase in drought severity. Here, we examined the effects of "unusual" extended drought on soil invertebrate prey availability and on diet composition (based on fecal contents) and diet selection of a fossorial amphisbaenian, the checkerboard worm lizard Trogonophis wiegmanni. Weather data show interannual variations in summer drought duration. The abundance and diversity of soil invertebrates in spring were high, and similar to those found in a "normal" early autumn, after some rain had ended with the summer drought. In contrast, in years with "unusual" extended drought, abundance, and diversity of soil invertebrates in early autumn were very low. Also, there were seasonal changes in amphisbaenians' diet; in autumn with drought, prey diversity, and niche breadth decreased with respect to spring and autumns after some rain had fallen. Amphisbaenians did not eat prey at random in any season, but made some changes in prey selection that may result from drought-related restrictions in prey availability. Finally, in spite that amphisbaenians showed some feeding flexibility, their body condition was lower in autumn than in spring, and much lower in autumn with drought. If extended drought became the norm in the future, amphisbaenians might suffer important negative effects for their health state.

Effects of Anthropogenic Disturbance of Natural Habitats on the Feeding Ecology of Moorish Geckos.

Urbanization and anthropic influences can drastically modify a natural habitat and transform it into an easily recognizable "urban habitat". Human activities can also induce less severe modifications of what apparently might still look like natural habitats. Therefore, these subtle alterations may be hidden but can still cause important negative effects on plant and animals. In contrast, some species seem able to take advantage of these anthropic alterations. Here, we examined the possible effects of the anthropogenic disturbance of an apparent natural habitat on the feeding ecology and body condition of Moorish geckos, Tarentola mauritanica. For this, we compared microhabitat structure, invertebrate availability, the diet composition (estimated from fecal contents), diet selection patterns and body condition of the two populations of geckos inhabiting two contiguous small islands. These islands have similar environmental characteristics, but highly contrasting differences in urbanization and anthropogenic influence. We found that, although the abundance of potential invertebrate prey was similar on both habitats, the diversity of invertebrate prey was lower in the altered habitat. As a consequence, although composition of the diet of geckos was similar on both islands, the diversity of prey and food niche breadth were lower in the altered habitat, and patterns of diet selection changed. However, these inter-habitat differences did not seem to affect the body size and body condition of geckos. We discuss how flexibility in feeding ecology may allow some species to cope with small anthropic disturbances of the habitat.

Intersexual and body size-related variation in chemical constituents from feces and cloacal products involved in intraspecific communication of a fossorial amphisbaenian.

Background: Many animals rely on chemical cues for intraspecific communication. This is especially important in fossorial animals because visual restrictions of the underground environment limit the opportunities for visual communication. Previous experiments showed the ability of the amphisbaenian Trogonophis wiegmanni to discriminate between several categories of conspecifics based on chemical cues alone. However, in contrast with many other reptile species, T. wiegmanni does not have external secretory glands, but uses uncharacterized secretions from the cloaca in intraspecific chemosensory communication. Methods: Using gas chromatography-mass spectrometry (GC-MS), we analyzed the lipophilic compounds from feces and cloacal products freshly extracted from the cloaca of male and female T. wiegmanni. We identified and estimated relative proportions of the compounds found, and tested for intersexual and body-size related differences. Results: We found a total of 103 compounds, being some steroids (mainly cholesterol and cholestanol), some alkanes and squalene the most abundant and frequent. Further, we found intersexual differences, with males, especially larger ones, having higher proportions of several alkanes between C13 and C24 and of squalene than females, which had higher proportions of several steroids and also of nonacosane and methylnonacosane than males. We compared these findings with secretions of other animals and discuss the potential role of these compounds and their variations in intraspecific communication of amphisbaenians.

Planar Crack Approach to Evaluate the Flexural Strength of Fiber-Reinforced Concrete Sections.

This article describes a model based on concepts of Fracture Mechanics to evaluate the flexural strength of fiber-reinforced concrete (FRC) sections. The model covers the need by structural engineers to have tools that allow, in a simple way, the designing of FRC sections and avoiding complex calculations through finite elements. It consists of an analytical method that models FRC post-cracking behavior with a cohesive linear softening law (σ - w). We use a compatibility equation based on the planar crack hypothesis, i.e., the assumption that the crack surfaces remain plane throughout the fracture process, which was recently proven true using digital image correlation. Non-cracked concrete bulk follows a stress-strain law (σ - ε) combined with the Bernoulli-Navier assumption. We define a brittleness number derived from non-dimensional analyses, which includes the beam size and the softening characteristics. We show that this parameter is key to determining the FRC flexural strength, characterizing fiber-reinforced concrete, and reproducing the size-effect of sections in flexure. Moreover, we propose an expression to calculate the flexural strength of FRC as a function of the cited brittleness number. The model also gives the ratio between the residual strength in service conditions and the flexural strength. Model results show a good agreement with tests in the scientific literature. Finally, we also analyze the brittle-ductile transition in FRC sections.

Probabilistic Assessment of the Dynamic Viscosity of Self-Compacting Steel-Fiber Reinforced Concrete through a Micromechanical Model.

This article develops a probabilistic approach to a micromechanical model to calculate the dynamic viscosity in self-compacting steel-fiber reinforced concrete (SCSFRC), which implies a paradigm shift in the approach of the deterministic models used. It builds on a previous work by the authors in which Bayesian analysis is applied to rheological micromechanical models in cement paste, self-compacting mortar, and self-compacting concrete. As a consequence of the varied characteristics of the particles in these suspensions (in terms of materials, shapes, size distributions, etc.), as well as their random nature, it seems appropriate to study these systems with probabilistic models. The Bayesian analysis, thorough Markov Chain Monte Carlo and Gibbs Sampling methods, allows the conversion of parametric-deterministic models into parametric-probabilistic models, which results in enrichment in engineering and science. The incorporation of steel fibers requires a new term in the model to account for their effect on the dynamic viscosity of SCSFRC, and this new term is also treated here with the Bayesian approach. The paper uses an extensive collection of experimental data to obtain the probability density functions of the parameters for assessing the dynamic viscosity in SCSFRC. The results obtained with these parameters' distributions are much better than those calculated with the theoretical values of the parameters, which indicates that Bayesian methods are appropriated to respond to questions in complex systems with complex models.

Relationships between soil pollution by heavy metals and melanin-dependent coloration of a fossorial amphisbaenian reptile.

Melanin is the basis of coloration in many animals, and although it is often used in communication, thermoregulation, or camouflage, melanin has many other physiological functions. For example, in polluted habitats, melanin can have a detoxifying function. Melanic coloration would help to sequester in the skin the heavy metal contaminants from inside the body, which will be expelled to the exterior when the skin is sloughed. Moreover, animals should have evolved more melanic colorations in more polluted habitats ("industrial melanism" hypothesis). We examined whether the fossorial amphisbaenian reptile, Trogonophis wiegmanni, is able to eliminate heavy metals, derived from soil pollution by seagull depositions, through sloughing its skin. Our results suggest a covariation between levels of soil pollution by heavy metals and the concentration of heavy metals in the sloughed skins of amphisbaenians. This suggests that amphisbaenians may expel heavy metals from their bodies when they slough the skins. We also tested whether amphisbaenians inhabiting soils with higher levels of heavy metal pollution had darker (melanin-dependent) body colorations. However, contrary to predictions from the "industrial melanization" hypothesis, we found a negative relationship between soil pollution and proportions of melanic coloration. This contradictory result could, however, be explained because heavy metals have endocrine disruption effects that increase physiological stress, and higher stress levels could result in decreased melanogenesis. We suggest that although amphisbaenians might have some detoxifying mechanism linked to melanin in the skin, this process might be negatively affected by stress and result ineffective under conditions of high soil pollution.

Hidden but Potentially Stressed: A Non-Invasive Technique to Quantify Fecal Glucocorticoid Levels in a Fossorial Amphisbaenian Reptile.

To understand wildlife responses to the changing environment, it is useful to examine their physiological responses and particularly their endocrine status. Here, we validated an enzyme immunoassay (EIA) to non-invasively quantify fecal corticosterone metabolites (FCM) in the fossorial amphisbaenian reptile Trogonophis wiegmanni from North Africa. We supplemented animals assigned to the treatment group with corticosterone dissolved in oil applied non-invasively on the skin for several days, while control groups received the oil-alone solution. Fresh feces were collected at the end of the supplementation period, and FCM levels were quantified by an EIA. Basal FCM levels were similar for both treatments and increased at the end of the test, but FCM increased significantly more in corticosterone-treated animals. A further examination of FCM levels in a wild population of this amphisbaenian did not find overall sexual, size or seasonal differences but showed a high range of variation among individuals. This suggests that different uncontrolled intrinsic or local environmental variables might increase the circulating glucocorticoid levels of different individuals. Our results confirmed the suitability of EIA for analyzing physiological changes in FCM in this amphisbaenian species. This technique may be useful for understanding and remediating the little-explored potential stressors of the soil environment that may negatively affect the health state of fossorial reptiles.

Soil pollution by heavy metals correlates with levels of faecal glucocorticoid metabolites of a fossorial amphisbaenian reptile.

Soil degradation may have strong negative consequences for soil biodiversity, but these potential effects are understudied and poorly understood. Concentration of nesting seabirds may be a source of soil pollution by heavy metals, which are incorporated into the food chain and may have toxicological effects in vertebrates, especially in fossorial animals with low dispersal ability. We examined whether contamination by heavy metals, derived from seagull depositions, and other soil characteristics, may affect the levels of faecal glucocorticoid metabolites (as a potential indicator of physiological stress) of the fossorial amphisbaenian reptile Trogonophis wiegmanni. We found a relationship between soil pollution by heavy metals and increased levels of faecal corticosterone metabolite of the amphisbaenians that live buried in those soils. This can be due to the strong endocrine disruption effect of heavy metals. In addition, there was an independent effect of the soil texture, with amphisbaenians showing higher levels of faecal corticosterone metabolite in soils with less sand and more silt and clay, which are more energetically costly to dig. Long-term exposure to high glucocorticoid levels might have serious effects on health state and fitness of fossorial animals that may be unnoticed. Our study emphasizes that, to prevent future conservation problems, we need to perform periodic surveys on the physiological health state of the little-known subterranean biodiversity.

Foraging decisions of rock lizards may be dependent both on current rival assessment and dear enemy recognition.

Foraging strategies aim to maximize the amount of food obtained while minimizing searching costs. To reduce these costs, animals use different strategies based on the use of personal or social information to exploit food patches. At the same time, the social attraction for food resources could increase competition intensity for them. Prior experiences of animals regarding social risk and the foreknowledge of the competitors might drive the foraging strategies. In this paper, we examined experimentally whether rock lizards used behavioural strategies to reduce the risks of foraging in presence of potential competitors. We measured the foraging behaviour of a lizard resident to a territory (i.e. terrarium), in the presence of both familiar and unfamiliar conspecifics (potential competitors). We considered whether foraging choices between two food sources of different value (i.e. quantity) are influenced by familiarity with the intruder and the evaluation of its competitive ability based on body size differences between lizards. We found differences in the number of attacks performed to the best food source, with more attacks when the intruder was unfamiliar. The results suggest evidence of both dear enemy recognition and current rival assessment modulate the foraging choices depending on the identity and the social relationship with the intruder.

Calculation of Dynamic Viscosity in Concentrated Cementitious Suspensions: Probabilistic Approximation and Bayesian Analysis.

We present a new focus for the Krieger-Dougherty equation from a probabilistic point of view. This equation allows the calculation of dynamic viscosity in suspensions of various types, like cement paste and self-compacting mortar/concrete. The physical meaning of the parameters that intervene in the equation (maximum packing fraction of particles and intrinsic viscosity), together with the random nature associated with these systems, make the application of the Bayesian analysis desirable. This analysis permits the transformation of parametric-deterministic models into parametric-probabilistic models, which improves and enriches their results. The initial limitations of the Bayesian methods, due to their complexity, have been overcome by numerical methods (Markov Chain Monte Carlo and Gibbs Sampling) and the development of specific software (OpenBUGS). Here we use it to compute the probability density functions that intervene in the Krieger-Dougherty equation applied to the calculation of viscosity in several cement pastes, self-compacting mortars, and self-compacting concretes. The dynamic viscosity calculations made with the Bayesian distributions are significantly better than those made with the theoretical values.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Going underground: short- and long-term movements may reveal the fossorial spatial ecology of an amphisbaenian.

BACKGROUND: The movement and spatial ecology of an animal depends on its morphological and functional adaptations to its environment. In fossorial animals, adaptations to the underground life help to face peculiar ecological challenges, very different from those of epigeal species, but may constrain their movement ability. METHODS: We made a long-term capture-recapture study of the strictly fossorial amphisbaenian reptile Trogonophis wiegmanni to analyze its long-term movement patterns. We also used passive integrated transponder (PIT) telemetry to detect and follow undisturbed individuals underground, obtaining data of their short-term movement patterns. RESULTS: Amphisbaenians showed a high site fidelity, moving short distances and over small areas, and spending some days without any noticeable movement, even under favorable conditions. We also found differences in movements between sexes and age classes. CONCLUSIONS: This movement and spatial strategy can be related to the energetic constrains of underground burrowing, or to the low metabolic requirements of fossorial reptiles, as distances and areas covered were much smaller than for epigeal reptiles of similar size. Individual differences probably reflect differential reproductive and social requirements of males and females, and that younger individuals might show more floating behavior until they can settle in a territory. This study is a rare example describing the movement ecology of a fossorial species and may contribute to the general understanding of the factors that affect space use and movement decisions in animals.

Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Guía de práctica clínica: tamizaje, diagnóstico y manejo de episodios agudos y profilaxis del angioedema hereditario ­ Parte I: Enfoque diagnóstico / Clinical practice guidelines: screening, diagnosis and management of acute events and prophylaxis of hereditary angioedema ­ Part I: Diagnostic approach

El angioedema hereditario (AEH) es una enfermedad genética rara, con una prevalencia aproximada entre 1 por cada 50.000 habitantes, caracterizada por episodios de edemas a nivel subcutáneo y de mucosas (abdominal, genitourinario, respiratoria), siendo potencialmente mortal cuando hay afectación de la laringe. En Perú se estiman 600 pacientes con AEH. El AEH se puede clasificar del siguiente modo: con deficiencia del inhibidor de C1 (tipos I y II), y sin deficiencia del inhibidor de C1 (denominado anteriormente tipo III). El diagnóstico de laboratorio incluye prueba de complemento C4, prueba cuantitativa y cualitativa para inhibidor de C1 esterasa, y estudios genéticos.

Hereditary angioedema (HAE) is a genetic rare disease with a prevalence of approximately 1 per 50,000 inhabitants, characterized by episodes of edema at the subcutaneous level and mucous membranes (abdominal, genitourinary, respiratory), being potentially fatal when there is involvement of the larynx. In Peru, there are an estimated 600 patients with HAE. HAE can be classified as follows: with C1 inhibitor deficiency (types I and II), and without C1 inhibitor deficiency (previously called type III). Laboratory diagnosis includes C4 complement test, quantitative and qualitative tests for C1 inhibitor esterase, and genetic studies. In this first part of the Clinical Practice Guide, we present the recommendations for the diagnostic approach of HAE.

Guía de práctica clínica: tamizaje, diagnóstico y manejo de episodios agudos y profilaxis del angioedema hereditario ­ Parte II: Manejo y tratamiento / Clinical practice guidelines: screening, diagnosis and management of acute events and prophylaxis of hereditary angioedema ­ Part II: Management and treatment

El angioedema hereditario (AEH) es una enfermedad genética rara, con una prevalencia aproximada entre 1 por cada 50.000 habitantes, caracterizada por episodios de edemas a nivel subcutáneo y de mucosas (abdominal, genitourinario, respiratoria), siendo potencialmente mortal cuando hay afectación de la laringe. En Perú se estiman 600 pacientes con AEH. El AEH se puede clasificar del siguiente modo: con deficiencia del inhibidor de C1 (tipos I y II), y sin deficiencia del inhibidor de C1 (denominado anteriormente tipo III). El diagnóstico de laboratorio incluye prueba de complemento C4, prueba cuantitativa y cualitativa para inhibidor de C1 esterasa, y estudios genéticos. Existen tratamientos específicos a nivel mundial para crisis agudas y profilaxis en AEH. Sin embargo, en Perú el único tratamiento registrado actualmente es el ecallantide, útil en crisis agudas; además, podemos utilizar tratamientos alternativos como el ácido tranexámico y el danazol. En esta segunda parte de la Guía de Práctica Clínica, presentamos las recomendaciones para el manejo y el tratamiento del AEH.

Hereditary angioedema (HAE) is a genetic rare disease with a prevalence of approximately 1 per 50,000 inhabitants, characterized by episodes of edema at the subcutaneous level and mucous membranes (abdominal, genitourinary, respiratory), being potentially fatal when there is involvement of the larynx. In Peru, there are an estimated 600 patients with HAE. HAE can be classified as follows: with C1 inhibitor deficiency (types I and II), and without C1 inhibitor deficiency (previously called type III). Laboratory diagnosis includes C4 complement test, quantitative and qualitative test for C1 inhibitor esterase, and genetic studies. There are specific treatments worldwide for acute crises and prophylaxis in HAE; in Peru the only currently registered treatment is ecallantide, useful in acute crises; we can also use alternative treatments such as tranexamic acid and danazol. In this second part of the Clinical Practice Guide, we present the recommendations for the management and treatment of HAE.

Propagation Speed of Dynamic Mode-I Cracks in Self-Compacting Steel Fiber-Reinforced Concrete.

The objective of this study is to measure the crack propagation speed in three types of self-compacting concrete reinforced with steel fibers loaded under four different loading rates. Central-notched prismatic beams with two types of fibers (13 mm and 30 mm in length), three fiber volume ratios, 0.51%, 0.77% and 1.23%, were fabricated. Four strain gages were glued on one side of the specimen notch to measure the crack propagation velocity, a fifth one at the notch tip to estimate the strain rates upon the initiation of a cohesive crack and the stress-free crack. A servo-hydraulic testing machine and a drop-weight impact device were employed to conduct three-point bending tests at four loading-point displacement rates, the former to perform tests at 2.2 µm/s, 22 mm/s and the latter for those at 1.77 m/s, 2.66 m/s, respectively. With lower fiber contents, smooth mode-I cracks were formed, the crack speed reached the order of 1 mm/s and 20 m/s. However, crack velocities up to 1417 m/s were obtained for the concrete with high content of fibers under impact loading. This value is fairly close to the theoretically predicted terminal crack velocity of 1600-1700 m/s. Numerical simulations based on cohesive theories of fracture and preliminary results based on the technique of Digital Image Correlation are also presented to complement those obtained from the strain gages. In addition, the toughness indices are calculated under all four loading rates. Strain hardening (softening) behavior accounting from the initiation of the first crack is observed for all three types of concrete at low (high) loading rates. Significant enhancement in the energy absorption capacity is observed with increased fiber content.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.