Search

Abstract Background Bidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC). Methods PALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression’s value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models. Results From the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p

Abstract In monarchE, adjuvant abemaciclib significantly improved invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS), with sustained benefit beyond the 2-year treatment period. Abemaciclib dose reductions were allowed to proactively manage adverse events. Exploratory analyses to investigate the impact of dose reductions on efficacy were conducted. Across the three patient subgroups as defined by relative dose intensity (≤66%, 66–93%, ≥93%), the estimated 4-year IDFS rates were generally consistent (87.1%, 86.4%, and 83.7%, respectively). In the time-dependent Cox proportional hazard model, the effect of abemaciclib was consistent at the full dose compared to being reduced to a lower dose (IDFS hazard ratio: 0.905; 95% confidence interval: 0.727, 1.125; DRFS hazard ratio: 0.942; 95% confidence interval: 0.742, 1.195). These analyses showed that the efficacy of adjuvant abemaciclib was not compromised by protocol mandated dose reductions for patients with node positive, hormone receptor positive, human epidermal growth factor 2-negative, high-risk early breast cancer.

ABSTRACTIeramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

Abstract This paper describes a dataset collected by infrared thermography, a non-contact, non-intrusive technique to acquire data and analyze the built environment in various aspects. While most studies focus on the city and building scales, an observatory installed on a rooftop provides high temporal and spatial resolution observations with dynamic interactions on the district scale. The rooftop infrared thermography observatory with a multi-modal platform capable of assessing a wide range of dynamic processes in urban systems was deployed in Singapore. It was placed on the top of two buildings that overlook the outdoor context of the National University of Singapore campus. The platform collects remote sensing data from tropical areas on a temporal scale, allowing users to determine the temperature trend of individual features such as buildings, roads, and vegetation. The dataset includes 1,365,921 thermal images collected on average at approximately 10-second intervals from two locations during ten months.

Introduction There are limited longitudinal data on the systemic and mucosal antibody responses to SARS-CoV-2 from Latin America, a region severely affected by COVID-19, and where vaccine strategies have been implemented during the evolving pandemic. Objective To evaluate determinants of seroprevalence and changes in levels of anti-SARS-CoV-2 antibodies longitudinally in adults with different levels of exposure to SARS-CoV-2 (defined a priori as low, medium, and high based on presumed occupational risk), in two Andean cities in Ecuador. Methods Longitudinal cohort study of 1,000 adults aged 18 years and older with questionnaire data and sample collection done at 0, 3, 6, and 12 months during the period 2020-2023. Observations collected included WHO-ISARIC questionnaire and peripheral blood and saliva samples for measurement of IgG and IgA antibodies, respectively. Planned analyses are tailored to the longitudinal nature of the outcomes defined by participants’ antibody levels and aim at estimating their average trends with time since infection in each of the occupational groups, adjusted for demographics and calendar-time levels of SARS-CoV-2 infection in the general population. The latter reflect the impact of the national control measures such as vaccinations and movement restrictions. Importance Understanding the duration and the dynamics of waning immunity to SARS-CoV-2, in the context of exposures to emerging virus variants and immunization, will inform the implementation of targeted public health strategies in the Latin American region. Ethics and Dissemination This study will observe the bioethical principles of the Declaration of Helsinki. Informed written consent will be obtained. Samples from participants will be stored for up to three years after which they will be destroyed. The study protocol was approved by the Ecuadorian Ministry of Public Health Ethics Committee for COVID-19 Research. Antibody results will be provided to participants and participating institutions and to the national health authorities.

BackgroundThe COVID-19 pandemic has caused over 68.7 million infections and 1.35 million deaths in South America. There are limited data on SARS-CoV-2 seropositivity and its determinants from Andean countries prior to mass vaccinations against COVID-19.ObjectiveTo estimate SARS-CoV-2 seropositivity and its determinants before vaccination in occupational groups of adults presumed to have different levels of exposure and associations with potential symptomatology.MethodsWe measured seropositivity of anti-SARS-CoV-2 IgG antibodies in a cross-sectional study of vaccine-naïve adults aged 18 years and older, recruited within three occupational risk groups (defined as low [LR], moderate [MR], and high [HR]) between January and September 2021 in two Andean cities in Ecuador. Associations with risk factors were estimated using logistic regression.ResultsIn a sample of 882 adults, IgG seropositivity for the three different occupational risk groups was 39.9% (CI 95% 35.3-44.6), 74.6% (CI 95% 66.4-81.4), and 39.0% (CI 95% 34.0-44.4) for the HR, MR, and LR groups, respectively. History of an illness with loss of taste and/or smell was significantly associated with seropositivity in all occupational groups, with adjusted ORs of 14.31 (95%CI, 5.83-35.12; pConclusionNotable proportions of seropositivity were seen in all occupational groups between January and September 2021 prior to mass vaccination. Loss of taste and/or smell was strongly associated with presence of anti-SARS-CoV-2 IgG antibodies irrespective of presumed occupational exposure risk.

BackgroundThere is a growing epidemic of chronic non-communicable diseases in low and middle-income countries, often attributed to urbanization, although there are limited data from marginalized rural populations. This study aimed to estimate prevalence of cardiometabolic diseases and associated risk factors in transitional rural communities.MethodsA cross-sectional study of Montubio adults aged 18-94 years living in agricultural communities in a tropical coastal region of Ecuador. Data were collected by questionnaires and anthropometry, and fasting blood was analyzed for glucose, glycosylated hemoglobin, insulin, and lipid profiles. Population-weighted prevalences of diabetes, hypertension, and metabolic syndrome were estimated. Associations between potential risk factors and outcomes were estimated using multilevel regression techniques adjusted for age and sex.ResultsOut of 1,010 adults recruited, 931 were included in the analysis. Weighted prevalences were estimated for diabetes (20.4%, 95% CI 18.3-22.5%), hypertension (35.6%, 95% CI 29.0-42.1%), and metabolic syndrome (54.2%. 95% CI 47.0-61.5%) with higher prevalence observed in women. Hypertension prevalence increased with age while diabetes and metabolic syndrome peaked in the 6th and 7th decades of life, declining thereafter. Adiposity indicators were associated with diabetes, hypertension, and metabolic syndrome.ConclusionWe observed an unexpectedly high prevalence of diabetes, hypertension, and metabolic syndrome in these marginalized agricultural communities. Transitional rural communities are increasingly vulnerable to the development of cardiometabolic risk factors and diseases. There is a need for targeted primary health strategies to reduce the burden of premature disability and death in these communities.

Abstract Background KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE. Methods Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive. Results Biomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups. Conclusions Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer. Trial Registration: ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

Background: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) vs. ET alone. Methods: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2– ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1. Results: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study. Conclusions: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2− ABC, including populations of interest (NCT02941926). Trial registration: ClinicalTrials.gov NCT02941926

Invasive algae, such as Halimeda incrassata, alter marine biodiversity in the Mediterranean Sea. Monitoring these changes over time is crucial for assessing the health of coastal environments and preserving local species. However, this monitoring process is resource-intensive, requiring taxonomic experts and significant amounts of time. Recently, deep learning approaches have attempted to automate the detection of certain seagrass species like Posidonia oceanica and Halophila ovalis from two different strategies: seagrass coverage estimation and detection. This work presents a novel approach to detect Halimeda incrassata and estimate its coverage, independently of the invasion stage of the algae. Two merging methods based on the combination of the outputs of an object detection network (YOLOv5) and a semantic segmentation network (U-net) are developed. The system achieves an F1-scoreof 84.2% and a Coverage Error of 5.9%, demonstrating its capability to accurately detect Halimeda incrassata and estimate its coverage independently of the invasion stage.

Broadly neutralizing antibodies (bnAbs) bind and neutralize diverse HIV isolates and demonstrate protective effects in primate models and humans against specific isolates. To develop an effective HIV vaccine, it is widely believed that inducing these antibodies is crucial. However, the high somatic hypermutation in bnAbs and the limited affinity of HIV Env proteins for bnAb germline precursors suggest that extended antigen exposure is necessary for their production. Consequently, HIV vaccine research is exploring complex sequential vaccination strategies to guide the immune response through maturation stages. In this context, the exploration of the factors linked to the generation of these antibodies across diverse age groups becomes critical. In this study, we assessed the anti-HIV-1 neutralization potency and breadth in 108 aviremic adults and 109 aviremic children under 15 years of age who were receiving ART. We used a previously described minipanel of recombinant viruses and investigated the factors associated with neutralization in these individuals. We identified individuals in both groups who were capable of neutralizing viruses from three different subtypes, with greater cross-neutralization observed in the adult group (49.0% vs. 9.2%). In both groups, we observed an inverse association between neutralization breadth and the CD4+/CD8+ ratio, as well as a direct association with the time to ART initiation. However, we found no association with time post-infection, cumulative ART duration, or CD8+ cell levels. The present study demonstrates that children receiving antiretroviral therapy generate broadly neutralizing responses to HIV-1, albeit with lower magnitude compared to adults. We also observed that neutralization breadth is associated with CD4+/CD8+ levels and time to treatment initiation in both children and adults living with HIV-1. Our interpretation of these results is that a delay in ART initiation could have prolonged the antigenic stimulation associated with viral replication and thus facilitate the capacity to elicit long-lasting broadly neutralizing responses. These results corroborate prior findings that show that HIV-1-neutralizing responses can persist for years, even at low antigen levels, implying an HIV-1 vaccine may induce lasting neutralizing antibody response.

Abstract While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor–positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135).

PURPOSEThe COVID-19 pandemic has affected healthcare systems globally, leading to reorganization of medical activities. We performed an international survey aimed to investigate the medium- and long-term impact on oncology units.MATERIALS AND METHODSAn 82-item survey was distributed from June 17 to July 14, 2020 among medical oncologists worldwide.RESULTSOne hundred nine medical oncologists from 18 countries in Europe (n = 93), United States (n = 5), and Latin America (n = 11) answered the survey. A systematic tracing of COVID-19–positive patients was continued in the postacute phase by 77.1% of the centers; 64.2% of the respondents participated in a local registry and 56% in international or national registries of infected patients. Treatment adaptations were introduced, and surgery was the most affected modality being delayed or canceled in more than 10% of patients in 34% of the centers, whereas early cessation of palliative treatment was reported in 32.1% of the centers; 64.2% of respondents reported paying attention to avoid undertreatments. The use of telemedicine has been largely increased. Similarly, virtual tools are increasingly used particularly for medical education and international or national or multidisciplinary meetings. 60.6% of the participants reduced clinical activity, and 28.4% compensated by increasing their research activity. Significant reduction of clinical trial activities is expected in 37% of centers this year. The well-being of healthcare staff would not recover by the end of the year according to 18% of the participants.CONCLUSIONThe COVID-19 outbreak has had a major impact on oncologic activity, which will persist in the future, irrespective of geographical areas.

Abstract Despite the recent recognition of jellyfish as an important component of marine ecosystems and existing concerns on their potential population increase, they are rarely monitored at the appropriate spatial and temporal scales. Traditional jellyfish monitoring techniques are costly and generally restrict the spatial–temporal resolution limiting the quantity and quality of monitoring data. We introduce Jellytoring 2.0, an automatic recognition tool for jellyfish species based on convolutional neural networks (CNN). We trained Jellytoring 2.0 to identify 15 jellyfish species with a global distribution. Our aim is to offer Jellytoring 2.0 as an open‐access tool to serve as the backbone for a system that promotes the creation of large‐scale and long‐term jellyfish monitoring data. Results reveal that Jellytoring 2.0 performed well in the identification of the 15 species with average precision values ranging between 90% and 99% for most of the species. Four of the species presented slightly lower values (75%–80%). Our system was trained on a relatively small dataset, implying that additional integration of image data will further improve the performance of the CNN. We show how the application of CNNs to image data can deliver a tool that will enable the cost‐effective collection of jellyfish data on larger spatial and temporal scales. For Jellytoring 2.0 to become a truly global automatic identification system, we ask scientists and nonscientists to actively contribute with jellyfish image data to extend the number of species it can identify.

El hígado graso agudo del embarazo es una enfermedad infrecuente que se presenta en el tercer trimestre. Su etiología es desconocida. El diagnóstico se realiza con criterios de Swansea. Produce disfunción hepática severa, renal y tiempos de coagulación prolongados, la morbimortalidad materno-fetal es del 20% y el tratamiento es finalizar el embarazo. Se reporta el caso de una gestante de 33 años, con 31,6 semanas de embarazo, consulta por dolor abdominal, malestar general, ictericia, náuseas, vómitos y polidipsia. La analítica mostró alteración del perfil hepático, renal y coagulopatía. La ecografía abdominal mostró infiltración hepática grasa. El manejo fue cesárea de emergencia por óbito fetal, reintervenida quirúrgicamente por hemoperitoneo y apendicitis aguda. La paciente fue dada de alta con mejoría clínica y laboratorial.

BackgroundPatients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL.MethodsWe performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices.ResultsThe effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: −0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated.ConclusionsOne year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany.

Abstract In MONARCH 3, continuous dosing of abemaciclib with an aromatase inhibitor (AI) conferred significant clinical benefit to postmenopausal women with HR+, HER2− advanced breast cancer. We report data for clinically prognostic subgroups: liver metastases, progesterone receptor status, tumor grade, bone-only disease, ECOG performance status, and treatment-free interval (TFI) from an additional 12-month follow-up (after final progression-free survival [PFS] readout). In the intent-to-treat population, after median follow-up of approximately 39 months, the updated PFS was 28.2 versus 14.8 months (hazard ratio [HR], 0.525; 95% confidence interval, 0.415–0.665) in abemaciclib versus placebo arms, respectively. Time to chemotherapy (HR, 0.513), time to second disease progression (HR, 0.637), and duration of response (HR, 0.466) were also statistically significantly prolonged with the addition of abemaciclib to AI. Treatment benefit was observed across all subgroups, as evidenced by objective response rate change from the addition of abemaciclib to AI, with the largest effects observed in patients with liver metastases, progesterone receptor-negative tumors, high-grade tumors, or TFI

Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.

Abstract Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.

Purpose: In the MONALEESA-3 Phase III trial of patients with hormone receptor–positive human epidermal growth factor receptor–negative advanced breast cancer, ribociclib plus fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL). Methods: Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status [GHS] from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs. Results: Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 [95% CI, 0.62–1.1]). Similar findings were noted for TTD ≥5% (HR = 0.79 [95% CI, 0.61–1.0]) and TTD ≥15% (HR = 0.81 [95% CI, 0.60–1.08]). TTD ≥10% in emotional functioning (HR = 0.76 [95% CI, 0.57–1.01]) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 [95% CI, 0.57–1.05]) and worst pain item score (HR = 0.81 [95% CI, 0.58–1.12]) trended in favor of ribociclib vs placebo. Conclusions: In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL.

La secuencia de perfusión arterial reversa es una complicación del embarazo gemelar monocoriónico, presentándose en 1 de cada 35.000. En esta anomalía ocurren anastomosis vasculares arteria-arteria en el lecho placentario, formando un gemelo bomba con presión de perfusión arterial alta y un gemelo receptor completamente acárdico. La mortalidad es probablemente por falla cardiaca y anemia que ocurre tempranamente durante el embarazo. Presentamos un caso de feto acárdico y acéfalo en un embarazo gemelar en una paciente de 22 años producto de una gestación gemelar monocorial biamniótica de 36 semanas un día, acudió a emergencia por perdida de líquido amniótico y ausencia de actividad cardiaca en un gemelo. El diagnóstico prenatal de la secuencia perfusión arterial reversa en gemelos es fundamental para mejorar el pronóstico.

The morphological analysis of dendritic spines is an important challenge for the neuroscientific community. Most state-of-the-art techniques rely on user-supervised algorithms to segment the spine surface, especially those designed for light microscopy images. Therefore, processing large dendritic branches is costly and time-consuming. Although deep learning (DL) models have become one of the most commonly used tools in image segmentation, they have not yet been successfully applied to this problem. In this article, we study the feasibility of using DL models to automatize spine segmentation from confocal microscopy images. Supervised learning is the most frequently used method for training DL models. This approach requires large data sets of high-quality segmented images (ground truth). As mentioned above, the segmentation of microscopy images is time-consuming and, therefore, in most cases, neuroanatomists only reconstruct relevant branches of the stack. Additionally, some parts of the dendritic shaft and spines are not segmented due to dyeing problems. In the context of this research, we tested the most successful architectures in the DL biomedical segmentation field. To build the ground truth, we used a large and high-quality data set, according to standards in the field. Nevertheless, this data set is not sufficient to train convolutional neural networks for accurate reconstructions. Therefore, we implemented an automatic preprocessing step and several training strategies to deal with the problems mentioned above. As shown by our results, our system produces a high-quality segmentation in most cases. Finally, we integrated several postprocessing user-supervised algorithms in a graphical user interface application to correct any possible artifacts.

Abstract Background In populations above 3,000 meters above sea level (m.a.s.l.) normal values of oxygen saturation (SpO2) above 90% have been reported. Few studies have been conducted in cities of moderate altitude (between 2,500 and 3,000 m a.s.l). We set out to describe the range of SpO2 values measured with a pulse oximeter in healthy children between 1 month and 12 years of age living in an Ecuadorian Andean city. Methods A cross-sectional study was carried out in Quito, Ecuador, located at 2,810 m a.s.l. SpO2 measurement in healthy children of ages ranging from 1 month to 12 years of age residents in the city were recorded by pulse oximetry. Age and gender were recorded, and median and 2.5th and 5th percentile were drawn. Non parametric tests were used to compare differences in SpO2 values by age and gender. Results 1,378 healthy children were included for the study, 719 (52.2%) males. The median SpO2 for the entire population was 94.5%. No differences were observed between SpO2 median values by age and gender. The 2.5th percentile for global SpO2 measurements was 90%, in children under 5 years of age was 91% and it was 90% in children older than 7. Conclusions Our results provide SpO2 values for healthy children from 1 to 12 years old residents in Quito, a city of moderate altitude. The SpO2 percentile curve could contribute as a healthy range for the clinical evaluation of children residing at this altitude.

Abstract Herpesvirus is ranked as one of the grand old members of all pathogens. Of all the viruses in the superfamily, Herpes simplex virus type 1 (HSV-1) is considered as a model virus for a variety of reasons. In a permissive non-neuronal cell culture, HSV-1 concludes the entire life cycle in approximately 18–20 h, encoding approximately 90 unique transcriptional units. In latency, the robust viral gene expression is suppressed in neurons by a group of noncoding RNA. Historically the lesions caused by the virus can date back to centuries ago. As a neurotropic pathogen, HSV-1 is associated with painful oral lesions, severe keratitis and lethal encephalitis. Transmission of pain signals is dependent on the generation and propagation of action potential in sensory neurons. T-type Ca2+ channels serve as a preamplifier of action potential generation. Voltage-gated Na+ channels are the main components for action potential production. This review summarizes not only the voltage-gated ion channels in neuropathic disorders but also provides the new insights into HSV-1 induced pain.

Background Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.Methods Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).Results In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.Conclusions Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.Trial registration number NCT02460224.

Nowadays, more frequently, it is necessary to perform underwater operations such as surveying an area or inspecting and intervening on industrial infrastructures such as offshore oil and gas rigs or pipeline networks. Recently, the use of Autonomous Underwater Vehicles (AUV) has grown as a way to automate these tasks, reducing risks and execution time. One of the used sensing modalities is vision, providing RGB high-quality information in the mid to low range, making it appropriate for manipulation or detail inspection tasks. This work presents the use of a deep neural network to perform pixel-wise 3D segmentation of pipes and valves on underwater point clouds generated using a stereo pair of cameras. In addition, two novel algorithms are built to extract information from the detected instances, providing pipe vectors, gripping points, the position of structural elements such as elbows or connections, and valve type and orientation. The information extracted on spatially referenced point clouds can be unified to form an information map of an inspected area. Results show outstanding performance on the network segmentation task, achieving a mean F1-score value of 88.0% at a pixel-wise level and of 95.3% at an instance level. The information extraction algorithm also showcased excellent metrics when extracting information from pipe instances and their structural elements and good enough metrics when extracting data from valves. Finally, the neural network and information algorithms are implemented on an AUV and executed in real-time, validating that the output information stream frame rate of 0.72 fps is high enough to perform manipulation tasks and to ensure full seabed coverage during inspection tasks. The used dataset, along with a trained model and the information algorithms, are provided to the scientific community.

The complex nature of debris flows suggests that the pore-water pressure evolution and dewatering of a flowing mass caused by the high permeability of soil or terrain could play an essential role in the dynamics behavior of fast landslides. Dewatering causes desaturation, reducing the pore-water pressure and improving the shear strength of liquefied soils. A new approach to landslide propagation modeling considering the dewatering of a mass debris flow has drawn research attention. The problem is characterized by a transition from saturated to unsaturated soil. This paper aims to address this scientific gap. A depth-integrated model was developed to analyze the dewatering of landslides, in which, desaturation plays an important role in the dynamics behavior of the propagation. This study adopted an SPH numerical method to model landslide propagation consisting of pore-water and a soil skeleton in fully or partially saturated soils. In a two-phase model, the soil–water mixture was discretized and represented by two sets of SPH nodes carrying all field variables, such as velocity, displacement, and basal pore-water pressure. The pore-water was described by an additional set of balance equations to take into account its velocity. In the developed two-layer model, an upper desaturated layer and a lower saturated layer were considered to enhance the description of dewatering. This is the so-called two-phase two-layer formulation, which is capable of simulating the entire process of landslides propagation, including the large deformation of soils and corresponding pore-water pressure evolutions, where the effect of the dewatering in saturated soils is also taken into account. A dam-break problem was analyzed through the new and previously developed model. A flume test performed at Trondheim was also used to validate the proposed model by comparing the numerical results with measurements obtained from the experiment. Finally, the model was applied to simulate a real case lahar, which is an appropriate benchmark case used to examine the applicability of the developed model. The simulation results demonstrated that taking into account the effects of dewatering and the vital parameter of relative height is essential for the landslide propagation modeling of a desaturated flowing mass.

Abstract Background The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1–associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. Methods In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan–Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. Results Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1–containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). Conclusions In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. Trial registration Registration number: NCT01120184. Date of registration: April 28, 2010 (registered prospectively).

Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009.

HSV-1 is a neurotropic pathogen associated with severe encephalitis, excruciating orofacial sensation, and other chronic neuropathic complications. After the acute infection, the virus may establish a lifelong latency in the neurons of trigeminal ganglia (TG) and other sensory and autonomic ganglia, including the dorsal root ganglia (DRG), etc. The reactivation occurred periodically by a variety of physical or emotional stressors. We have been developing a human DRG neuronal cell-culture model HD10.6, which mimics the mature neurons for latency and reactivation with robust neuronal physiology. We found that miR124 overexpression without acyclovir (ACV) could maintain the virus in a quiescent infection, with the accumulation of latency-associate transcript (LAT). The immediate-early (IE) gene ICP0, on the other hand, was very low and the latent viruses could be reactivated by trichostatin A (TSA) treatment. Together, these observations suggested a putative role of microRNA in promoting HSV-1 latency in human neurons.

Background COVID-19 appeared in late 2019, causing a pandemic spread. This led to a reorganisation of oncology care in order to reduce the risk of spreading infection between patients and healthcare staff. Here we analysed measures taken in major oncological units in Europe and the USA.Methods A 46-item survey was sent by email to representatives of 30 oncological centres in 12 of the most affected countries. The survey inquired about preventive measures established to reduce virus spread, patient education and processes employed for risk reduction in each oncological unit.Results Investigators from 21 centres in 10 countries answered the survey between 10 April and 6 May 2020. A triage for patients with cancer before hospital or clinic visits was conducted by 90.5% of centres before consultations, 95.2% before day care admissions and in 100% of the cases before overnight hospitalisation by means of phone calls, interactive online platforms, swab test and/or chest CT scan. Permission for caregivers to attend clinic visits was limited in many centres, with some exceptions (ie, for non-autonomous patients, in the case of a new diagnosis, when bad news was expected and for terminally ill patients). With a variable delay period, the use of personal protective equipment was unanimously mandatory, and in many centres, only targeted clinical and instrumental examinations were performed. Telemedicine was implemented in 76.2% of the centres. Separated pathways for COVID-19-positive and COVID-19-negative patients were organised, with separate inpatient units and day care areas. Self-isolation was required for COVID-19-positive or symptomatic staff, while return to work policies required a negative swab test in 76.2% of the centres.Conclusion Many pragmatic measures have been quickly implemented to deal with the health emergency linked to COVID-19, although the relative efficacy of each intervention should be further analysed in large observational studies.

Background The inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.Methods We used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.Results We demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.Conclusions Our results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

Slow economic recovery, market concentration, and scant alternative energy sources make the Iberian energy market quite idiosyncratic when compared to the rest of the EU. This paper focusses on the Iberian energy market by dealing with the analysis of the relationship between energy consumption and energy prices by using fractional integration in the Iberian market. This technique is used in order to examine the degree of persistence of the series, looking at the spot and futures markets in Spain and Portugal. The results indicate that all the series are fractionally integrated, showing long memory and mean reverting behaviour. Moreover, a close relation between energy consumption and energy prices is found in the spot market whereas it is not found in the futures market. In fact, there is a weak relationship between the futures market and energy consumption. However, regarding energy pricing, the relationship is stronger but with the spot market itself.

The activation of purinergic receptors by nucleotides and/or nucleosides plays an important role in the control of vascular function, including modulation of vascular smooth muscle excitability, and vascular reactivity. Accordingly, purinergic receptor actions, acting as either ion channels (P2X) or G protein-coupled receptors (GCPRs) (P1, P2Y), target diverse downstream effectors, and substrates to regulate vascular smooth muscle function and vascular reactivity. Both vasorelaxant and vasoconstrictive effects have been shown to be mediated by different purinergic receptors in a vascular bed- and species-specific manner. Purinergic signaling has been shown to play a key role in altering vascular smooth muscle excitability and vascular reactivity following acute and short-term elevations in extracellular glucose (e.g., hyperglycemia). Moreover, there is evidence that vascular smooth muscle excitability and vascular reactivity is severely impaired during diabetes and that this is mediated, at least in part, by activation of purinergic receptors. Thus, purinergic receptors present themselves as important candidates mediating vascular reactivity in hyperglycemia, with potentially important clinical and therapeutic potential. In this review, we provide a narrative summarizing our current understanding of the expression, function, and signaling of purinergic receptors specifically in vascular smooth muscle cells and discuss their role in vascular complications following hyperglycemia and diabetes.

Recent studies have shown evidence of a significant decline of the Posidonia oceanica (P.O.) meadows on a global scale. The monitoring and mapping of these meadows are fundamental tools for measuring their status. We present an approach based on a deep neural network to automatically perform a highprecision semantic segmentation of the P.O. meadows in sea-floor images, offering several improvements over the state-of-the-art techniques. Our network demonstrates outstanding performance over diverse test sets, reaching a precision of 96.57% and an accuracy of 96.81%, surpassing the reliability of labeling the images manually. Moreover, the network is implemented in an autonomous underwater vehicle, performing an online P.O. segmentation, which will be used to generate real-time semantic coverage maps.

Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called ‘metabophenotypes’, in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.

Background: In hormone receptor-positive (HR+)/HER2-negative breast cancer, the HER2-enriched and Basal-like intrinsic subtypes are associated with poor outcome, low response to anti-estrogen therapy and high response to chemotherapy. To date, no validated biomarker exists to identify both molecular entities other than gene expression.Methods: PAM50 subtyping and immunohistochemical data were obtained from 8 independent studies of 1,416 HR+/HER2-negative early breast tumors. A non-luminal disease score (NOLUS) from 0 to 100, based on percentage of estrogen receptor (ER), progesterone receptor (PR) and Ki67 tumor cells, was derived in a combined cohort of 5 studies (training dataset) and tested in a combined cohort of 3 studies. The performance of NOLUS was estimated using Area Under the ROC Curve (AUC).Results: In the training dataset (n = 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%, p < 0.01) and PR-positive cells (33.2 vs. 56.4%, p < 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%, p = 0.01). A NOLUS formula was derived: −0.45*ER −0.28*PR +0.27*Ki67 + 73.02. The proportion of non-luminal tumors in NOLUS-positive (≥51.38) and NOLUS-negative (

Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.

The desire to move to music appears to be a human universal. This behavioral response seems to be supported by a tight coupling of auditory and motor networks, even in the absence of overt movement. The prevailing theories explain this phenomenon either in terms of passive brain network entrainment to musical periodicity or motor system involvement in predictive coding. Both explanations recognize the role of rhythmic complexity in modulating motor activity. However, the precise nature of the relationship between rhythmic complexity and motor activity remains unclear. In this work, we conducted an fMRI literature review to examine this relationship. Out of 110 screened articles, 24 met inclusion criteria, reporting findings ranging from non-existent to linear or inverted-U-shaped. Underlying these findings, we encountered significant heterogeneity in the measurement and conceptualization of rhythmic complexity. We provide a summary of the relationships found, the approaches to measuring rhythmic complexity and the different types of tasks and stimuli used. We conclude that, in order to move forward, more agreement is needed regarding measures and notions of complexity.

During the past few decades, the need to intervene in underwater scenarios has grown due to the increasing necessity to perform tasks like underwater infrastructure inspection and maintenance or archaeology and geology exploration. In the last few years, the usage of Autonomous Underwater Vehicles (AUVs) has eased the workload and risks of such interventions. To automate these tasks, the AUVs have to gather the information of their surroundings, interpret it and make decisions based on it. The two main perception modalities used at close range are laser and video. In this paper, we propose the usage of a deep neural network to recognise pipes and valves in multiple underwater scenarios, using 3D RGB point cloud information provided by a stereo camera. We generate a diverse and rich dataset for the network training and testing, assessing the effect of a broad selection of hyperparameters and values. Results show F1-scores of up to 97.2% for a test set containing images with similar characteristics to the training set and up to 89.3% for a secondary test set containing images taken at different environments and with distinct characteristics from the training set. This work demonstrates the validity and robust training of the PointNet neural in underwater scenarios and its applicability for AUV intervention tasks.

During the past decades, the composition and distribution of marine species have changed due to multiple anthropogenic pressures. Monitoring these changes in a cost-effective manner is of high relevance to assess the environmental status and evaluate the effectiveness of management measures. In particular, recent studies point to a rise of jellyfish populations on a global scale, negatively affecting diverse marine sectors like commercial fishing or the tourism industry. Past monitoring efforts using underwater video observations tended to be time-consuming and costly due to human-based data processing. In this paper, we present Jellytoring, a system to automatically detect and quantify different species of jellyfish based on a deep object detection neural network, allowing us to automatically record jellyfish presence during long periods of time. Jellytoring demonstrates outstanding performance on the jellyfish detection task, reaching an F1 score of 95.2%; and also on the jellyfish quantification task, as it correctly quantifies the number and class of jellyfish on a real-time processed video sequence up to a 93.8% of its duration. The results of this study are encouraging and provide the means towards a efficient way to monitor jellyfish, which can be used for the development of a jellyfish early-warning system, providing highly valuable information for marine biologists and contributing to the reduction of jellyfish impacts on humans.

Following publication of the original article [1], the authors reported the following errors in the article.

An outbreak of sylvatic rabies was reported in indigenous communities located in the Ecuadorian Amazon in November 2011. The objective of this study was to analyze family dwelling characteristics and other sociodemographic factors associated with the perception of an increase in hematophagous bat bites in humans and domestic animals to assist the implementation of intervention policies in the region. A total of 381 households from communities covered by the outbreak response activities were surveyed. Despite being associated with poorer dwelling conditions, the possession of domestic animals is associated with the perception of an increase in bat bites among animals. Better dwelling conditions, use of protective measures, access to electricity, and no domestic animals are variables associated with the perception of a rise in attacks on humans. The analysis of perceptions of bite frequency is fundamental to improve the effectiveness of vaccination programs and strategies to promote the adoption of preventive measures against rabies among the population.

Herpes Simplex Virus Type -1 (HSV-1) infections can cause serious complications such as keratitis and encephalitis. The goal of this study was to identify any changes in the concentrations of volatile organic compounds (VOCs) produced during HSV-1 infection of epithelial cells that could potentially be used as an indicator of a response to stress. An additional objective was to study if any VOCs released from acute epithelial infection may influence subsequent neuronal infection to facilitate latency. To investigate these hypotheses, Vero cells were infected with HSV-1 and the emission of VOCs was analyzed using two-dimensional gas chromatograph/mass spectrometry (2D GC/MS). It was observed that the concentrations of gamma-butyrolactone (GBL) in particular changed significantly after a 24-hour infection. Since HSV-1 may establish latency in neurons after the acute infection, GBL was tested to determine if it exerts neuronal regulation of infection. The results indicated that GBL altered the resting membrane potential of differentiated LNCaP cells and promoted a non-permissive state of HSV-1 infection by repressing viral replication. These observations may provide useful clues towards understanding the complex signaling pathways that occur during the HSV-1 primary infection and establishment of viral latency.

The choice of a pure cohesive or a pure frictional viscoplastic model to represent the rheological behaviour of a flowslide is of paramount importance in order to obtain accurate results for real cases. The principal goal of the present work is to clarify the influence of the type of viscous model—pure cohesive versus pure frictional—with the numerical reproduction of two different real flowslides that occurred in 1966: the Aberfan flowslide and the Gypsum tailings impoundment flowslide. In the present work, a depth-integrated model based on the v - p w Biot–Zienkiewicz formulation, enhanced with a diffusion-like equation to account for the pore pressure evolution within the soil mass, is applied to both 1966 cases. For the Aberfan flowslide, a frictional viscous model based on Perzyna viscoplasticity is considered, while a pure cohesive viscous model (Bingham model) is considered for the case of the Gypsum flowslide. The numerical approach followed is the SPH method, which has been enriched by adding a 1D finite difference grid to each SPH node in order to improve the description of the pore water evolution in the propagating mixture. The results obtained by the performed simulations are in agreement with the documentation obtained through the UK National Archive (Aberfan flowslide) and the International Commission of large Dams (Gypsum flowslide).

OBJETIVO: Caracterizar o perfil do paciente atendido em ambulatório de doenças profissionais de um hospital geral e, em especial, o portador da condição patológica mais freqüente: as lesões por esforços repetitivos (LER). MÉTODOS: Foram analisadas as 565 fichas-resumo de atendimento ambulatorial em saúde do trabalhador, em 1996, em função de variáveis sociodemográficas, de características do trabalho e de diagnóstico. Foram adotados os seguintes procedimentos: descrição univariável de todas as variáveis; análise bivariada, utilizando-se o teste do qui-quadrado (chi²) para variáveis categóricas; comparação de médias ou amplitudes para variável categórica e outra quantitativa; análise multivariada por meio de modelos log-linear, com transformação logit, para detectar os grupos com maior proporção de LER. RESULTADOS: Houve predomínio no atendimento de pacientes do sexo feminino com menos de 40 anos, sendo que, nos casos de LER, esse predomínio mostrou-se mais acentuado. As ocupações agrupadas apareceram em ordem decrescente, na seqüência: administrativos, operários e prestadores de serviços, sendo 59,6% pertencentes ao ramo de atividade econômica de serviços. As LER corresponderam a 56% dos diagnósticos feitos nas primeiras consultas. CONCLUSÕES: Confirmou-se a tendência de mudança no perfil epidemiológico das demandas atendidas no ambulatório de doenças profissionais, no final da década de 80, quando emergiram as LER. Deslocaram-se para uma minoria as antigas doenças profissionais decorrentes da exposição a riscos químicos e físicos, em função daquelas relacionadas às condições ergonômicas inadequadas.OBJECTIVE: To assess the profile of outpatients seen at an occupational disease clinic of a general and repetitive strain injury (RSI) patients by using multivariate analyze. METHODS: The first 565 visit registries for the year 1996 were assessed regarding their social and demographics aspects, work characteristics, and diagnosis. All the variables were analyzed by univariate analysis method. Bivariate data were analyzed using Chi square test (chi²) for categorical variables, comparison of means or ranges for quantitative and categorical variables. Multivariate data were analyzed using log-linear models with logit-transformation to identify the groups with a larger proportion of RSI. RESULTS: Women sought the occupational diseases clinic more frequently than men, and there was a predominance of RSI cases. The occupation distribution was in order of priority as following: office workers, factory workers, and service workers. Of them, 56.9% were from the economic sector of services. RSI was seen in 56% of the patients diagnosed at their first visit. CONCLUSIONS: The analysis confirms the trends seen in the 80s regarding the epidemiological changes in occupational diseases, when RSI started to be identified and displaced to a secondary position the other common diseases (due to physical and chemical hazards) because of inadequacy of ergonomics.

INTRODUÇÃO: As estatísticas dos acidentes de trabalho, como qualquer outro sistema de notificação, devem servir de base para determinar prioridades e decidir quais medidas preventivas devem ser adotadas. Neste contexto, o objetivo do estudo é aprofundar a análise dos acidentes de trabalho através da utilização de técnicas estatísticas descritivas que permitam estabelecer a relação entre o número de acidentes de trabalho ocorridos em Barcelona (Espanha) e as variáveis tipo de acidente, setor econômico, tamanho da empresa e tipo de contrato. MÉTODO: Como fonte de dados foi utilizado o sistema de notificação de acidentes graves e mortais ocorridos na cidade de Barcelona (Espanha), entre 1992 e 1993. Foram examinados 848 registros de acidentes de trabalho em trabalhadores do sexo masculino e a partir desses dados efetuou-se uma análise mediante modelos log-lineares. RESULTADOS E CONCLUSÕES: Os resultados evidenciam que os acidentes traumáticos e o setor de construção têm uma associação positiva, verificada, da mesma forma, entre os acidentes de trânsito e o setor de serviços. Os acidentes traumáticos e de trânsito apresentaram uma associação com as pequenas empresas e os acidentes não traumáticos demonstraram associar-se com as grandes empresas. Verificou-se, ainda, associação entre os trabalhadores temporais e o setor da construção frente aos trabalhadores com contrato fixo, em que se constatou uma associação com os setores de indústria e de serviços. Foi verificada associação positiva entre os acidentes ocorridos com os trabalhadores temporais e as pequenas e médias empresas.

The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34+ hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34+ cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34+ cells with high (CD34+ MitoHigh) versus low (CD34+ MitoLow) mitochondrial mass. The CD34+ MitoLow fraction contained 6-fold more CD34+CD38− primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34+ MitoHigh fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34+ MitoLow cells was significantly delayed as compared to that of CD34+ MitoHigh cells. The eventual complete differentiation of CD34+ MitoLow cells, which coincided with a robust expansion of the CD34− differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34+ cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineage-committed CD34− cells.