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In order to discern the causes of the health and developmental problems of children, and thence develop preventative strategies, longitudinal cohort studies offer major advantages. They can monitor the consequences of exposure to physical and psychological events and thence identify antecedents of various disorders. We describe the historical background to the development in the UK of this study design, and the uptake of longitudinal birth cohorts in low- and middle-income countries (LMICs), using the cohorts in Jamaica, South Africa and Brazil as exemplars. We describe the benefits of such studies and show how undertaking longitudinal cohort studies can have major health and financial benefits to the populations concerned. Additionally, the paper outlines the advantages of collaboration between studies and the pooling of data. [ABSTRACT FROM AUTHOR]

In preparation to the launch of a pharmaceutical product, an estimate of its shelf life via stability testing is required by regulatory agencies. The ICH-Q1E guidance has been the worldwide reference to reach this objective, but in recent years several authors have criticized many of its aspects. To that end we discuss a complete Bayesian transcript of the ICH-Q1E, treating all the apparent shortcomings, while also addressing the presence of multiple batches using a linear mixed model (LMM) for proper shelf life prediction by explicitly modelling the batch-to-batch variability. This comprises a redefinition of the linear models proposed in the ICH-Q1E by suitable LMM counterparts, and a Bayesian analogue for model selection, which is more intuitive and remedies detrimental features of the ICH approach. In that context, a proper mathematical foundation of shelf life is provided that we use to investigate and mathematically compare the two available approaches to shelf life determination via shelf life distribution and batch distribution. The discussed method is then tested and evaluated using real data in comparison with the ICH-Q1E approach demonstrating their approximate equivalency for 6 batches. As a major objective, we extended the LMM with auxiliary fixed effects, here the concentration, which interconnect data sets allowing a prediction of shelf lives for concentrations lacking a sufficient number of batches. This establishes a novel approach to accelerate the speed to submission while retaining the patients' safety. Both case studies underline the inherent superiority of LMMs within a Bayesian framework regarding predictability and interpretability, and we hope that the relevant authorities will accept this approach in the future. [ABSTRACT FROM AUTHOR]

Herein we describe the synthesis and photophysical and electrochemical characterization of pyrimidopteridine‐based photoredox catalysts. The pyrimidopteridines can be obtained from the corresponding N‐oxides through photo‐mediated oxygen atom transfer to a sacrificial acceptor molecule on gramscale. The presence of a triplet excited state was evidenced by means of transient absorption spectroscopy. Pyrimidopteridines are potent excited state oxidants with excited state reduction potentials exceeding +2.10 V vs. SCE in MeCN. The catalytic activity is illustrated in the photo‐mediated oxidative annulation of 2‐phenylbenzoic acid. [ABSTRACT FROM AUTHOR]

Background Case reports might have a prominent role in the rare diseases field, due to the small number of patients affected by one such disease. A previous systematic review regarding the efficacy of laronidase therapy in patients with mucopolysaccharidosis type I (MPS-I) who initiated enzyme replacement therapy (ERT) in adult age has been published. The review included a meta-analysis of 19 clinical studies and the description of eleven case reports. It was of interest to perform a meta-analysis of those case reports to explore the role of such meta-analyses as a tool for evidence-based medicine in rare diseases. Methods The study included all case reports with standard treatment regimen. Primary analysis was the percentage of case reports showing an improvement in a specific outcome. Only when that percentage was statistically higher than 5%, the improvement was confirmed as such. The outcomes that accomplished this criterion were ranked and compared to the GRADE criteria obtained by those same outcomes in the previous meta-analysis of clinical studies. Results There were three outcomes that had a significant improvement: Urine glycosaminoglycans, liver volume and 6-minute walking test. Positive and negative predictive values, sensitivity and specificity for the results of the meta-analysis of case reports as compared to that of clinical studies were 100%, 88.9%, 75% and 100%, respectively. Accordingly, absolute (Rho = 0.82, 95%CI: 0.47 to 0.95) and relative agreement (Kappa = 0.79, 95%CI: 0.593 to 0.99) between the number of case reports with improvement in a specific outcome and the GRADE evidence score for that outcome were good. Sensitivity analysis showed that agreement between the meta-analysis of case reports and that of the clinical studies were good only when using a strong confirmatory strategy for outcome improvement in case reports. Conclusions We found an agreement between the results of meta-analyses from case reports and from clinical studies in the efficacy of laronidase therapy in patients with MPS-I who initiated ERT in adult age. This agreement suggests that combining case reports quantitatively, rather than analyzing them separately or qualitatively, may improve conclusions in the field of rare diseases. [ABSTRACT FROM AUTHOR]

The article presents a study on persistent abnormalities in peripheral blood dendritic cells and monocytes from human immunodeficiency virus (HIV)-1-positive patients after one year of antiretroviral therapy (ART) in the U.S. The subjects were tested before therapy and after a number of weeks after starting ART. The results of the study show an incomplete T-cell immune reconstitution in chronically infected patients who had undetectable plasma viremia while taking ART for 1 year.

The article examines the international students program at the National War College of National Defense University in the U.S. International student participation in the university includes the international military and civilian personnel. International students are able to advance their studies and complete them. Also, long-lasting ties of friendship are formed between the U.S. and international students.

Adolescence represents a fundamental stage for interactions between excessive food intake and drug consumption. The association between obesity and drug use is unclear, but inhibitory control has been proposed as a common mechanism. The current study aimed to examine differences in inhibitory control measures in adolescents with overweight and/or substance use. Eighty-five adolescents 15–16 years of age were grouped according to a factorial design as cannabis users (n = 44) versus abstainers (n = 41), and alcohol users (n = 50) versus abstainers (n = 35). Participants were also classified depending on their BMI range as normal weight (n = 47) or overweight (n = 38). To measure inhibitory control, participants completed a Go-Nogo task while their brain activity was registered through electroencephalography, recording the event-related potentials during the task. No behavioral differences were found, but overweight teens exhibited lower P3 amplitudes (for both Go and Nogo conditions) compared with normal-BMI teens, indicating general difficulties in recruiting cognitive resources. Also, alcohol users showed higher Nogo-P3 amplitudes compared with alcohol abstainers, suggesting increased need of inhibitory control effort to achieve a good behavioral performance. Results indicate distinct altered inhibitory control functions in overweight adolescents and alcohol users. These findings suggest that different specific mechanisms of modulation of inhibitory control brain processes are involved in excessive food versus drug consumption, against the notion of food-drug competition. Understanding of associations between excessive food intake and substance use in adolescence will require identification of both common and specific risk factors. [ABSTRACT FROM AUTHOR]

Despite the large amounts of resources destined to developing filtering algorithms of LiDAR point clouds in order to obtain a Digital Terrain Model (DTM), the task remains a challenge. As a society advancing towards the democratization of information and collaborative processes, the researchers should not only focus on improving the efficacy of filters, but should also consider the users' needs with a view toward improving the usability and accessibility of the filters in order to develop tools that will provide solutions to the challenges facing this field of study. In this work, we describe the Hybrid Overlap Filter (HyOF), a new filtering algorithm implemented in the free R software environment. The flow diagram of HyOF differs in the following ways from that of other filters developed to date: (1) the algorithm is formed by a combination of sequentially operating functions (i.e., the output of the first function provides the input of the second), which are capable of functioning independently and thus enabling integration of these functions with other filtering algorithms; (2) the variable penetrability is defined and used, along with slope and elevation, to identify ground points; (3) prior to selection of the seed points, the original point cloud is processed with the aim of removing points corresponding to buildings; and (4) a new method based on a moving window, with longitudinal overlap between windows and transverse overlap between passes, is used to select the seed points. Our hybrid filtering method is tested using 15 reference samples acquired by the International Society of Photogrammetry and Remote Sensing (ISPRS) and is evaluated in comparison with 33 existing filtering algorithms. The results show that our hybrid filtering method produces an average total error of 3.34% and an average Kappa coefficient of 92.62%. The proposed algorithm is one of the most accurate filters that has been tested with the ISPRS reference samples. [ABSTRACT FROM AUTHOR]

Background: A preliminary exploratory study shows solid agreement between the results of case reports and clinical study meta-analyses in mucopolysaccharidosis Type I (MPS-I) adult patients. The aim of the present study is to confirm previous results in another patient population, suffering from mucopolysaccharidosis Type II (MPS-II).Methods: A systematic review and meta-analysis of case reports published by April 2018 was conducted for MPS-II patients treated with enzyme replacement therapy (ERT). The study is reported in accordance with PRISMA and MOOSE guidelines (PROSPERO database code CRD42018093408). The assessed population and outcomes were the same as previously analyzed in a meta-analysis of MPS-II clinical studies. The primary endpoint was the percent of clinical cases showing improvement in efficacy outcome, or no harm in safety outcome after ERT initiation. A restrictive procedure to aggregate case reports, by selecting standardized and well-defined outcomes, was proposed. Different sensitivity analyses were able to evaluate the robustness of results.Results: Every outcome classified as "acceptable evidence group" in our case report meta-analysis had been graded as "moderate strength of evidence" in the aforementioned meta-analysis of clinical studies. Sensitivity, specificity, and positive-negative predictive values for results of both meta-analyses reached 100%, and were deemed equivalent.Conclusions: Aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine. Additionally, we propose some methods to evaluate publication bias and heterogeneity of the included studies in a meta-analysis of case reports. [ABSTRACT FROM AUTHOR]

The assembly of dinuclear complexes with the ultimate smallest ditopic ligands based on side-on complexes of methyl substituted alkynes is presented. In fact, the coordination of Ru(II) and Ir(III) by a W alkyne complex based cyclometallating metalla-ligand causes close intermetallic electronic cooperation, which substantially changes the electrochemical and photophysical properties of the single isolated moieties. [ABSTRACT FROM AUTHOR]

Current environmental crises call for an integrated knowledge of landscapes and their ecosystems in a broader sense. This article presents a pedagogical framework for cross-disciplinary landscape research at postgraduate level. The framework is grounded in the use of geospatial epistemic discomfort as a creative force to develop and enhance inquiry skills able to cross and merge disciplinary boundaries. Developed within the Erasmus+ KA2 project “CROSSLAND”, the pedagogical framework is based on the scaffolding of epistemic discomfort through four key didactic elements: 1) cross-disciplinary group work and open-ended assignment, 2) in-field inquiry as pre-training on space-time, 3) replacement of traditional lectures by student-led seminars, 4) GIS labs centred on the exploration of cross-disciplinary portfolios of geospatial approaches and methods given as worked-out examples. Main results from the evaluation of the framework implementation in a Summer School show how learning cross-disciplinarity happened thanks to a scaffolding that allowed, first and foremost, the socialisation of different conceptualisations of space. While students felt at ease with geospatial epistemic discomfort, we can conclude that spatial cognitive processes are powerful in improving abilities beyond the spatial domain. [ABSTRACT FROM AUTHOR]

In cost–benefit analysis of lidar data acquisition, point density is often artificially reduced in order to examine how this affects the quality of derived products. However, the performance of the different density reduction methods has not yet been compared and their influence on the accuracy of the models and results has not been evaluated. A novel method for reducing the point density, termed Proportional per Cell (PpC), is presented and compared with the performance of three other reduction methods, examining their influence on the accuracy of lidar‐derived digital surface models using ISPRS reference data. The results indicate that the PpC method was better at conserving the characteristics of the original data. However, point density, sample type and slope had a greater influence than the reduction method used. [ABSTRACT FROM AUTHOR]

We present a computational approach for predicting key properties of organic radical anions, including excited-state lifetimes and redox potentials. The approach shows good agreement with experimental data and has potential for in silico screening to facilitate the rational design of photocatalysts. [ABSTRACT FROM AUTHOR]

A series of thienoindolizine structural isomers have been synthesized in a one‐pot, two‐step procedure starting from easily accessible gem‐difluoroalkene functionalized bromothiophenes. The developed method gives easy access to a range of thienoindolizine products containing thieno[3,2‐g]‐, thieno[3,4‐g]‐ and thieno[2,3‐g]indolizine core structures. The described synthesis strategy consists of a base mediated, transition metal free nucleophilic substitution of fluorine atoms by nitrogen containing heterocycles followed by a Pd catalyzed intramolecular cyclization. A series of 22 final product examples has been obtained with yields ranging from 29 % to 95 %. UV/Vis absorption, fluorescence spectroscopy, fluorescence lifetime measurements and cyclic voltammetry were carried out with selected final products to evaluate structural effects on photophysical and electrochemical properties. (TD)DFT and NICS calculations were performed to provide insight into the electronic properties of the four core molecular structures. [ABSTRACT FROM AUTHOR]

• The optimal management of severe COVID-19 represents an unmet clinical need. • Programmed cell death-1/interleukin-6 receptor blockade might restore immunocompetence and interrupt hyperinflammation. • COPERNICO assessed pembrolizumab plus tocilizumab and standard of care (SOC) compared with SOC in high-risk patients with COVID-19. • The addition of pembrolizumab plus tocilizumab to SOC reduced the hospitalization period. • The addition of pembrolizumab plus tocilizumab to SOC reduced the rate of discharge without sequelae. Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone. [ABSTRACT FROM AUTHOR]

The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. Median rPFS was 5.5 months (95% CI 5.3–5.5). Median rPFS of patients with AR-V7(−) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2–not reached) and was significantly greater for AR-V7(−) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile. • 223Ra had a promising antitumour activity in patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases. • 223Ra showed an acceptable safety profile similar to that reported in other studies. • Overall survival of androgen receptor splice variant 7 (−) patients was significantly higher than androgen receptor splice variant 7 (+) patients. [ABSTRACT FROM AUTHOR]

Background Elucidating risk pathways for under-achieving at school can inform strategies to reduce the number of adolescents leaving school without passing grades in core subjects. Maternal depression can compromise the quality of parental care and is associated with multiple negative child outcomes. However, only a few small studies have investigated the association between perinatal maternal depression and poor academic achievement in adolescence. The pathways to explain the risks are also unclear. Method Prospective observational data from 5,801 parents and adolescents taking part in a large UK population cohort (Avon-Longitudinal-Study-of-Parents-and-Children) were used to test associations between maternal and paternal depression and anxiety in the perinatal period, executive function ( EF) at age 8, and academic achievement at the end of compulsory school at age 16. Results Adolescents of postnatally depressed mothers were 1.5 times (1.19, 1.94, p = .001) as likely as adolescents of nondepressed mothers to fail to achieve a 'pass' grade in math; antenatal anxiety was also an independent predictor of poor math. Disruption in different components of EF explained small but significant proportions of these associations: attentional control explained 16% (4%, 27%, p < .001) of the association with postnatal depression, and working memory explained 17% (13%, 30%, p = .003) of the association with antenatal anxiety. A similar pattern was seen for language grades, but associations were confounded by maternal education. There was no evidence that paternal factors were independently associated with impaired child EF or adolescent exams. Conclusion Maternal postnatal depression and antenatal anxiety are risk factors for adolescents underachieving in math. Preventing, identifying, and treating maternal mental health in the perinatal period could, therefore, potentially increase adolescents' academic achievement. Different aspects of EF partially mediated these associations. Further work is needed, but if these pathways are causal, improving EF could reduce underachievement in math. [ABSTRACT FROM AUTHOR]

Objective: To validate the translated and cross culturally adapted Chilean version of the 8 and 18month Ages and Stages Questionnaire (ASQ-CL) in a community sample.Methods: Participants: Parents of 1572 term children (82.9%) and 324 children at risk for developmental delay (17.1%) were included.Instrument: ASQ-3rd edition translated and culturally adapted for Chilean urban population.Main Measures: 8 and 18months ASQ-CL reliability, validity and mean scores. Feasibility was assessed using qualitative methods in healthcare professionals and mothers.Results: ASQ-CL mean scores were comparable to U.S. normative data. The overall total score and all domains were reliable (Cronbach alpha 0.66-0.85). Test-retest and inter-rater reliability were high (Pearson's r range 0.73-0.94; intraclass correlation r range 0.68-0.93). Early preterm infants were more likely to fail on several criteria. Qualitative methods confirmed ASQ-CL as a feasible tool in this Chilean urban community.Conclusions: ASQ-CL is a valid, reliable and feasible tool for assessing development in children at 8 and 18months in Chilean urban population. [ABSTRACT FROM AUTHOR]

Background: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.Methods: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.Results: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.Conclusions: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017.Trial registration: The PHERGain study (NCT03161353) is assessing early metabolic responses to neoadjuvant treatment with trastuzumab-pertuzumab and chemotherapy de-escalation using a [18Fluorine]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) and a pathological complete response-adapted strategy in HER2-positive (HER2+) early breast cancer (EBC). Herein, we present RESPONSE, a PHERGain substudy, where clinicopathological and molecular predictors of [18F]FDG-PET disease detection were evaluated.A total of 500 patients with HER2 + EBC screened in the PHERGain trial with a tumor size > 1.5 cm by magnetic resonance imaging (MRI) were included in the RESPONSE substudy. PET[−] criteria entailed the absence of  ≥ 1 breast lesion with maximum standardized uptake value (SUVmax) ≥ 1.5 × SUVmean liver + 2 standard deviation. Among 75 PET[−] patients screened, 21 with SUVmax levels < 2.5 were randomly selected and matched with 21 PET[+] patients with SUVmax levels ≥ 2.5 based on patient characteristics associated with [18F]FDG-PET status. The association between baseline SUVmax and [18F]FDG-PET status ([−] or [+]) with clinicopathological characteristics was assessed. In addition, evaluation of stromal tumor-infiltrating lymphocytes (sTILs) and gene expression analysis using PAM50 and Vantage 3D™ Cancer Metabolism Panel were specifically compared in a matched cohort of excluded and enrolled patients based on the [18F]FDG-PET eligibility criteria.Median SUVmax at baseline was 7.2 (range, 1–39.3). Among all analyzed patients, a higher SUVmax was associated with a higher tumor stage, larger tumor size, lymph node involvement, hormone receptor-negative status, higher HER2 protein expression, increased Ki67 proliferation index, and higher histological grade (p < 0.05). [18F]FDG-PET [−] criteria patients had smaller tumor size (p = 0.014) along with the absence of lymph node involvement and lower histological grade than [18F]FDG-PET [+] patients (p < 0.01). Although no difference in the levels of sTILs was found among 42 matched [18F]FDG-PET [−]/[+] criteria patients (p = 0.73), [18F]FDG-PET [−] criteria patients showed a decreased risk of recurrence (ROR) and a lower proportion of PAM50 HER2-enriched subtype than [18F]FDG-PET[+] patients (p < 0.05). Differences in the expression of genes involved in cancer metabolism were observed between [18F]FDG-PET [−] and [18F]FDG-PET[+] criteria patients.These results highlight the clinical, biological, and metabolic heterogeneity of HER2+ breast cancer, which may facilitate the selection of HER2+ EBC patients likely to benefit from [18F]FDG-PET imaging as a tool to guide therapy.Clinicaltrials.gov; NCT03161353; registration date: May 15, 2017. [ABSTRACT FROM AUTHOR]

Background: Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy.Methods: We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I-IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration-time curve 6 mg/mL  per  min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353), and is ongoing.Findings: Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3-6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6-44·5; p<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively INTERPRETATION: 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy.Funding: F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

Pembrolizumab has modest activity if used in patients with hormone-receptor–positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1–2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0–71∙7) , objective response in 18 (40∙9%, 95% CI: 26∙3–56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7–8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8–76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy. • Pembrolizumab + eribulin showed clinical benefit in luminal metastatic breast cancer (BC). • Objective responses were achieved regardless of programmed death ligand 1 status. • Its safety profile is similar to eribulin or pembrolizumab monotherapy. • New predictive biomarkers are required in endocrine-resistant BC. [ABSTRACT FROM AUTHOR]

Variations in parenting across large populations have rarely been described. It also remains unclear which specific domains of parenting are important for which specific offspring developmental outcomes. This study describes different domains of early parenting behaviours and their genetic heritability, then determines the extent to which specific domains of parenting are associated with later offspring outcomes. Parenting behaviours (birth to 3 years) were extracted from self-reported questionnaires administered to 12,358 mothers from the UK-based birth cohort study, the Avon Longitudinal Study of Parents and Children and modelled as a latent factor using Confirmatory Factor Analysis. Genetic heritability and correlations between parenting factors were estimated using genome-wide complex trait analysis. Three parenting factors were derived: parental enjoyment, conflictual relationships and stimulation; all showed low genetic heritability. There was no evidence of association between parental enjoyment and offspring behavioural disorders and depressed mood. Stimulation was associated with better English grades (standardised β = 0.195, p < 0.001) and enjoyment was negatively associated with English grades (β = − 0.244, p = < 0.001). Conflictual relationships were associated with higher risk of offspring behavioural disorders (β = 0.228, p = 0.010) and depressed mood (β = 0.077, p = 0.005). Higher enjoyment reduced the association between conflict and behavioural problems (interaction term β = 0.113, p < 0.001). We found evidence for predictive specificity of early parenting domains for offspring outcomes in adolescence. Early stimulation, unlike enjoyment, promoted later educational achievement. Conflictual relationships were associated with greater risk of behavioural problems, buffered by increased enjoyment. These findings hold implications for parenting interventions, guiding their focus according to the specificity of parenting domains and their long-term outcomes in children. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a longitudinal association exists between differential disciplinary parenting practices at 3 years of age and later child psychopathology at 11 years.Method: Data were obtained from the Millennium Cohort Study, a UK-wide cohort. Discipline style was assessed using a validated maternal reported questionnaire at 3 years of age for which later outcome data were available. "Active" (including smacking, shouting, and telling off) and "withdrawal" (including ignoring, removal of privileges, and sending to bedroom) approaches were distinguished. Child emotional and behavioral problems were assessed at 3 and 11 years of age using the maternally completed Strengths and Difficulties Questionnaire (SDQ). The independence of associations between early discipline and later child mental health was investigated using mutually adjusted regression analyses and potential reverse causality was considered by looking at changes in SDQ subscale scores from 3 to 11 years.Results: Differential associations with change in child psychopathology according to discipline type were observed. Active and withdrawal forms of discipline were associated with a decrease in conduct problems from 3 to 11 years (active, β = -0.28, 95% CI -0.34 to -0.21, p < .001; withdrawal, β = -0.19, 95% CI -0.24 to -014, p < .001). However, active approaches also were associated with an increase in emotional problems (β = 0.07, 95% CI 0.00-0.14, p = .03) not observed for withdrawal approaches.Conclusion: Different approaches to discipline appear to have differential associations with later child mental health. Further research accounting for a larger number of parent and child characteristics is needed to assess whether such associations are causal. [ABSTRACT FROM AUTHOR]

Herein we report the photo‐ and electrochemical characterization of pyrimidopteridine N‐oxide‐based heterocycles. The potential of their application as organic photoredox catalysts is showcased in the photomediated contra‐thermodynamic E→Z isomerization of cinnamic acid derivatives and oxidative cyclization of 2‐phenyl benzoic acid to benzocoumarin using molecular oxygen as a mild oxidant. Furthermore, unprecedented intermolecular non‐covalent n–π‐hole interactions in solid state are discussed based on crystallographic and theoretical data. PyrimidopteridineN‐oxide‐based heterocycles exhibit excellent excited state reduction potentials paired with a suitable ground state reduction potential allowing for catalyst turnover with mild oxidants. The structural similarity between pyrimidopteridines and recently uncovered flavine N‐oxides may draw an important link between organic photoredox catalysis and chemical biology. [ABSTRACT FROM AUTHOR]

Background: Nutritional problems, anaemia and infectious diseases are themain causes of morbidity andmortality in children and adolescents in tropical and subtropical areas. The main objective of this study was to determine the nutritional status in children from low-income countries who migrated to Spain and the value of the usual biochemistry markers of nutrition in these children, as well as to evaluate the nutritional status associated with imported infectious diseases. Moreover, we evaluated the association between anaemia and nutrition problems. Methods: We prospectively evaluated immigrants younger than 18 years of age, from tropical or subtropical areas, who were referred on suspicion of or screening for imported diseases. Detailed medical records and physical and oral examinations were obtained. Blood count and biochemical measures of micronutrients and nutritional biomarkers were performed. We included microbiological methods for diagnosing imported infectious diseases according to the region of origin and clinical setting. Results: 373 minors were evaluated, including 250 (67.0%) from sub-Saharan Africa, 67 (18.0%) from North Africa and 56 (15.0%) from Latin America. The mean BMI of the subjects was 19.8±0.2. BMI increased by 0.02 for each month of stay in Spain. Nineteen patients (6.8%) had a nutritional risk of growth problems, and 50 (17.8%) were overweight. The time since arrival was longer in patients who were overweight (p<0.05). Twentyone minors (5.7%) had a haemoglobin count less than 11.5 g/dL. Children infected with intestinal helminthiasis had anaemia more frequently than uninfected patients, and children infected with intestinal protozoa had anaemia more frequently than uninfected patients (OR=2.7 I.C 1.1-7.0, p<0.05). Conclusions: Immigrant children in Spain have a low prevalence of growth problem, and being overweight is a frequent nutritional issue. A low level of ferritin is the most frequently detected nutritional problem and the main cause of anaemia. [ABSTRACT FROM AUTHOR]

In recent years lidar technology has experienced a noticeable increase in its relevance and usage in a number of scientific fields. Therefore, software capable of handling lidar data becomes a key point in those fields. In this article, we present GPU-based viewer lidar (GVLiDAR), a novel web framework for visualization and geospatial measurement of lidar data point sets. The design of the framework is focused on achieving three key objectives: performance in terms of real-time interaction, functionality, and online availability for the lidar datasets. All lidar files are pre-processed and stored in a lossless data structure, which minimizes transfer requirements and offers an on-demand lidar data web framework. [ABSTRACT FROM AUTHOR]

To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization ( aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph− (MPN-Ph−), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph− and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia. [ABSTRACT FROM AUTHOR]

Taking into consideration a behavioral approach a scale called the "Adolescent Food Habits Checklist" was developed in England to assess behaviors of adolescents with autonomous eating habits. To develop cross-cultural adaptation from English to Spanish of the "Adolescent Food Habits Checklist" to be applied in Venezuelan adolescents. A translation into Spanish by two independent translators was carried out. The obtained version was retranslated into English and evaluated by the original scale authors. Their recommendations were considered to confirm the content validity of the Spanish version. Last version was applied on 4 pilot tests to get a suitable scale with construct validity and internal consistency reliability. These parameters were reached in the fourth pilot test, which was developed with 200 adolescents between 15 and 19 years of age, of both male and female. An 18-item scale with a Cronbach alpha of 0.863 was obtained. Every item helped to keep a coefficient within 0.849 and 0.864 when they were removed. In addition, all of the items achieved a correlation item -- total higher than 0.3. The analysis of factors showed that most of the items are grouped into three factors that define the construct assessed with a weighing of each factor equal or over 0.4. The cumulative percentage of variance explained for these three factors was 50%. A cross-cultural adaptation of the scale with content validity, construct validity and high internal consistency reliability to be applied in Venezuelan adolescents was obtained. [ABSTRACT FROM AUTHOR]

We have recently evaluated an ELISA for the diagnosis of human schistosomiasis using S. bovis adult worm antigens (AWA Sb), showing a sensitivity of 94% and a specificity of 97% for patients diagnosed by egg detection. Nevertheless, the comparison of this AWA Sb ELISA with direct parasitological findings as the gold standard could introduce a selection bias, due to the well-known lack of sensitivity of direct methods in the detection of acute schistosomiasis and of low burden infections. The objective of the present work is to compare it with parasitological methods and commercial indirect haemagglutination test using S. mansoni antigens (WA Sm IHA) in 254 immigrants and travellers with different clinical settings; in addition, to find specific bands in the EITB of different phases of schistosomiasis. The AWA Sb ELISA showed 72% of seropositivity in patients with Katayama fever, while patients with eosinophilia and genito-urinary complaints showed 27% and 93%, respectively. The diagnosis yield was globally higher than direct egg detection or WA Sm IHA test with regard to the clinical setting. Finally, the utilization of EITB with S. bovis AWA permits the confirmation of diagnosis in chronic and acute phases of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Obesity and overweight, considered the pandemic disease in the 21st century, is highly related to breast cancer. Leptin receptor (Ob-R) and its ligand leptin display an important role in driving this connection. Nowadays, translational cancer research is mainly focused on the identification of new biomarkers able to discriminate those patients deriving greater efficacy from a given therapy. In this regard, our study examines the role of Ob-R, namely, the correlation between Ob-R and pathological complete Response (pCR) in early breast cancer patients receiving neoadjuvant systemic therapy. Here, we decoded the correlation of Ob-R with certain clinical features such as breast cancer subtype, age, body mass index (BMI), menopausal status, and mammogram breast density. The study provides further support for the potential value of Ob-R for the first time as a possible role for predicting pCR. Moreover, we would like to highlight the importance of Ob-R as independent predictive factors for pCR in breast cancer patients. The primary aim of this retrospective study was to investigate the correlation between the immunohistochemical expression of Ob-R (leptin receptor) with pCR (pathological complete response) in early breast cancer patients receiving neoadjuvant systemic treatment (NST). A total of 100 women with breast cancer receiving NST (2017–2020) followed by surgical resection were retrospectively obtained. Demographic parameters and clinicopathological factors (e.g., treatment modalities, immunohistochemistry (IHC), and cancer subtype) were obtained from the patient's clinical records. In the analyzed breast cancer cohort, high expression of Ob-R was found in 52% of tumors and there was a significantly higher incidence in the HER2+ and TNBC subgroups. Overall, a significantly greater percentage of patients with Ob-R positive tumors achieved pCR compared with Ob-R negative patients (57.7% vs. 27.1%; p = 0.002). This result was observed in most breast cancer subtypes. In patients with HER2+ breast cancer, there was no difference in Ob-R expression in relation to the HR status. Ob-R cell positivity was significantly higher in younger breast cancer patients (p = 0.008), those who were premenopausal (p = 0.011), and in those with a BMI > 25 kg/m2 (p = 0.019). A significantly greater percentage of early breast cancer patients with Ob-R positive tumors achieved pCR compared with Ob-R negative patients. Furthermore, breast cancer patients with positive Ob-R expression were significantly younger than those with negative Ob-R expression. This association was not explained by differences in BMI between young and old patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Considering the favorable overall safety profile of trastuzumab emtansine (T-DM1), the low expected rate of cardiotoxicity, and the synergistic effect of anthracyclines with Human Epidermal Growth Factor Receptor 2 (HER2)-targeting agents, it is hypothesized that T-DM1 may be safely combined with non-pegylated liposomal doxorubicin (NPLD). In the THELMA trial, the effect of adding NPLD to T-DM1 was evaluated with the aim of enhancing T-DM1 efficacy using an extensive cardiological assessment in trastuzumab- and taxane-pretreated patients with HER2-positive metastatic breast cancer. Despite an unlikely drug synergism, this combination was generally well tolerated without clinically relevant worsening of cardiac function. No relationship was identified between early predictors of heart failure and left ventricular ejection fraction changes. Thus, the combination of T-DM1 plus NPLD is safe, but this regimen does not seem to improve T-DM1 antitumor activity in this setting. The paper assesses the dose-limiting toxicities and the maximum tolerated dose (MTD) of trastuzumab emtansine (T-DM1) combined with non-pegylated liposomal doxorubicin (NPLD) in HER2-positive (HER2+) metastatic breast cancer (MBC). This single-arm, open-label, phase Ib trial (NCT02562378) enrolled anthracycline-naïve HER2+ MBC patients who had progressed on trastuzumab and taxanes. Patients received a maximum of 6 cycles of NPLD intravenously (IV) at various dose levels (45, 50, and 60 mg/m2) in the "3 plus 3" dose-escalation part. During expansion, they received 60 mg/m2 of NPLD every 3 weeks (Q3W) plus standard doses of T-DM1. The MTD was T-DM1 3.6 mg/kg plus NPLD 60 mg/m2 administered IV Q3W. No clinically relevant worsening of cardiac function was observed. Among all evaluable patients, the overall response rate was 40.0% (95%CI, 16.3–67.7) with a median duration of response of 6.9 months (95%CI, 4.8–9.1). Clinical benefit rate was 66.7% (95%CI, 38.4–88.2) and median progression-free survival was 7.2 months (95%CI, 4.5–9.6). No significant influence of NPLD on T-DM1 pharmacokinetics was observed. The addition of NPLD to T-DM1 is feasible but does not seem to improve the antitumor efficacy of T-DM1 in HER2+ MBC patients. [ABSTRACT FROM AUTHOR]

Background: Cystic echinococcosis (CE) is a well-known neglected parasitic disease. However, evidence supporting the four current treatment modalities is inadequate, and treatment options remain controversial. The aim of this work is to analyse the available data to answer clinical questions regarding medical treatment of CE.Methods: A thorough electronic search of the relevant literature without language restrictions was carried out using PubMed (Medline), Cochrane Central Register of Controlled Trials, BioMed, Database of Abstracts of Reviews of Effects, and Cochrane Plus databases up to February 1, 2017. All descriptive studies reporting an assessment of CE treatment and published in a peer-reviewed journal with available full-text were considered for a qualitative analysis. Randomized controlled trials were included in a quantitative meta-analysis. We used the standard methodological procedures established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Results: We included 33 studies related to the pharmacological treatment of CE in humans. Of these, 22 studies with levels of evidence 2 to 4 were qualitatively analysed, and 11 randomized controlled trials were quantitatively analysed by meta-analysis.Conclusions: Treatment outcomes are better when surgery or PAIR (Puncture, Aspiration, Injection of protoscolicidal agent and Reaspiration) is combined with benzimidazole drugs given pre- and/or post-operation. Albendazole chemotherapy was found to be the primary pharmacological treatment to consider in the medical management of CE. Nevertheless, combined treatment with albendazole plus praziquantel resulted in higher scolicidal and anti-cyst activity and was more likely to result in cure or improvement relative to albendazole alone. [ABSTRACT FROM AUTHOR]