bluuebunny/crossref_metadata_2025 huggingface dataset:
Casos Lagos Del Campo X Acevedo Buendía
Authors: De Moraes Maria Valentina , Hennig Leal Mônia Clarissa
Published: February 2023

A justiciabilidade dos direitos sociais é constantemente debatida no cenário interamericano, já existindo decisões da Corte IDH envolvendo esse grupo de direitos. Uma dessas sentenças, posteriormente invocada no Caso Lagos del Campo v. Peru como um precedente estabelecido, é o Caso Acevedo Buendía e outros v. Peru. Embora a sentença do Caso Lagos del Campo indique o precedente como favorável a justiciabilidade direita dos DESCA, questiona-se: trata-se de um reforço do precedente existente ou, apesar da referência expressa ao mesmo, de uma mudança de posicionamento da Corte de San José quanto à justiciabilidade dos direitos sociais? Utilizando-se dos métodos dedutivo e comparativo, é possível concluir que, embora a decisão faça referência ao precedente determinado no Caso Acevedo Buendía, o posicionamento adotado no caso Lagos del Campo é distinto daquele, atribuindo maior alcance à competência da Corte e a exigibilidade direta dos DESCA através do artigo 26 da Convenção Americana sobre Direitos Humanos, não definida no, em tese, precedente sobre o tema.
The need for na Environmental Democracy to Guarantee Human Rights in Latin America
Authors: Fernando Alvarez Rodriguez Juan , Francisco Nagao Menezes Daniel
Published: February 2023

The Regional Agreement on Access to Information, Public Participation and Access to Justice in Environmental Matters in Latin America and the Caribbean (Escazú Agreement) entered into force in 2021, after achieving ratification in 11 countries. This is the first environmental treaty in the region, where it considers the greatest advance in terms of environmental democracy. This text addresses the international context that currently characterizes Latin America and later focuses on the motivations, stages and characteristics of the negotiation of this binding instrument. Likewise, the text develops the meaning and scope of the main provisions of the Agreement, highlighting its nature as an environmental and human rights treaty. In addition, the current status of the treaty and the next steps to be taken are presented. Finally, the main political arguments used by certain actors to question the Escazú Agreement are discussed.
Preferências Adaptativas, Pobreza Multidimensional e Políticas Públicas
Authors: Uchôa de Oliveira Flávia , Nandy Shailen , Vedovato Luis Renato
Published: February 2023

As preferências adaptativas são sustentadas no pressuposto de que a experiência de privação enviesa as preferências dos sujeitos para a sua adaptação a condições adversas de vida, impactando o que se considera dignidade humana. Por isso, alguns autores indicam que esse viés deveria ser considerado para a formulação e a implementação de políticas públicas voltadas a populações vulneráveis e empobrecidas. Este estudo tem por objetivo apresentar evidências empíricas para o debate crítico sobre as preferências adaptativas, encontradas no estudo sobre pobreza multidimensional na cidade de São Paulo e como contribui para os contornos do conceito de dignidade humana. A partir da Abordagem Consensual, investigamos os níveis de consenso entre várias parcelas da população paulistana e o seu nível de privação. Eram esperados impactos das preferências adaptativas no consenso e na predileção dos mais pobres sobre o que é necessário para um padrão de vida digno no Brasil de hoje. No entanto, os resultados alcançados indicam evidências empíricas pouco significativas que apontam para impactos significativos das preferências adaptativas em nossa amostra. Não há diferença relevante entre as opiniões dos mais pobres e dos não pobres sobre o que deve ser garantido a todas e todos, o que permite construir o que deve fazer parte da dignidade humana. Os dados apresentam similaridade das preferências de pobres e não pobres. Este estudo está em consonância com pesquisas anteriores que indicam que as preferências adaptativas não impactam de forma significativa a Abordagem Consensual.
O Papel Epistêmico da Política Criminal nas Ciências Penais:
Authors: Diéz Ripollés José Luis
Published: February 2023

A contribuição de v. Liszt para a identificação dos saberes que devem tratar da questão do delito e do delinquente foi determinante na evolução dessas ciências ao longo do último século e meio. O presente estudo analisa detidamente o conteúdo atribuído a esses conhecimentos pelo referido autor, com especial atenção no papel atribuído à política criminal frente à dogmática e à criminologia. Entre as numerosas descobertas dessa investigação, merecem destaque a pouca atenção dada por v. Liszt aos conteúdos prescritivos do direito penal, e a limitada, porém relevante, função atribuída à política criminal, centrada no manejo eficaz das penas e medidas de segurança. A análise crítica de sua decisiva contribuição serve também para esboçar as necessidades que a política criminal deve atender na atualidade.
Ultrasound imaging of atrophic levator labii superioris and levator anguli oris after aesthetic facial botulinum toxin injection
Authors: Wu Wei-Ting , Chang Ke-Vin , Mezian Kamal , Ricci Vincenzo , Ozcakar Levent
Published: February 2023

.
Ultrasonic findings of transient perivascular inflammation of the carotid artery syndrome: a case report
Authors: Ge Lijing , Wu Jiangfeng , Wu Qin
Published: February 2023

.
Ultrasound examination and follow-up of post traumatic injury of the proximal lateral head of gastrocnemius
Authors: Poenaru Daniela
Published: February 2023

.
Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2
Authors: Saini Pratima , Adeniji Opeyemi S. , Bordoloi Devivasha , Kinslow Jennifer , Martinson Jeff , Parent Danielle M. , Hong Kai Ying , Koshy Jane , Kulkarni Abhijeet J. , Zilberstein Netanel F. , Balk Robert A. , Moy James N. , Giron Leila B. , Tracy Russell P. , Keshavarzian Ali , Muthumani Kar , Landay Alan , Weiner David B. , Abdel-Mohsen Mohamed
Published: February 2023

One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity.
mSphere of Influence: Pertussis Vaccination and Antibodies in Mothers and Infants
Authors: Portillo Susana
Published: February 2023

Susana Portillo works in the field of mother-infant immunity with an emphasis on vaccination and prevention of respiratory diseases. In this mSphere of Influence, she reflects here on how two pertussis vaccine articles made an impact on her research.
Supplemental Material: Mantle serpentinization and associated hydrogen flux at North Atlantic magma-poor rifted margins
Authors: Liu Zhonglan , al. et
Published: February 2023

Detailed information on the model formulation and setup. 
Supplemental Material: A tale of an orbicule in the eastern Gangdese belt of southern Tibet: Petrographic, geochemical, and submagmatic structural perspectives on its formation
Authors: Ma Xuxuan , et al.
Published: February 2023

Table S1: Zircon LA-ICP-MS U-Pb dating results for the orbicule matrix and orbicule core in the Gangdese belt, southern Tibet. Table S2: Zircon trace elemental results for the orbicule matrix and orbicule cores in the Gangdese belt, southern Tibet. Table S3: Whole-rock geochemical data for the orbicule matrix and orbicule core in the Gangdese belt, southern Tibet. Table S4: Zircon Lu-Hf isotopic results for the orbicule matrix and orbicule core in the Gangdese belt, southern Tibet. Table S5: Whole-rock Sr-Nd data for the orbicule matrix and orbicule cores in the Linzhi region of the eastern Gangdese magmatic belt, Eastern Himalayan Syntaxis. Table S6: Hornblende electron microprobe analyzed data for the orbicule matrix, orbicule shells and orbicule cores in the Gangdese belt, southern Tibet. Figure S1: Field photos and photomicrographs of the collected orbicule in the Gangdese belt, southern Tibet. Figure S2: Representative zircon Cathodoluminescence (CL) images and the spots for the zircon U-Pb and Lu-Hf analyses. Figure S3: Whole-rock Harker diagrams and trace elemental spider diagrams for the matrix and core of the orbicule. Supplemental Text: Analytical Methods.
Supplemental Material: Early Cretaceous (Late Barremian-Early Albian) expanding aeolian activity in East Asia: evidence from the stratigraphic evolution of aeolian deposition in the Baiyin-Jingyuan Basin, Northern China
Authors: Wang Fei , et al.
Published: February 2023

Field photos of three sections, aa′, bb′, cc′, of Hekou Group in the 8 Baiyin-Jingyuan Basin.
Assessment of parental decision making in congenital heart disease, cardiomyopathy and heart transplantation: an observational study analysing decisional characteristics and preferences
Authors: Tadros Hanna J , Saidi Arwa , Rawlinson Alana R , Cattier Celine , Black Erik W , Rackley Jennifer , Breault Leah , Pietra Biagio A , Fricker Fredrick J , Gupta Dipankar
Published: February 2023

Objective

We explore shared decision making (DM) in guardians of children with heart disease by assessing the desired weight of influence on DM and factors that may alter the relative weight of parent or medical team influence.

Methods

Guardians of patients <21 years and admitted >1 week in the paediatric cardiac intensive care unit (PCICU) were recruited. Twelve vignettes were designed including technical (antibiotic selection, intubation, peripherally inserted central catheter placement, ventricular assist device placement, heart transplant, organ rejection, heart rhythm abnormalities and resuscitation effort) and non-technical vignettes (cessation of life-sustaining therapies, depression treatment, obesity and palliative care referral). Participants responded to questions on DM characteristics and one question querying preference for relative weight of parent or medical team influence on DM.

Results

Of 209 participants approached, 183 were included. Most responded with equal desire of medical team and parental influence on DM in all vignettes (range 41.0%–66.7%). Technical scenarios formed one cluster based on DM characteristics, compared with non-technical scenarios. Factors that increase the relative weight of parental influence on DM include desired input and involvement in big-picture goals (OR 0.274, CI [0.217 to 0.346]; OR 0.794, CI [0.640 to 0.986]). Factors that increase the relative weight of medical team influence on DM include perception of medical expertise needed (OR 1.949 [1.630 to 2.330]), urgency (OR 1.373 [1.138 to 1.658]), benefit (OR 1.415 [1.172 to 1.710]), number of PCICU admissions (OR 1.134 [1.024 to 1.256]) and private insurance (OR 1.921 [1.144 to 3.226]).

Conclusion

Although factors may alter the weight of influence on DM, most parents desire equal parental and medical team influence on DM.
Effect of early childhood development interventions delivered by healthcare providers to improve cognitive outcomes in children at 0–36 months: a systematic review and meta-analysis
Authors: Hirve Raeena , Adams Claire , Kelly Clare B , McAullay Daniel , Hurt Lisa , Edmond Karen M , Strobel Natalie
Published: February 2023

Objective

To determine the effect of early childhood development interventions delivered by healthcare providers (HCP-ECD) on child cognition and maternal mental health.

Design

Systematic review, meta-analysis.

Setting

Healthcare setting or home.

Participants

Infants under 1 month of age.

Interventions

HCP-ECD interventions that supported responsive caregiving, early learning and motor stimulation. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects and Cochrane Database of Systematic Reviews were searched until 15 November 2021. Studies reporting prespecified outcomes were pooled using standard meta-analytical methods.

Main outcome measures

Cognitive development in children at 0–36 months.

Results

Forty-two randomised controlled trials with 15 557 infants were included in the narrative synthesis. Twenty-seven trials were included in the meta-analyses. Pooled data from 13 trials suggest that HCP-ECD interventions may improve cognitive outcomes in children between 0 and 36 months (Bayley Scales of Infant Development version IIII (BSID-III) mean difference (MD) 2.65; 95% CI 0.61 to 4.70; 2482 participants; low certainty of evidence). Pooled data from nine trials suggest improvements in motor development (BSID-III MD 4.01; 95% CI 1.54 to 6.48; 1437 participants; low certainty of evidence). There was no evidence of improvement in maternal mental health (standardised MD −0.13; 95% CI −0.28 to 0.03; 2806 participants; 11 trials; low certainty of evidence).

Conclusions

We report promising evidence, particularly for cognitive and motor outcomes, of the effect of HCP-ECD interventions. However, effect sizes were small, and the certainty of evidence ranged from very low to moderate. Additional high-quality research is required.

PROSPERO registration number

CRD42019122021.
Development of indicators for integrated antenatal care service provision: a feasibility study in Burkina Faso, Kenya, Malawi, Senegal and Sierra Leone
Authors: Sheffel Ashley , Tampe Tova , Katwan Elizabeth , Moran Allisyn C
Published: February 2023

Objectives

While service integration has gained prominence as an objective of many global initiatives, there is no widely recognised single definition of integration nor a clear understanding of how programmes are integrated into health systems to achieve improved health outcomes. This study aims to review measurement approaches for integrated antenatal care (ANC) services, propose and operationalise indicators for measuring ANC service integration and inform an integrated ANC indicator recommendation for use in low-income and middle-income countries (LMICs).

Design

Feasibility study.

Setting

Burkina Faso, Kenya, Malawi, Senegal and Sierra Leone.

Methods

Our six-step approach included: (1) conceptualise ANC service integration models; (2) conduct a targeted literature review on measurement of ANC service integration; (3) develop criteria for ANC service integration indicators; (4) propose indicators for ANC service integration; (5) use extant data to operationalise the indicators; and (6) synthesise information to make an integrated ANC indicator recommendation for use in LMICs.

Results

Given the multidimensionality of integration, we outlined three models for conceptualising ANC service integration: integrated health systems, continuity of care and coordinated care. Looking across ANC service integration estimates, there were large differences between estimates for ANC service integration depending on the model used, and in some countries, the ANC integration indicator definition within a model. No one integrated ANC indicator was consistently the highest estimate for ANC service integration. However, continuity of care was consistently the lowest estimate for ANC service integration.

Conclusions

Integrated ANC services are foundational to ensuring universal health coverage. However, our findings demonstrate the complexities in monitoring indicators of ANC service quality using extant data in LMICs. Given the challenges, it is recommended that countries focus on monitoring measures of service quality. In addition, efforts should be made to improve data collection tools and routine health information systems to better capture measures of service integration.
Heat transfer in granular media consisting of particles in humid air at low confining pressure
Authors: Persson B. N. J.
Published: February 2023

I study the heat transfer in systems of weakly interacting particles at low confining pressure in the normal atmosphere. The particles have surface roughness with self-affine fractal properties, as expected for mineral particles produced by fracture, e.g., by crunching brittle materials in a mortar. I show that for small particles (say$$<10 \ \mathrm{\mu m}$$<10μm) with hydrophilic surfaces, at large humidity water capillary bridges dominate the heat transfer, while for big particles heat transfer via the air dominates. This differs from vacuum conditions where the propagating electromagnetic (EM) waves give the dominant heat transfer for large particles, while for small particles both the evanescent EM-waves and the phononic contribution from the area of real contact are most important.
GIS-Based Landslide Susceptibility Mapping Using Frequency Ratio and Shannon Entropy Models in Dejen District, Northwestern Ethiopia
Authors: Addis Abinet
Published: February 2023

A GIS-based study has been carried out to map areas landslide susceptibility using both frequency ratio (FR) and Shannon entropy (SE) bivariate statistical models. A total of 270 landslides were identified and classified randomly into training landslides datasets (70%) and the remaining (30%) of landslides datasets were used for validation purpose. The 11 landslides conditioning factors like slope, elevation, aspect, curvature, topographic wetness index, normalized difference vegetation index, distance from road, distance from river, distance from faults, land use, and rainfall were integrated with training landslides to determine the weights of each landslide conditioning factor and factor classes using both frequency ratio and Shannon entropy models. The landslide susceptibility maps were produced by overlay the weights of all the landslide conditioning factors using raster calculator of the spatial analyst tool in ArcGIS 10.4. The final landslide susceptibility maps were reclassified as very low, low, moderate, high, and very high susceptibility classes both FR and SE models. This susceptibility maps were validated using landslide area under the curve (AUC). The results of AUC accuracy models showed that the success rates of the FR and SE models were 0.761 and 0.822, while the prediction rates were 0.753 and 0.826, respectively.
Assessment of Safety, Effects, and Muscle-Specific Accumulation of Dietary Butylated Hydroxytoluene (BHT) in Paralichthys olivaceus
Authors: Lee Seunghan , Kim Min-Gi , Hur Sang-Woo , Katya Kumar , Kim Kang-Woong , Lee Bong-Joo
Published: February 2023

Butylated hydroxytoluene (BHT) is a commonly used antioxidant added to animal/fish feed to limit lipid autoxidation and peroxidation. Although there have been reviews and reports of BHT toxicity in animals, limited information is available with respect to the toxic effects and accumulation of BHT due to oral exposure in aquaculture species. Therefore, 120 days of feeding trial was conducted to evaluate the effects of dietary BHT on the marine fish olive flounder Paralichthys olivaceus. Graded levels of BHT were added to the basal diet in increments of 0, 10, 20, 40, 80, and 160 mg BHT/kg, corresponding to 0 (BHT0), 11 (BHT11), 19 (BHT19), 35 (BHT35), 85 (BHT85), and 121 (BHT121) mg BHT/kg diets, respectively. Fish with an average weight of

77.5
±
0.3

 g (

mean
±
SD

) were fed one of the six experimental diets in triplicate groups. Growth performance, feed utilization, and survival rate were not significantly affected by the dietary BHT levels among all experimental groups, whereas BHT concentration in the muscle tissue was found to increase in a dose-dependent manner up to 60 days of the experimental period. Thereafter, BHT accumulation in muscle tissue showed a declining trend among all treatment groups. Furthermore, the whole-body proximate composition, nonspecific immune responses, and hematological parameters (except triglycerides) were not significantly influenced by the dietary levels of BHT. Blood triglyceride content was significantly higher in fish fed the BHT-free diet compared to all other treatment groups. Thus, this study demonstrates that dietary BHT (up to 121 mg/kg) is a safe and effective antioxidant without exhibiting any adverse effects on the growth performance, body composition, and immune responses in the marine fish olive flounder, P. olivaceus.
Clinical Factors to Predict Difficult Ureter during Ureteroscopic Lithotripsy
Authors: Imano Masashi , Tabei Tadashi , Ito Hiroki , Ota Junichi , Kobayashi Kazuki
Published: February 2023

Objective. To identify risk factors for difficult ureters during ureteroscopic lithotripsy and to determine the appropriate indications for preoperative stenting. Methods. We retrospectively analyzed 156 ureteroscopic procedures for upper urinary tract stones after excluding those with preoperative stenting or percutaneous nephrostomy. Traceability of the ureter was assessed by two urologists. Traceability was defined as positive if either or both urologists discerned the ureter in all slices on preoperative plain computed tomography. Patients’ backgrounds were compared between the nondifficult ureter and difficult ureter groups. A multivariate logistic regression model was used to evaluate the relationships between difficult ureters and other clinical factors. Results. Of 156 patients, 31 (19.9%) were classified into the difficult ureter group. The positive traceability was higher in the nondifficult ureter group (48.3% vs. 83.2%,

P
<
0.001

). The major axis was smaller in the difficult ureter group than in the nondifficult ureter group (8.8 ± 3.9 mm vs. 10.9 ± 4.5 mm,

P
<
0.018

). A major axis <8 mm (odds ratio: 4.495, 95% confidence interval: 1.791–11.278, and

P
=
0.001

), negative traceability (odds ratio: 7.565, 95% confidence interval: 2.693–21.248, and

P
<
0.001

), smoking status (odds ratio: 3.196, 95% confidence interval: 1.164–8.773, and

P
=
0.024

), and absence of diabetes mellitus (odds ratio: 5.813, 95% confidence interval: 1.121–30.142, and

P
=
0.036

) were identified as independent predictors of difficult ureters on multivariate logistic regression analysis. Conclusion. Patients with smaller stones, negative traceability, ongoing tobacco consumption, and absence of diabetes mellitus were at higher risk of difficult ureters. In these patients, preoperative stenting may be considered.
A Review on the Applications of Time‐Frequency Methods in ECG Analysis
Authors: Pradhan Bikash K. , Neelappu Bala Chakravarty , Sivaraman J. , Kim Doman , Pal Kunal
Published: February 2023

The joint time‐frequency analysis method represents a signal in both time and frequency. Thus, it provides more information compared to other one‐dimensional methods. Several researchers recently used time‐frequency methods such as the wavelet transform, short‐time Fourier transform, empirical mode decomposition and reported impressive results in various electrophysiological studies. The current review provides comprehensive knowledge about different time‐frequency methods and their applications in various ECG‐based analyses. Typical applications include ECG signal denoising, arrhythmia detection, sleep apnea detection, biometric identification, emotion detection, and driver drowsiness detection. The paper also discusses the limitations of these methods. The review will form a reference for future researchers willing to conduct research in the same field.
Predictive Analytics and Software Defect Severity: A Systematic Review and Future Directions
Authors: Olaleye T. O. , Arogundade O. T. , Misra Sanjay , Abayomi-Alli A. , Kose Utku
Published: February 2023

Software testing identifies defects in software products with varying multiplying effects based on their severity levels and sequel to instant rectifications, hence the rate of a research study in the software engineering domain. In this paper, a systematic literature review (SLR) on machine learning-based software defect severity prediction was conducted in the last decade. The SLR was aimed at detecting germane areas central to efficient predictive analytics, which are seldom captured in existing software defect severity prediction reviews. The germane areas include the analysis of techniques or approaches which have a significant influence on the threats to the validity of proposed models, and the bias-variance tradeoff considerations techniques in data science-based approaches. A population, intervention, and outcome model is adopted for better search terms during the literature selection process, and subsequent quality assurance scrutiny yielded fifty-two primary studies. A subsequent thoroughbred systematic review was conducted on the final selected studies to answer eleven main research questions, which uncovers approaches that speak to the aforementioned germane areas of interest. The results indicate that while the machine learning approach is ubiquitous for predicting software defect severity, germane techniques central to better predictive analytics are infrequent in literature. This study is concluded by summarizing prominent study trends in a mind map to stimulate future research in the software engineering industry.
Possibilities of Interpreting the Night-to-Day Ratio Specified by 24-Hour Blood Pressure Monitoring
Authors: Havelkova Alena , Dvorak Petr , Siegelova Jarmila , Dobsak Petr , Filipensky Petr , Cornelissen Germaine
Published: February 2023

Aim. Specify the risk rate of incorrect patient classification based on the night-to-day ratio specification from singular 24-h ABPM in comparison to the results of 7-day ABPM monitoring Materials and Methods. 1197 24 h cycles were enrolled in 171 subjects in the study and divided into 4 groups: group 1 (40 healthy men and women without exercise), group 2 (40 healthy exercise-training men and women), group 3 (40 patients with ischemic coronary artery disease without exercise), and group 4 (51 patients with ischemic coronary artery disease following cardiovascular rehabilitation). The subject of the evaluation was the percentage rate of incorrect subject classification (dipper, nondipper, extreme dipper, and riser) based on the mean blood pressure values for 7 days and from seven independent 24-hour cycles (the mean value mode). Results. In the case of the individuals included in the monitored groups, the mean night-to-day ratio-based (mode for the 7 days versus the individual days of 24-hour monitoring) classification accordance ranged between 59% and 62%. Only in singular cases did the accordance reach 0% or 100%. The accordance size was not dependent on the health or cardiovascular disease (

p
<
0.594

; 56% vs. 54%) or physical activity (

p
<
0.833

; 55% vs. 54%) of the monitored individuals. Conclusion. The specification of the night-to-day ratio of each individual for each day of the 7-day ABPM monitoring would be the most convenient option. In many patients, diagnosing could thus be based on the most frequently occurring values (mode specification). The study protocol was registered with ClinicalTrials.gov (NCT05264090)
Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance inEGFR-Mutant Lung Adenocarcinomas
Authors: Elkrief Arielle , Makhnin Alex , Moses Khadeja A. , Ahn Linda S. , Preeshagul Isabel R. , Iqbal Afsheen N. , Hayes Sara A. , Plodkowski Andrew J. , Paik Paul K. , Ladanyi Marc , Kris Mark G. , Riely Gregory J. , Michor Franziska , Yu Helena A.
Published: February 2023

Purpose:

Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.

Patients and Methods:

We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.

Results:

Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%–88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%–58%).

Conclusions:

We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.
Blood Liquid Biopsy in an Advanced Medullary Thyroid Carcinoma: A Case Study with Rearranged during Transfection Heterogeneity
Authors: Gumà Josep , Peña Karla Beatríz , Riu Francesc , Lucia-Gozálvez Clara , Vidaller Ana , Maldonado Vanesa , Parada David
Published: February 2023

Introduction: Liquid biopsy is an innovative and efficient method for studying circulating tumor DNA. In conjunction with innovative techniques such as next-generation sequencing, it can provide real-time information on prognostic and predictive factors. Case Presentation: We report a case of advanced, unresectable medullary thyroid carcinoma with various rearranged during transfection (RET) and Kirsten rat sarcoma viral (KRAS) mutations in both blood liquid and tissue biopsies. After the initial failure of treatment with a tyrosine kinase inhibitor (TKI), a liquid biopsy analyzed by next-generation sequencing showed the presence of six different RET mutations and KRAS. Tissue biopsy also revealed two RET mutations. Due to these biopsy findings, the treatment was changed to another TKI, and the patient is now clinically stable. Discussion/Conclusion: Liquid biopsy makes it possible to analyze different genetic alterations that may have implications as predictive factors. It also reveals tumor heterogeneity and its implications for prognostic factors.
Vestibulotoxicity in Patients Undergoing Cisplatin-Based Cancer Treatment: A Phase IIIB Randomized Controlled Clinical Trial
Authors: Moreno Inmaculada , Belinchon Antonio
Published: February 2023

Introduction: This study aimed to evaluate the incidence of balance disorders and the efficacy of dexamethasone in protecting patients undergoing cisplatin-based cancer treatment against vestibulototoxicity. Methods: This study was a randomized controlled phase IIIB clinical trial. The subjects participating in the clinical trial were patients with a neoplastic disease whose treatment protocol included cisplatin. The average dose of cisplatin was 444.87 mg (SD 235.2 mg). Treatment consisted of intratympanically administering dexamethasone via a passive diffusion device called Microwick (8 mg/24 h dose) from the start of treatment with cisplatin to 3 weeks after the last cycle. Patients were administered the medication to one ear, and the contralateral ear was used as the control. The treated ears were randomly chosen using a computer system (randomization). Vestibular system was evaluated by video head impulse test before each cisplatin cycle. Results: Thirty-four patients were recruited over a 2-year period at a reference tertiary hospital, of whom 11 were excluded. Forty-six ears were analyzed (23 treated and 23 control ears). Vestibular analysis presented no changes in the mean increase in the vestibulo-ocular response in all patients evaluated, both in treated and control ears. Both 8.69% infection complications during treatment and 34.8% permanent perforation at 6 months were detected after device removal. Conclusion: Ototoxicity related to cisplatin-based treatment does not affect the vestibular system. Long-term high-dose intratympanic dexamethasone treatment is safe for the vestibular system.
Impacto de la materia particulada fina (PM2.5) en la morbilidad y mortalidad respiratoria
Authors: Martínez-Valdeavellano Luisa Fernanda
Published: February 2023

Background: Environmental pollution is a worldwide problem that has a negative impact on respiratory health. Fine particulate matter (PM2.5) is one of the most harmful pollutants for the respiratory system. The objective of the study was to evaluate the association between exposure to PM2.5 concentrations and respiratory mortality. Methods: 8,825 daily respiratory mortality data were collected from the National population death information registration management system in Changsha from January 2015 to December 2018. Daily measurements of environmental pollutants were obtained from 10 environmental monitoring stations. Results: There is a significant association between PM2.5 concentrations and the risk of respiratory mortality. The increase in mortality occurs both in acute exposure to PM2.5 and in its accumulated exposure. Due to the increase in PM2.5 levels, the cold season increases the risk of respiratory pathology. Conclusion: There is an increase in respiratory disease morbidity and mortality secondary to PM2.5 exposure.
Ungewöhnliche akute Hepatitisfälle bei Kindern 2022 – Evidenz für eine immunvermittelte Erkrankung – ein Fall von Long-COVID?
Authors: Bengsch Bertram
Published: February 2023

Objectives: Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. Methods: This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. Results: We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. Conclusions: We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.
Calciprotein Particles Induce Endothelial Dysfunction by Impairing Endothelial Nitric Oxide Metabolism
Authors: Feenstra Lian , Kutikhin Anton G. , Shishkova Daria K. , Buikema Hendrik , Zeper Lara W. , Bourgonje Arno R. , Krenning Guido , Hillebrands Jan-Luuk
Published: February 2023

Background:

Calciprotein particles (CPPs) are associated with the development of vascular calcifications in chronic kidney disease. The role of endothelial cells (ECs) in this process is unknown. Here, we investigated the interaction of CPPs and ECs, thereby focusing on endothelial nitric oxide metabolism and oxidative stress.

Methods:

CPPs were generated in calcium- and phosphate-enriched medium. Human umbilical vein endothelial cells were exposed to different concentrations of CPPs (0–100 µg/mL) for 24 or 72 hours. Ex vivo porcine coronary artery rings were used to measure endothelial cell–dependent vascular smooth muscle cell relaxation after CPP exposure. Serum samples from an early chronic kidney disease cohort (n=245) were analyzed for calcification propensity (measure for CPP formation) and nitrate and nitrite levels (NO
x
).

Results:

CPP exposure for 24 hours reduced eNOS (endothelial nitric oxide synthase) mRNA expression and decreased nitrite production, indicating reduced nitric oxide bioavailability. Also, 24-hour CPP exposure caused increased mitochondria-derived superoxide generation, together with nitrotyrosine protein residue formation. Long-term (72 hours) exposure of human umbilical vein endothelial cells to CPPs induced eNOS uncoupling and decreased eNOS protein expression, indicating further impairment of the nitric oxide pathway. The ex vivo porcine coronary artery model showed a significant reduction in endothelial-dependent vascular smooth muscle cell relaxation after CPP exposure. A negative association was observed between NO
x
levels and calcification propensity (r=−0.136;
P
=0.049) in sera of (early) chronic kidney disease patients.

Conclusions:

CPPs cause endothelial cell dysfunction by impairing nitric oxide metabolism and generating oxidative stress. Our findings provide new evidence for direct effects of CPPs on ECs and pathways involved.
Abstract 1: The Very Core Limit Of Endovascular Therapy For Acute Stroke With A Large Ischemic Region
Authors: Inoue Manabu , Yoshimoto Takeshi , Toyoda Kazunori , Sakai Nobuyuki , Yamagami Hiroshi , Matsumaru Yuji , Matsumoto Yasushi , Kimura Kazumi , Ishikura Reiichi , Uchida Kazutaka , Beppu Mikiya , Sakakibara Fumihiro , Morimoto Takeshi , Yoshimura Shinichi
Published: February 2023

Background and Purpose:
To assess the actual malignant core volume in endovascular therapy (EVT) eligible patients with large ischemic regions from the RESCUE-Japan LIMIT database.

Methods:
RESCUE-Japan LIMIT was a multicenter, open-label, randomized clinical trial in large vessel occlusion patients with large ischemic region indicated by an ASPECTS valued from 3 to 5. We assessed the volumetrically measured core volume which identifies an unfavorable outcome (modified Rankin Scale; mRS 4-6 at 90 days) by receiver operating characteristic (ROC) analysis in the endovascular therapy (EVT) group. Predictive marginal probabilities were also assessed to identify the unfavorable outcome. Symptomatic intracranial hemorrhages and death within 90 days in the EVT group and the medical management (MM) group were compared. Clinical characteristics and radiological values were also compared.

Results:
Of the 203 cases enrolled, 182 patients (92 in EVT group vs. 90 in MM group) had adequate core volume. The mean age was 75.6±10 years old and 46% of females in the EVT group and 77.0±10 years old and 42% of females in the MM group. Median core volume was 94 (IQR; 65.3-147.5) mL in EVT patients and 110 (IQR; 74.0-140.0) mL in those with MM group (P=0.84). ROC analysis identified a core volume of 120 mL as the unfavorable outcome (61/92) in the EVT group (51% sensitivity and 77% specificity, area under curve=0.65) and 99 mL in the MM group (77/91, 62% sensitivity and 54% specificity, area under curve=0.56). Predictive marginal probabilities indicated 132 mL as an overlay of the two groups for achieving the unfavorable functional outcome. Symptomatic intracranial hemorrhage was seen in 9.8% in the EVT group and 5.6% in the MM group (p=0.28), and death within 90 days was 17.4% in the EVT group and 23.3% in the MM group (p=0.32).

Conclusions:
The current analysis demonstrates that a core threshold of approximately 130 mL is the upper limit for identifying large ischemic region stroke patients treated with EVT who are unlikely to suffer from unfavorable outcomes. EVT-eligible patients under this threshold may benefit from EVT.

Registration:
URL: http://www.clinicaltrials.gov; Unique identifier: NCT03702413.
Abstract 100: Endovascular Treatment With Intravenous Tirofiban Or Alteplase Versus Endovascular Treatment Alone For Acute Ischemic Stroke With Large Vessel Occlusion: A Pooled Analysis Of The Devt And Rescue Bt Trials
Authors: Qiu Zhongming , Yuan Junjie , Xie Dongjing , Wu Deping , Luo Weidong , Zhaojun Tao , Liu Shuai , Han Qin , Sun Dong , Lei Bo , Li Jinglun , Miao Jian , Liu Shudong , Jin Zhenglong , Zeng Guoyong , Wen Changming , Yuan Guangxiong , Yang Qingwu , Nguyen Thanh , Saver Jeffrey L , Nogueira Raul G , Li Fengli , Sang Hongfei , Zi Wenjie
Published: February 2023

Background:
In acute ischemic stroke patients with large vessel occlusion, the role of intravenous tirofiban or alteplase as an adjunct to endovascular treatment (EVT) is still uncertain.

Methods:
This post hoc analysis used data from 467 patients included in two multicenter, randomized clinical trials that assessed intravenous adjunctive medications in stroke thrombectomy (DEVT and RESCUE BT). Patients were treated with EVT alone (EVT-alone group), intravenous tirofiban plus EVT (tirofiban+EVT group), and intravenous alteplase plus EVT (alteplase+EVT group). The primary outcome was functional independence (modified Rankin scale score 0-2) at 90 days. Safety outcomes included intracranial hemorrhage and mortality.

Results:
Of 467 patients included in the cohort, there were 172, 172, and 123 patients in EVT-alone, tirofiban+EVT, and alteplase+EVT group, respectively. Patients in the alteplase+EVT group were less likely to achieve functional independence than patients in the tirofiban+EVT group (adjusted risk ratio [RR], 0.80; 95% confidence interval [CI], 0.65-0.99;
P
= 0.04). Patients in the EVT-alone group compared with the tirofiban+EVT group (adjusted RR, 1.12; 95% CI, 0.92-1.36;
P
= 0.27) or the alteplase+EVT group (adjusted RR, 0.81; 95% CI, 0.65-1.02;
P
= 0.07) were similarly likely to obtain functional independence. Patients in the alteplase+EVT group had a higher risk of any intracranial hemorrhage than in the EVT-alone group (adjusted RR, 1.49; 95% CI, 1.03-2.14;
P
= 0.03) and tirofiban+EVT group (adjusted RR, 1.49; 95% CI, 1.02-2.18;
P
= 0.04). No significant difference was detected in the incidence of symptomatic intracranial hemorrhage and mortality among the three groups.

Conclusions:
Tirofiban before thrombectomy is associated with a better functional outcome and lower risk of any intracranial hemorrhage than alteplase among patients with large vessel occlusion treated within 4.5 hours after stroke onset.

Trial Registration:
chictr.org.cn, ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.
Abstract 102: Imaging Markers Of Energy Metabolism In The Post-stroke Mouse Brain
Authors: Sylvain Nicole J , Pushie Michael , Hou Huishu , DuVal Claire N , Caine Sally , Hackett Mark J , Kelly Michael E
Published: February 2023

Introduction:
Cerebral ischemia results in a lesion comprised of dying cells surrounded by a band of tissue containing cells at risk of dying, called the penumbra. Understanding the status of energy metabolism in the stroke is necessary to get a clearer picture of the formation of the lesion, and may provide insights into potential therapeutic targets. The detection and distribution of energy metabolism biomarkers, particularly in ischemic brain tissue, presents significant challenges for conventional laboratory techniques due to the labile nature of these markers and the lack of unique chemical or spectroscopic handles. Fourier Transform infrared (FTIR) spectroscopic imaging can be used to map the distribution of different biochemical parameters, such as lipids, proteins, aggregated proteins, glycogen, lactate, pyruvate, ATP/ADP, NADH and glutamate.

Methods:
We employed the photothrombotic stroke model in adult mice to produce a permanent focal stroke lesion. Brain tissue was collected at multiple time points (1h to 4 weeks post-stroke). FTIR imaging was employed to map the distribution of unique biochemical fingerprints for over a dozen key metabolic markers. Immunohistochemistry was also performed on adjacent tissues to correlate biomarkers revealed by FTIR with the distribution of astrocytes, myelin and macrophages.

Results:
During the first week poststroke, the lesion shows decreased lipid esters, protein, ATP/ADP, NADH content while showing an increase in glutamate, aggregated protein, lactate and pyruvate. Glycogen can be seen to accumulate in the penumbra starting at 1 day post-stroke until 1 week post-stroke, which correlates with the appearance of astrocytes around the border of the stroke lesion. From 1 week to 4 weeks post-stroke, we observe an increase in lipid esters in the lesion, as well as a decrease in glycogen, lactate and pyruvate, while an increase in ATP/ADP and NADH can be observed.

Conclusion:
We are showing for the first time novel images of multiple energy metabolism biomarkers across a range of post-stroke time points in a mammalian brain. This type of imaging will be important in studying post-stroke interventions, particularly drugs that are known to alter energy metabolism.
Abstract 103: Isomir Diversity Is Increased In Peripheral Blood Following Ischemic Stroke And May Represent Shifts In Regulation Of Neuroinflammatory Response
Authors: Lenz Garreck H , Navi Babak B , Knepp Bodie , Liu Dazhi , Jickling Glen C , Hull Heather D , Sharp Frank R , Stamova Boryana , Ander Bradley P
Published: February 2023

MicroRNA (miRNA) expression is altered following ischemic stroke. Advances in RNA sequencing and bioinformatic tools allow study of isomiRs, isoforms of miRNA, which can have altered regulatory actions from canonical parent miRNA due to base modifications within the molecule or on the flanking regions. Here, we characterize isomiRs in the blood of ischemic stroke patients compared to vascular risk factor controls (VRFCs) and elucidate diversity of the post-stroke miRNA environment. Total RNA was isolated from peripheral blood of 47 ischemic stroke patients and 31 VRFCs using PAXgene protocol. Small RNA libraries were prepared using QIAseq miRNA Library Kit and sequenced to 14±2 M 1x75 bp reads. Raw sequence reads were trimmed, de-duplicated, and profiled using
isomiRmap
, which separates isomiRs from canonical miRNA sequences based on 3’ and 5’ miRNA modifications. Analysis of differentially expressed isomiRs was performed with DESeq2. A total of 74,562 unique isomiRs were identified, the majority expressed at very low level. Filtering for low abundance left 2,133 isomiRs (from 335 canonical miRNA) expressed in all subjects. Of these, 505 isomiRs (from 129 canonical miRNA) were differentially expressed (LFC > |0.5|, p
adj
< 0.05) between stroke and VRFCs. These isomiRs represent significant elevations in 3’ modifications (68.3% of DE isomiRs), 5’ modifications (20.2%) and non-template additions (34.3%). miRNA previously implicated in stroke had diverse isomiR profiles including cases where all isomiRs within a miRNA group were differentially expressed (e.g. let-7i) and cases where multiple isomiRs were present but not differentially expressed (e.g. miR-363). Four of 28 differentially expressed let-7i isomiRs have changes to the seed region that interacts with mRNA. Thus, miRNA-mRNA interactions distinct from the canonical let-7i seed may exist and play an altered role in stroke pathology and neuroinflammation. Analysis of small noncoding RNA sensitive to base-specific variations detects many differentially expressed isomiRs and highlights the complexity of the post-stroke miRNA environment. Further study of these isomiRs within mRNA regulatory networks will deepen our understanding of stroke related neuroinflammation and neural repair.