bluuebunny/crossref_metadata_2025 huggingface dataset:
Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy
Authors: Deng Jing , Paulus Aneel , Fang Douglas D. , Manna Alak , Wang Guangfeng , Wang Hengbang , Zhu Saijie , Chen Jianyong , Min Ping , Yin Yan , Dutta Navnita , Halder Nabanita , Ciccio Gina , Copland John A. , Miller James , Han Bing , Bai Longchuan , Liu Liu , Wang Mi , McEachern Donna , Przybranowski Sally , Yang Chao-Yie , Stuckey Jeanne A. , Wu Depei , Li Caixia , Ryan Jeremy , Letai Anthony , Ailawadhi Sikander , Yang Dajun , Wang Shaomeng , Chanan-Khan Asher , Zhai Yifan
Published: September 2022

Purpose:

Development of B-cell lymphoma 2 (BCL-2)–specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein–protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575).

Experimental Design:

Computational modeling was used to design “lead” compounds. Biochemical binding, mitochondrial BH3 profiling, and cell-based viability or apoptosis assays were used to determine the selectivity and potency of BCL-2 inhibitor lisaftoclax. The antitumor effects of lisaftoclax were also evaluated in several xenograft models.

Results:

Lisaftoclax selectively binds BCL-2 (Ki < 0.1 nmol/L), disrupts BCL-2:BIM complexes, and compromises mitochondrial outer membrane potential, culminating in BAX/BAK-dependent, caspase-mediated apoptosis. Lisaftoclax exerted strong antitumor activity in hematologic cancer cell lines and tumor cells from patients with chronic lymphocytic leukemia, multiple myeloma, or Waldenström macroglobulinemia. After lisaftoclax treatment, prodeath proteins BCL-2‒like protein 11 (BIM) and Noxa increased, and BIM translocated from cytosol to mitochondria. Consistent with these apoptotic activities, lisaftoclax entered malignant cells rapidly, reached plateau in 2 hours, and significantly downregulated mitochondrial respiratory function and ATP production. Furthermore, lisaftoclax inhibited tumor growth in xenograft models, correlating with caspase activation, poly (ADP-ribose) polymerase 1 cleavage, and pharmacokinetics of the compound. Lisaftoclax combined with rituximab or bendamustine/rituximab enhanced antitumor activity in vivo.

Conclusions:

These findings demonstrate that lisaftoclax is a novel, orally bioavailable BH3 mimetic BCL-2–selective inhibitor with considerable potential for the treatment of certain hematologic malignancies.
Detection of BRCA1, BRCA2, and ATM Alterations in Matched Tumor Tissue and Circulating Tumor DNA in Patients with Prostate Cancer Screened in PROfound
Authors: Chi Kim N. , Barnicle Alan , Sibilla Caroline , Lai Zhongwu , Corcoran Claire , Barrett J. Carl , Adelman Carrie A. , Qiu Ping , Easter Ashley , Dearden Simon , Oxnard Geoffrey R. , Agarwal Neeraj , Azad Arun , de Bono Johann , Mateo Joaquin , Olmos David , Thiery-Vuillemin Antoine , Harrington Elizabeth A.
Published: August 2022

Purpose:

Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure. Optimization of screening techniques may reduce failure rates; however, a need remains for additional testing methods to detect cancers with alterations in homologous recombination repair genes. We evaluated the utility of plasma-derived circulating tumor DNA (ctDNA) in identifying deleterious BRCA1, BRCA2 (BRCA), and ATM alterations in screened patients with mCRPC from the phase III PROfound study.

Patients and Methods:

Tumor tissue samples were sequenced prospectively at Foundation Medicine, Inc. (FMI) using an investigational next-generation sequencing (NGS) assay based on FoundationOne®CDx to inform trial eligibility. Matched ctDNA samples were retrospectively sequenced at FMI, using an investigational assay based on FoundationOne®Liquid CDx.

Results:

81% (503/619) of ctDNA samples yielded an NGS result, of which 491 had a tumor tissue result. BRCA and ATM status in tissue compared with ctDNA showed 81% positive percentage agreement and 92% negative percentage agreement, using tissue as reference. At variant-subtype level, using tissue as reference, concordance was high for nonsense (93%), splice (87%), and frameshift (86%) alterations but lower for large rearrangements (63%) and homozygous deletions (27%), with low ctDNA fraction being a limiting factor.

Conclusions:

We demonstrate that ctDNA can greatly complement tissue testing in identifying patients with mCRPC and BRCA or ATM alterations who are potentially suitable for receiving targeted PARP inhibitor treatments, particularly patients with no or insufficient tissue for genomic analyses.
Abstract IA19: Impact of single checkpoint inhibitors and biomarkers of response
Authors: El-Khoueiry Anthony
Published: September 2022

Single agent anti PD-1 antibodies have shown consistent safety and efficacy for the treatment of advanced hepatocellular carcinoma (HCC). Response rates range between 15 and 20% and the rate of grade 3 and 4 adverse events is generally below 25%. Recently, the HIMALAYA trial showed that durvalumab was non-inferior to sorafenib for first-line treatment of HCC. Further, Keynote-394 showed that pembrolizumab improved survival compared to placebo in second line treatment of HCC. Nivolumab was evaluated in a dedicated cohort of Checkmate 040 in patients with child pugh B cirrhosis and determined to have a manageable safety profile, similar to that in child pugh A. Given the fact that immunotherapy-based combinations are the current standard of care for advanced HCC, and given the absence of biomarkers for patient selection, the use of single agent anti PD-1 or PD-L1 antibodies in advanced first line HCC treatment is limited to patients who are not candidates for combination therapy or patients with compromised liver function. Single agent anti PD-1/PD-L1 antibodies are being evaluated in the adjuvant setting and in combination with liver directed therapy. Emerging biomarker data suggest an association between T cell inflammation signature and outcome with single agent anti PD-1 and PD-L1 agents. Further research is needed to validate the early biomarker data.

Citation Format: Anthony El-Khoueiry. Impact of single checkpoint inhibitors and biomarkers of response [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA19.
Abstract IA24: IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit
Authors: Zhu Andrew X.
Published: September 2022

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers including cholangiocarcinoma. These hotspot gain-of-function mutations will lead to the IDH enzyme to aberrantly produce high levels of R-2-hydroxyglutarate (2-HG), which is thought to be the oncometabolite. 2-HG can competitively inhibit enzymes that regulate epigenetics, DNA repair, metabolism, and it can also modulate tumor immune microenvironment. IDH-1 mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA), and their frequency varies depending on the geographic location and underlying etiology. Many inhibitors targeting mutant IDH (mIDH) are under active clinical development. Results from the phase III ClarIDHy trial have demonstrated that ivosidenib-a first-in-class, oral, small-molecule inhibitor of mutant IDH1, was well tolerated and could improve progression-free survival and a favorable overall survival benefit versus placebo, leading to the regulatory approval of ivosidenib in mIDH1 cholangiocarcinoma. The author will discuss the rationale, current clinical development, unanswered questions including the mechanism of resistance, and the optimal combination strategies that can more effectively harness mIDH as a therapeutic target.

Citation Format: Andrew X. Zhu. IDH Inhibitors: Rationale, Molecular Mechanisms and Benefit [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA24.
Abstract IA28: Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms
Authors: Lopez-Terrada Dolores (Lola)
Published: September 2022

Hepatocellular neoplasms are the most common primary liver malignancies in children, with hepatoblastoma (HB) accounting for more than two-thirds of all cases. HB is a histologically heterogeneous embryonal tumor often recapitulating liver developmental stages, more commonly diagnosed during the first three years of life. HB classification has been historically challenged by its rarity and the lack of a systematic review of diagnostic tumor specimens. Recent international initiatives resulted in the development of international datasets (CHIC) and muti-consortia therapeutic trials (PHITT) that required a new pediatric liver tumors consensus classification. Meanwhile, genomic profiling is quickly advancing our understanding of HB and its biological heterogeneity, and allowing for the identification of biomarkers and biological subgroups of potential clinical relevance. Preliminary biological annotation of the International Consensus Classification, including diagnostic and prognostically relevant tumor subtypes, is ongoing. Molecular profiling of high-risk tumors, such as those in the HCN-NOS provisional category, is revealing histological and molecular features which are important to recognize to correctly diagnose and risk-stratify this group of patients. Current initiatives, including those led by clinical consortia participating in the International Pediatric Liver Tumors Trial (PHITT), are validating potential diagnostic and risk-stratifying biomarkers and engaged in exploratory studies, such genomic tumor profiling and investigation of novel therapeutic strategies, to be considered in upcoming trials.

Citation Format: Dolores (Lola) Lopez-Terrada. Advances in the pathogenesis and classification of pediatric hepatocellular neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA28.
Abstract IA29: Present and future of precision oncology in hepatoblastoma
Authors: Armengol Carolina
Published: September 2022

Pediatric liver cancer is rare (~1 case/1 million) with increasing incidence. The commonest tumor seen usually in young children and infants without underlying liver disease is hepatoblastoma (HB). Despite significant advances during last decades thanks to improvements in chemotherapeutic regimens and efficient surgical approaches, treatment options remain limited for ~20% of patients with aggressive resistant tumours and more than 40% survivors have long-term effects derived from treatment toxicity. Because of the rarity of the disease, global international efforts on clinical, pathological and biological fields are crucial to improve the current clinical management of HB. In this talk, current clinical patient stratification (Children's Hepatic tumors International Collaboration Hepatoblastoma Stratification, CHIC-HS) and treatment of patients with HB (Pediatric Hepatic International Tumor Trial, PHITT) will be exposed. The main clinical, pathological and biological prognostic factors used at present will be also explained. Since it is well-known that therapy response in oncology is intimately associated with cancer biology, the need to improve the current CHIC stratification by incorporating biological data will be emerged as a way to significant move forward towards precision medicine in pediatric liver cancer patients. Moreover, a summary of the latest advances in genomic, transcriptomic and methylation studies and the diagnostic/prognostic biomarkers as well as newest therapeutic targets/drugs will be exposed. As a rare disease, the unmet need for banking human samples, patient-derived cell lines and animal models to enable and boost translational research of childhood liver tumors will be stressed. Finally, Dr. Armengol will explain the latest advances on biological and pathological studies associated to PHITT in Europe, ranging from sample collection to identification and validation of diagnostic/prognostic biomarkers. The ongoing PHITT patient cohort and its associated biorepositories will be exposed as an exceptional opportunity to validate a panel of diagnostic and prognostic biomarkers and novel therapeutic strategies that could be incorporated in the upcoming clinical trial (PHITT-2). Nowadays, ongoing international efforts at clinical, pathological and biological level from the three main childhood liver study groups of Europe (SIOPEL), United States (COG) and Japan (JCCG) are being conducted and will move forward precision medicine in HB, impacting on the quality of life and survival of patients with HB in a near future.

Citation Format: Carolina Armengol. Present and future of precision oncology in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA29.
Abstract PO019: Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma
Authors: Hedrich Viola , Chen Doris , Huber Heidemarie , Mikulits Wolfgang
Published: September 2022

The receptor tyrosine kinase Axl, binding to its ligand Gas6, fosters oncogenic effects during the progression of hepatocellular carcinoma (HCC) which is accompanied by increased mortality of patients. The specific role of Gas6/Axl signaling in neoplastic hepatocytes and its pathophysiological consequences are poorly understood at the current stage of research. We aimed at identifying and functionally analyzing targets of Gas6/Axl signaling in HCC by exploiting well-characterized human HCC tumor models. HCC cells transformed by epithelial to mesenchymal transition (EMT) and expressing high levels of Axl or harboring CRISPR/Cas9-mediated Axl deficiency, the latter in absence or presence of Axl reconstitution, were subjected to Gas6 stimulation and subsequent RNA-seq analysis. Bioinformatics and VENN relations were applied to identify novel targets of the Gas6/Axl axis. Expression of Gas6/Axl targets was assessed in publicly available HCC patient datasets and in HCC tissue microarrays. In vitro analysis was performed including gain and loss of functions studies to unravel target genes contribution to EMT and HCC progression. RNA-seq analyses revealed PRAME (preferentially expressed antigen in melanoma) and C15orf48 among others as novel targets of Gas6/Axl. Notably, these target genes showed elevated expression levels in Axl-stratified HCC patients and significant impact on patient survival. Pharmacological or genetic interference with Axl signaling resulted in strongly reduced expression of PRAME and C15orf48, suggesting bona fide targets of Gas6/Axl signaling. PRAME expression positively regulated 2D cell migration and invasion of 3D hepatospheres while proliferation and survival of HCC cells remained unaffected by altered PRAME levels. In accordance, PRAME expression strongly associated with a mesenchymal-like phenotype in human HCC. Intriguingly, HCC patients expressing PRAME correlated with Axl expression and vascular invasion in a large proportion of HCC patients. Our study demonstrates that PRAME is a novel target of Gas6/Axl signaling in HCC linked to EMT. Translation of in vitro findings into the HCC patient situation provides first insights that PRAME plays a crucial role in HCC progression.

Citation Format: Viola Hedrich, Doris Chen, Heidemarie Huber, Wolfgang Mikulits. Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO019.
Cost-Effectiveness of Low-Dose Compared to Standard-Dose Alteplase for Acute Ischemic Stroke in China: A Within-Trial Economic Evaluation of the ENCHANTED Study
Authors: Si Lei , Chen Xiaoying , Ouyang Menglu , Wang Xia , Chen Guofang , Cao Yong-jun , Wu Guojun , Zhang Jinli , Zhang Jingfen , Liu YuKai , Zhang Shihong , Song Lili , Delcourt Candice , Arima Hisatomi , Wang Lidan , Lung Thomas , Chen Mingsheng , Anderson Craig S. , Jan Stephen ,   for the ENCHANTED Investigators
Published: August 2022

Introduction: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. Methods: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2–6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer’s perspective. The equivalence margin for cost and effectiveness was set at USD 691 and −0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. Results: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: −1,000–1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415–509) and 410 (95% CI: 363–457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: −0.016–0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. Conclusions: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.
XXXI Congress of the Spanish Nutrition Society (SEÑ)
Cartagena (Spain), 15th to 17th September 2022.
Topic: Personalized Nutrition and Health
Authors: Larqué Elvira
Published: September 2022

It is a plaesaure to announce the celebration of the XXXI Congress of the Spanish Nutrition Society that will be held in Cartagena (Murcia, Spain), from September 15th to 17th, 2022. As is already a tradition in our society, the day before, on September 14th, the IX Meeting of young researchers will take place, aimed at promoting interaction and knowledge exchange among young people working in the field of nutrition and food in Spain. In addition, young reserachers will receive a workshop about how to produce videos of research with high impact in the social media.
The congress will offer a scientific and multidisciplinary journey through all aspects related to a personalized diet from children to adults, healthy, safe and sustainable. The connections between lifestyles and chronic non-communicable diseases and especially obesity, will be updated, as well as precision nutrition, incorporating the outstanding advances in nutrigenomics, epigenetics and metabolomic markers. New evidence of healthy effects of bioactive, prebiotic and probiotic components is also contemplated, without forgetting the issue of food allergies and intolerances, which are increasingly prevalent in our society.
The circular economy and the new preferences for sustainable and local food pose challenges that will also be addressed at the congress and in the sessions for young researchers. In addition, the problem generated by the dissemination of nutritional information poorly contrasted in the media and social networks will be considered.
We encourage you to schedule these dates in your 2022 agenda to attend and participate in our congress, whose program we have designed with great enthusiasm. We would also like to extend the invitation to participate to companies and institutions related to food, which will help us reflect that optimal food is only achieved with the involvement of EVERYONE.
We hope that the proposal of this congress will be attractive to you and that we can share enriching experiences in Cartagena, Spain. The program of the congress is available in the URL https://www.xxxicongresosen2022.com/index.asp
Yours sincerely,
Elvira Larqué Daza, Organizer of the Spanish Nutrition Society (SEÑ) Congress 2022, Cartagena, Spain.
Salvador Zamora Navarro, Honour member from the Spanish Nutrition Society (SEÑ).
María Puy Portillo Baquedano, President of the Spanish Nutrition Society (SEÑ).
Effects of an Impulse on the Sterno-Cleido-Mastoid Muscle on Back Pain, Discomfort, and Well-Being: A Randomized Controlled Trial in People with Low Back Pain
Authors: Kleinert Jens , Bastemeyer Carolin , Watson Matthew , Pels Fabian
Published: September 2022

Introduction: In the treatment of low back pain (LBP), passive regimens (e.g., relaxation) as opposed to active regimens (e.g., muscle training) may be a useful adjunct or, in certain cases, the only possible approach. Passive relaxation may be particularly useful for individuals who have lost the ability to adequately perceive relaxed muscles. The aim of the randomized controlled trial presented here was to investigate a specific and novel treatment for passive relaxation, namely, the Vitametik impulse (VI). Methods: Participants (n = 135; 73.3% women; 26.7% men) were individuals with mild to moderate LBP aged from 19 to 76 years (M = 48.8). The participants were randomly assigned to one of four different groups (three different 8-week interventions, one control group). Pain, discomfort, and well-being were measured before and after the intervention period and at an 8-week follow-up. Results: In the VI group, the decrease in various pain variables and discomfort was higher compared to the control group and compared to an education program (EP). There were no differences between the VI group and a combined VI/EP group. The effects remained stable until follow-up. Conclusion: VI appears to be an effective approach in the treatment of LBP, although the underlying mechanism remains unproven. Future studies should compare VI treatment with specific relaxation techniques or active muscle training. In addition, the results of the study need to be replicated.
Hábitos de vida saludable en estudiantes del sur de Chile
Authors: Infante-Grandón Matías , Cerda Cristian , León-Herrera Miriam
Published: September 2022

(analítico)Clasificar estudiantes según hábitos de vida saludable podría contribuir a optimizar programas de salud escolar, dado que existe escasa evidencia al respecto en Chile. Se determinaron grupos de estudiantes chilenos del sur, según hábitos de vida saludable. Se extrajeron datos de 1183 sujetos, desde una encuesta aplicada en 2017 en Lautaro. Se realizó un análisis de conglomerado jerárquico y se identificaron tres grupos. El primero presentó mayor actividad física y conducta alimentaria saludable (p < 0.05). El segundo presentó mayor tiempo de pantalla y conducta alimentaria menos saludable (p < 0.05). El tercero presentó menor tiempo de actividad física y menor conducta alimentaria (p < 0.05). Los estudiantes que practican más actividad física se alimentan mejor y quienes se mueven menos se alimentan menos. Estos hallazgos resultan útiles para el gobierno local.
Palabras clave:  Estudiantes; actividad física; conducta alimentaria; tiempo de pantalla; análisis por conglomerados; Chile.
Neurostigma xanthopterum New, 1980 (Psocodea: Psocoptera: Epipsocidae): updated diagnosis, description of a female specimen, morphological variations and a checklist of all known species of the genus
Authors: Reategui Natália Soares , Rafael José Albertino , Silva-Neto Alberto Moreira da
Published: September 2022

The holotype of the Neurostigma xanthopterum New, 1980 is here illustrated based on photographs. We also describe and illustrate a previously unknown female individual that is assigned to this species. New records for five localities in the Brazilian state of Amazonas, one in the Brazilian state of Acre and another in the Brazilian state of Amapá, are presented. The mouthparts of both sexes are here describe and illustrate. Thirteen types of variation and anomalies in the fore-hindwing veins were found. We found unique patterns in the number and shape of transverse veins in the pterostigma between individuals. We also identified a large variation in the denticles present in the lacinia. Therefore, we suggest these variable characteristics (fore-hindwing veins and lacinia denticles) are not to be used for the diagnosis of species of this genus. A revised diagnosis of N. Xanthopterum is also presented.
FAIR Equivalency with Regulatory Framework for Digital Health in Uganda
Authors: Basajja Mariam , Van Reisen Mirjam , Oladipo Francisca
Published: August 2022

This study explores the possibility of opening a policy window for the adoption of the FAIR Guidelines— that data be Findable, Accessible, Interoperable, and Reusable (FAIR)—in Uganda's eHealth sector. Although the FAIR Guidelines were not mentioned in any of the policy documents relevant to Uganda's eHealth sector, the study found that 83% of the documents mentioned FAIR Equivalent efforts, such as the adoption of the National Identification Number (NIN) as a unique identifier in Uganda's national Electronic Health Management Information System (eHMIS) (findability), the planned/ongoing integration of various information systems (interoperability), and the alignment of various projects with international best practices/standards (reusability). A FAIR Equivalency Score (FE-Score), devised in this study as an aggregate score of the mention of the equivalent of FAIR facets in the policy documents, showed that the documents at the core of Uganda's digital health/eHealth policy have the highest score of all the documents analysed, indicating that there is a degree of alignment between Uganda's National eHealth Vision and the FAIR Guidelines. Therefore, it can be concluded that favourable conditions exist for the adoption and implementation of the FAIR Guidelines in Uganda's eHealth sector. Hence, it is recommended that the FAIR community adopt a capacity building strategy through organisations with a worldwide mandate, such as the World Health Organization, to promote the adoption of the FAIR Guidelines as part of international best practices.
Bahrain’s Enduring Constitutional Crisis
Authors: Fakhro Elham , Al-Noaimi Bader
Published: August 2022

This chapter provides an overview of constitutional development in Bahrain. It outlines the main provisions of Bahrain’s first constitution of 1973, the procedural terms of its enactment following approval by a partially-elected committee, and its consequent role in enshrining the terms of a social contract between ruler and ruled. It examines the Ruler’s suspension of the constitution shortly after its enactment as a revocation of this agreement, and the beginning of a twenty-five year period marked by the absence of constitutional life. The chapter describes the accession of the Amir’s son to power in 1999, and his enactment of a new constitution that expanded some liberties, while weakening power-sharing. The chapter details social opposition to these changes, and contextualizes Bahrain’s Arab Spring movement as driven, in part, by activists’ demands for the restoration of the country’s first constitution. The chapter analyzes the main provisions of the 2002 Constitution to show how it weakens popular oversight, and institutes a model of governance that favors the cooperation of the three branches of government over their accountability under the aegis of the head of state. It argues that although the constitution of 1973 survived for little more than a year, it remains idolized in the popular consciousness as a symbol for the kind of democratic power-sharing that was once promised– and which may someday appear within reach.
Introduction: Three circles and a few promises
Authors: Fakhro Elham , Mallat Chibli
Published: August 2022

The chapter introduces the volume on constitutionalism in the Arab Gulf states. It situates the development of national constitutionalism against three backdrops: the global constitutional realm, the regional Middle East system, and the Gulf sub-region. It considers the integration of Gulf constitutions in the global study of constitutionalism by emphasizing that these texts – while often highly circumscribed – ought to be examined as the expression of an evolving balance of powers between ruler and ruled. The chapter reflects on common themes underlying Arab Gulf constitutional development, including the rise of social movements in many states calling for parliamentary representation, the continued domination of monarchies on all branches of government, and the budding but limited role of courts. It sets these themes against the mostly unyielding commitment by Rulers to a mode of governance that is (i) monarchical, (ii) conservative, (iii) centralized, (iv) monolithic and (v) patriarchal, and which appears to contradict some of the very basis of constitutionalism. A final section draws on the historic roots of the promise of istiham, translated as voting, a concept developed in the Ahkam sultaniyya of Abu Ya‘la’s, an 11th century Hanbali jurist, as an alluring harbinger of the right to vote for the political leader of the community.
Nuremberg’s Enduring Legacy to International Justice
Authors: Lobo de Souza I.M.
Published: August 2022

The historic Nuremberg trial represented a first step toward an adequate response by the international society to grave crimes under international law committed by individuals in position of governmental authority. This article discusses three particular ways in which the Nuremberg trial has advanced international justice. From a normative perspective, it has helped crystallise the principle of individual criminal responsibility for crimes under international law. Furthermore, the Nuremberg tribunal’s extraordinary jurisdiction paved the way for domestic and international courts’ jurisdiction over crimes under international law, while instigating the evolution of relevant law concerning immunity from jurisdiction. Finally, in associating international crimes with the maintenance of international peace and security, it allowed the UN system of collective security to consider situations involving the commission of those crimes as a threat to international peace and security, preventing impunity and promoting the efficacy of international humanitarian law.
Pupil maximum constriction velocity predicts post-induction hypotension in patients with lower ASA status: a prospective observational study
Authors: Shao Luyi , Zhou Yaqing , Yue Zichuan , Gu Zhongya , Zhang Jie , Hui Kangli , Xiong Jingwei , Xu Miaomiao , Duan Manlin
Published: August 2022

Background

Individuals affected by autonomic dysfunction are at a higher risk of developing hypotension following anesthesia induction. Dynamic pupillometry has previously been employed as a means of assessing autonomic function. This prospective observational study was developed to determine whether pupillary light reflex (PLR) parameters can reliably predict post-induction hypotension (PIH).

Methods

This study enrolled patients with lower ASA status (I-II) undergoing elective surgery. PLR recordings for these patients prior to anesthesia induction were made with an infrared pupil camcorder, with a computer being used to assess Average Constriction Velocity (ACV), Maximum Constriction Velocity (MCV), and Constriction Ratio (CR). PIH was defined by a > 30% reduction in mean arterial pressure (MAP) or any MAP recording < 65 mmHg for at least 1 min from the time of induction until 10 minutes following intubation. Patients were stratified into PIH and non-PIH groups based on whether or not they developed hypotension.

Results

This study enrolled 61 total patients, of whom 31 (50.8%) exhibited one or more hypotensive episodes. Patients in the PIH group exhibited significantly smaller ACV (P = 0.003) and MCV values (P < 0.001), as well as a higher CR (P = 0.003). Following adjustment for certain factors (Model 2), MCV was identified as a protective factor for PIH (Odds Ratio: 0.369). Receiver operating characteristic (ROC) analyses revealed that relative to CR (AUC: 0.695, 95% CI: 0.563–0.806;P = 0.004), the reciprocal of MCV (1/MCV) offered greater value as a predictor of PIH (AUC: 0.803,95%CI: 0.681–0.894;P < 0.001).

Conclusion

These results indicate that pupil maximum constriction velocity is a reliable predictor of post-induction hypotension in individuals of ASA I-II status undergoing elective surgery.

Trial registration

This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2200057164, registration date: 01/03/2022).
Bridging the resources gap: deep learning for fluorescein angiography and optical coherence tomography macular thickness map image translation
Authors: Abdelmotaal Hazem , Sharaf Mohamed , Soliman Wael , Wasfi Ehab , Kedwany Salma M.
Published: September 2022

Background

To assess the ability of the pix2pix generative adversarial network (pix2pix GAN) to synthesize clinically useful optical coherence tomography (OCT) color-coded macular thickness maps based on a modest-sized original fluorescein angiography (FA) dataset and the reverse, to be used as a plausible alternative to either imaging technique in patients with diabetic macular edema (DME).

Methods

Original images of 1,195 eyes of 708 nonconsecutive diabetic patients with or without DME were retrospectively analyzed. OCT macular thickness maps and corresponding FA images were preprocessed for use in training and testing the proposed pix2pix GAN. The best quality synthesized images using the test set were selected based on the Fréchet inception distance score, and their quality was studied subjectively by image readers and objectively by calculating the peak signal-to-noise ratio, structural similarity index, and Hamming distance. We also used original and synthesized images in a trained deep convolutional neural network (DCNN) to plot the difference between synthesized images and their ground-truth analogues and calculate the learned perceptual image patch similarity metric.

Results

The pix2pix GAN-synthesized images showed plausible subjectively and objectively assessed quality, which can provide a clinically useful alternative to either image modality.

Conclusion

Using the pix2pix GAN to synthesize mutually dependent OCT color-coded macular thickness maps or FA images can overcome issues related to machine unavailability or clinical situations that preclude the performance of either imaging technique.

Trial registration

ClinicalTrials.gov Identifier: NCT05105620, November 2021. “Retrospectively registered”.
Prognostic factors and scoring systems associated with outcome in pediatric acute liver failure
Authors: Walabh Priya , Meyer Anja , de Maayer Tim , Moshesh Porai N. , Hassan Ibrahim E. , Walabh Pravina , Hajinicolaou Christina
Published: August 2022

Background

Pediatric acute liver failure (PALF) is an uncommon, devastating illness with significant mortality. Liver transplantation remains the mainstay of treatment for irreversible PALF. The purpose of this study was to determine the etiology and prognostic factors associated with outcome of PALF in South Africa and to evaluate prognostic scoring systems used.

Methods

Records of 45 pediatric patients younger than 16 years of age who presented with PALF from 1 January 2015 till 31 October 2020 were analysed. Patients were divided into two groups with one group consisting of patients with spontaneous recovery of the liver with supportive treatment (6/45:13.3%) and the second group consisting of patients with poor outcomes who demised (19/45: 42%) or underwent liver transplantation (20/45: 44%).

Results

The median age of presentation was 3.3 years (IQR 1.8–6.9) with the 1–5 years age group constituting majority of patients (55.6%). Median time to follow up was 6.1 months (IQR 0.2–28.8). Higher liver injury unit scores were observed in patients who had poorer outcomes (P = 0.008) with a threshold of greater than 246 having a sensitivity of 84% and specificity of 83% (P < 0.001). Higher peak PELD/MELD (P = 0.006) and admission UKELD (P = 0.002) scores, were found in patients with poorer outcomes. Kings College Hospital criteria (KCHC) was useful in predicting which patients would die without liver transplantation (P = 0.002). Liver transplantation was performed in 20/45 (44%) patients with a post transplantation 1 year patient and graft survival of 80%.

Conclusion

Although, survival of PALF patients was lower than high and other low-middle income countries, outcomes post transplantation were good. Our study demonstrates the utility of dynamic scoring systems in PALF patients, it underscores the need for early referral and clinical monitoring in a tertiary center once the criteria for PALF have been met.
Prevalence of pediatric surgical problems among east African refugees: estimates from a cross-sectional survey using random cluster sampling
Authors: Enumah Zachary Obinna , Rafiq Mohamed Yunus , Rhee Daniel , Manyama Frank , Ngude Hilary , Stevens Kent , Juma Omar , Sakran Joseph V.
Published: September 2022

Importance

Surgery is a foundational aspect to high functioning health care systems. In the wake of the Lancet Commission on Global Surgery, previous research has focused on defining the burden of surgical conditions among a pediatric population, however these studies often fail to include forced migrant or refugees. The goal of this study was to estimate the prevalence of pediatric surgical conditions among refugees in east Africa.

Methods

We used the previously validated Surgeons OverSeas Assessment of Surgical Need (SOSAS) that utilizes cross-sectional design with random cluster sampling to assess prevalence of surgical disease among participants aged 0 to 18 years in Nyarugusu refugee camp, Tanzania. We used descriptive and multivariable analyses including an average marginal effects model.

Results

A total of 1,658 participants were included in the study. The mean age of our sample was 8.3 ± 5.8 years. A total of 841 participants (50.7%) were male and 817 participants (49.3%) were female. A total of 513 (n = 30.9%) reported a history or presence of a problem that may be surgical in nature, and 280 (54.6%) of them reported the problem was ongoing or untreated. Overall, 16.9% had an ongoing problem that may be amenable to surgery. We found that increasing age and recent illness were associated with having a surgical problem on both our multivariable analyses.

Conclusion

To our knowledge, this is the first and largest study of prevalence of surgical conditions among refugee children in sub-Saharan Africa. We found that over 16% (one-in-six) of refugee children have a problem that may be amenable to surgery. Our results provide a benchmark upon which other studies in conflict or post-conflict zones with refugee or forced migrant populations may be compared.
Simplified Chinese adaptation of the Yale Physical Activity Survey: reliability and validity measurement in mainland China elderly women
Authors: Yang Yuan , Wang Chen , Xu Mingchao , Zhong Xiaoke , Yuan Xiaoxia , Yan Shoufu , Jiang Changhao
Published: August 2022

Objective

To verify the reliability and validity of the simplified Chinese version of the Yale Physical Activity Survey (YPAS) scale in the measurement of physical activity of elderly women in mainland China to provide a new standardized scale for evaluating the level of physical activity.

Methods

Twenty-one healthy elderly women completed all the research procedures. The participants completed the questions on the YPAS and wore an Omegawave Sport Technology®System diagnostic system that recorded maximum oxygen uptake and the adaptation index of the energy metabolism system. The reliability of the YPAS was evaluated based on the consistency of the two measurements (pre-test and post-test), and its validity was verified based on the relevant indicators in the Omegawave diagnostic system. Descriptive statistics, intraclass correlation coefficient and Pearson correlation analysis were used. The significance level was set at p < 0.05.

Results

In terms of reliability, the Pearson correlation coefficient and ICC of the total physical activity time of YPAS (r = 0.917, ICC = 0.897) was high. In terms of total calories, the Pearson correlation coefficient and ICC of the two test results was high (r = 0.958, ICC = 0.934). On the YPAS total index, the Pearson correlation coefficient and ICC of the two test was high (r = 0.930, ICC = 0.920). In terms of validity, there was a moderate correlation between the energy metabolism system adaptation index and the YPAS-total time (r = 0.472) and a moderate correlation with total calories (r = 0.472). There was a high correlation between the YPAS-total index and the maximum oxygen uptake (r = 0.782).

Conclusion

The simplified Chinese version of the YPAS can measure the level of physical activity and energy metabolism of elderly women in mainland China. It is a reliable tool for measuring the physical activity of the elderly.
Association between overweight, obesity and sleep duration and related lifestyle behaviors is gender and educational stages dependent among children and adolescents aged 6-17 years: a cross-sectional study in Henan
Authors: Wang Yiran , Luo Shuying , Hou Yuwei , Wang Kaijuan , Zhang Yaodong
Published: August 2022

Background

To investigate the associations between overweight, obesity and sleep duration and related lifestyle behaviors in children and adolescents at different gender and educational stages.

Methods

A cross-sectional study comprising 18723 children and adolescents with a stratified cluster sampling method of Henan Province was conducted in 2019. A self-reported questionnaire was used to collect the information about demographic characteristics as well as sleep and lifestyle behaviors. Anthropometric measurements (height and weight) were taken and body mass index was computered as an indicator of overweight and obesity. The Chi-square test, one-way analysis of variance and multiple logistic regression were used to data analysis.

Results

Among the respondents, 12657(67.6%) were with normal weight, 3711(19.8%) were overweight and 2355(12.6%) were obesity. The average age of the participants was 12.6 years old. The proportion of overweight and obesity in the 10191 boys was 18.7% and 14.2% respectively. The proportion of overweight and obesity in the 8532 girls was 21.2% and 10.6% respectively. In trend analyses, sleep duration at different gender found with the decreased of the sleep duration, the proportions of overweight/obesity in boys and girls were gradually increased (Ptrend<0.05). In the adjusted logistic regression models, the results showed stratified by gender, compared with the recommended sleep duration group, students with very short sleep duration and short sleep duration showed an increased ORadj of 2.56 and 2.13 in boys, 2.34 and 2.09 in girls respectively. According to different educational stages, those in very short sleep duration and short sleep duration showed an increased ORadj of 2.15 and 1.69 in primary school, 2.26 and 1.58 in middle school, 2.23 and 1.51 in high school respectively.

Conclusions

Children and adolescents with very short sleep duration and short sleep duration may increase the risk of overweight/obesity, the association differed based on the gender-specific and educational stages-specific. Gender and educational stages should be regarded as specific characteristics for the effects on overweight/obesity in Henan Province.
Demographic and clinical profile of patients treated with proximal femoral nails – a 10-year analysis of more than 40,000 Cases
Authors: Finkemeier Christopher G. , Holy Chantal E. , Ruppenkamp Jill W. , Vanderkarr Mollie , Sparks C.
Published: September 2022

Background

Hip fractures are common in elderly populations and can be life threatening. Changes in healthcare delivery and outcomes for patients with hip fracture treated with intramedullary nails are not well characterized. The objectives of our study were: 1) the characterization of patients treated with the Trochanteric Fixation Nail -Advanced™(TFNA) Proximal Femoral Nailing System or comparable nails (index) and estimate 12-month all-cause readmissions (ACR) and reoperations following index; and 2) the evaluation of 10-year healthcare utilization (HCU) trends for treatment of femoral fractures with femoral nails.

Methods

This is a retrospective database analysis using the Premier hospital database. All adults with femoral fracture treated with an intramedullary nail, from 2010 to Q3 2019, in the inpatient setting, were identified. Exclusion criteria included patients with bilateral hip surgery and presence of breakage at time of initial surgery. The primary outcome was ACR and reoperation, the secondary outcomes were healthcare utilization metrics. Variables included demographics, comorbidities (Elixhauser Index (EI)), surgical intervention variables and hospital characteristics.

Results

Forty-one thousand one hundred four patients were included in the study, of which 14,069 TFNA patients, with average age 77.9 (Standard deviation (SD): 12.0), more than 60% with 3 or more comorbidities (more than 64% for TFNA), 40% with severe or extreme disease severity and one third with severe or extreme risk for mortality. ACR reached 60.1% (95% confidence interval (CI): 59.6%-60.5%) – for TFNA: 60.0% (95%CI: 59.2%-60.8%). The reoperation rate was 4.0% (95%CI: 3.8%-4.2%) – for TFNA: 3.8% (95%CI: 3.5%-4.1%). Length of stay (LOS) averaged 5.8 days (SD: 4.8), and 12-month hip reoperation was 4.0% (3.8%-4.2%), in TFNA cohort: 3.8% (3.5%-4.1%). From 2010 to 2019: the percentage patients operated within 48 h of admission significantly increased, from 75.2% (95%CI: 74.3%-76.1%) to 84.3% (95%CI: 83.9%-84.6%); LOS significantly decreased, from 6.2 (95%CI: 6.0–6.4) to 5.6 (95%CI: 5.5–5.7) days; discharge to skilled nursing facilities (SNF) increased from 56.0% (95%CI: 54.8%-57.2%) to 61.5% (95%CI: 60.8%-62.2%); ACR rates decreased but reoperation rates remained constant.

Conclusions

ACR and reoperation rates were similar across device types and averaged 60.1% and 4.0%, respectively. Ten-year analyses showed reductions in hospital HCU and greater reliance on SNF.