bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of integrated chronic care models for cardiometabolic multimorbidity in sub-Saharan Africa: a systematic review and meta-analysis
Authors: Otieno Peter , Agyemang Charles , Wao Hesborn , Wambiya Elvis , Ng’oda Maurine , Mwanga Daniel , Oguta James , Kibe Peter , Asiki Gershim
Published: June 2023

Objectives

This review aimed at identifying the elements of integrated care models for cardiometabolic multimorbidity in sub-Saharan Africa (SSA) and their effects on clinical or mental health outcomes including systolic blood pressure (SBP), blood sugar, depression scores and other patient-reported outcomes such as quality of life and medication adherence.

Design

Systematic review and meta-analysis using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach.

Data sources

We systematically searched PubMed, Embase, Scopus, Web of Science, Global Health CINAHL, African Journals Online, Informit, PsycINFO, ClinicalTrials.gov, Pan African Clinical Trials Registry and grey literature from OpenSIGLE for studies published between 1999 and 2022.

Eligibility criteria for selecting studies

We included randomised controlled trial studies featuring integrated care models with two or more elements of Wagner’s chronic care model.

Data extraction and synthesis

Two independent reviewers used standardised methods to search and screen included studies. Publication bias was assessed using the Doi plot and Luis Furuya Kanamori Index. Meta-analysis was conducted using random effects models.

Results

In all, we included 10 randomised controlled trials from 11 publications with 4864 participants from six SSA countries (South Africa, Kenya, Nigeria, Eswatini, Ghana and Uganda). The overall quality of evidence based on GRADE criteria was moderate. A random-effects meta-analysis of six studies involving 1754 participants shows that integrated compared with standard care conferred a moderately lower mean SBP (mean difference=−4.85 mm Hg, 95% CI −7.37 to −2.34) for people with cardiometabolic multimorbidity; Hedges’ g effect size (g=−0.25, (−0.39 to −0.11). However, integrated care compared with usual care showed mixed results for glycated haemoglobin, depression, medication adherence and quality of life.

Conclusion

Integrated care improved SBP among patients living with cardiometabolic multimorbidity in SSA. More studies on integrated care are required to improve the evidence pool on chronic care models for multimorbidity in SSA. These include implementation studies and cost-effectiveness studies.

PROSPERO registration number

CRD42020187756.
Serum apolipoprotein A1 and B are associated with 6-month persistent and incident diabetic macular oedema in type 2 diabetes
Authors: Soedarman Soefiandi , Julia Madarina , Gondhowiardjo Tjahjono D , Prasetya Alberthus Donni Budi , Kurnia King Hans , Sasongko Muhammad Bayu
Published: June 2023

Aims

To investigate the associations of baseline apolipoprotein A1 (ApoA1) and B (ApoB) levels with persistent and incident diabetic macular oedema (DMO) after 6 months of follow-up.

Methods

This is a prospective cohort study of patients aged ≥30 years with untreated diabetic retinopathy. Examinations, fundus photography and spectral domain optical coherence tomography (SD-OCT) were assessed at baseline, 1, 3 and 6 months. Serum lipids and apolipoproteins were analysed at a pathology laboratory. DMO was confirmed using SD-OCT, classified as (1) incident DMO, (2) persistent DMO and (3) regressed DMO. Eye-specific data were used, controlling for covariates and cluster effect.

Results

We recruited 53 patients but only 38 completed the study [(62 eyes), 20 eyes (32.3%) with DMO]. Higher quartile of ApoA1 was associated with lower risk of persistent/incident DMO (p for trend 0.02), while higher ApoB/A1 was associated with higher risk of persistent/incident DMO (p for trend 0.02). Every 10 mg/dL increase in ApoA1 levels was associated with lower risk of persistent/incident DMO (OR 0.69; 95% CI 0.49 to 0.92; p value 0.016), whereas every 0.2 increase in ApoB/A1 was significantly associated with higher risk of persistent/incident DMO (OR 1.4; 95% CI 1.1 to 1.9; p value 0.013) at the end of the study.

Conclusion

Individuals with diabetes with higher ApoA1 had lower risk of persistent/incident DMO and those with higher ApoB/A1 had higher risk of persistent/incident DMO at the end of 6 months. These suggest that serum ApoA1 and ApoB/A1 levels may be important risk factors for DMO and could be predictive of persistent/incident DMO despite anti-vascular endothelial growth factor treatment.
Efficacy of a prolonged stability melphalan formulation for intra-arterial treatment of retinoblastoma
Authors: Jubran Jubran H , Luong Hanna , Naik Anant , Srinivasan Visish M , Ramasubramanian Aparna , Li Amanda , Scherschinski Lea , Feldman Michael J , Albuquerque Felipe C , Abruzzo Todd A
Published: June 2023

Background

Melphalan, which is poorly soluble at room temperature, is widely used for the treatment of retinoblastoma by selective ophthalmic artery infusion. Evomela, a propylene glycol-free formulation of melphalan with improved solubility and stability, has recently been used as an alternative.

To compare the safety and efficacy of Evomela with standard-formulation melphalan (SFM) in the treatment of retinoblastoma by selective ophthalmic artery infusion.

Methods

We performed a retrospective case–control study of patients with retinoblastoma undergoing selective ophthalmic artery infusion with SFM or Evomela at a single institution. Cycle-specific percent tumor regression (CSPTR) was estimated by comparing photos obtained during pretreatment examination under anesthesia (EUA) with those obtained during post-treatment EUA 3–4 weeks later. CSPTR, ocular salvage rates, complication rates, operation times (unadjusted and adjusted for difficulty of ophthalmic artery catheterization), and intraprocedural dose expiration rates were compared between Evomela- and SFM-treated groups. Univariate and multivariate analyses were performed.

Results

Ninety-seven operations (melphalan: 45; Evomela: 52) for 23 patients with 27 retinoblastomas were studied. The ocular salvage rate was 79% in the SFM-treated group and 69% in the Evomela-treated group. Multivariate regression controlling for tumor grade, patient age, and treatment history revealed no significant differences in ocular salvage rate, CSPTR, complication rates, or operation times. Although the dose expiration rate was higher for the SFM-treated group, the difference was not statistically significant. Notably, there were no ocular or cerebral ischemic complications.

Conclusion

Evomela has non-inferior safety and efficacy relative to SFM when used for the treatment of retinoblastoma by selective ophthalmic artery infusion.
Nurses knowledge of palliative care: systematic review and meta-analysis
Authors: Li Ling , Wang Fang , Liang Qian , Lin Lunwei , Shui Xiaoling
Published: June 2023

Lack of knowledge about palliative care is one of the most common reasons for hindering the delivery of high-quality palliative care. Nurses play a major role in providing palliative care, and the degree of their mastery of this knowledge is crucial to whether they can effectively deliver the ideal palliative care. Therefore, it is necessary to understand the level of palliative care knowledge in this population. As of 8 November 8, 2022, we performed systematic searches in 10 databases. Meta-analysis of quantitative data that measuring the level of palliative care knowledge of nurses using the Palliative Care Quiz for Nursing (PCQN) was conducted using Stata software (version: V.15). A pooled mean score <10 indicated a low/insufficient knowledge level. The funnel plot and Egger’s regression test were used to detect publication bias, and finally, the robustness of the results was evaluated through sensitivity analysis. The pooled mean score for the level of nurses’ knowledge of palliative care was 9.68 (95% CI: 9.40 to 9.96). Among the three dimensions of the PCQN scale, the pooled mean score for the ‘“Philosophy and Principles of Palliative Care’” section was 1.73 (95% CI: 1.38 to 2.08); the ‘“Pain and Other Symptom Control’” section was 6.73 (95% CI: 6.41 to 7.05); and the ‘“Psychological, Spiritual and Social Care’” section was 1.21 (95% CI: 0.72 to 1.69). It can be seen that nurses’ mastery of palliative care knowledge is not sufficient. It is recommended that relevant departments formulate and promote the implementation of targeted measures to improve the knowledge level of this population.
Geodynamic studies of southwestern Canada: subduction zone processes and backarc mantle dynamics
Authors: Currie Claire A. , Yu Tai-Chieh
Published: June 2023

Geodynamic models allow insights into the processes that control lithosphere structure and evolution. Here, we review geodynamic studies along a profile across southwestern Canada, from the Cascadia subduction zone into the Laurentian craton. Geophysical and geological observations show distinct changes in thermal structure along this profile. One major change is between the cool forearc and hot volcanic arc. This marks the transition from (1) a stagnant forearc mantle that is cooled by the subducting Juan de Fuca Plate to (2) an advection-dominated arc region, where high temperatures arise from mantle flow driven by the subducting plate (corner flow). High temperatures occur for 400–500 km east of the arc to the Rocky Mountain Trench (RMT), where lithosphere thickness increases from 60 to 70 km below the Cordillera to >200 km below the craton. The timing of Cordillera lithosphere thinning is debated. A long-lived (>100 Ma) thin lithosphere inherited from earlier tectonics requires vigorous convection of a weak, hydrated mantle. Conversely, thinning may have occurred through gravitational removal of the lower lithosphere in the Eocene. Models show that a removal event only allows for a short-lived thin lithosphere (∼25 Myr), owing to conductive cooling. Even if there was Eocene delamination, the present-day thin lithosphere requires small-scale convection in the Cordillera mantle. The thermal contrast across the RMT is enhanced by edge-driven convection at the Cordillera–craton lithosphere step. The step itself is an enigmatic feature, and its long-term preservation requires that the craton mantle lithosphere is strong (dry) with moderate chemical depletion.
Determining the effectiveness of using acoustic velocity as an indirect measurement of branchiness in standing longleaf pine
Authors: Hausle Jacks M.T. , Forrester Jodi A. , Walker Trevor D.
Published: June 2023

Branches reduce stem quality, and the level of the effect is determined by the geometry, size, and number, of associated knots. Quantifying branchiness is difficult, as visual estimates are subjective, and mechanical measurements are impractical. Acoustic velocity (AV) is a relatively novel measurement capturing the speed stress travels through wood. AV is correlated with wood stiffness and is affected by internal characteristics like knots. This project tested AV as an indirect branchiness metric by measuring AV, height, diameter, and counting branches classified by diameter on 255 standing 8 year old longleaf pine ( Pinus palustris). AV was highly correlated with height (r = 0.76, p < 0.0001) and slenderness (r = 0.52, p < 0.0001). AV was moderately correlated with large living branches (diameter > 2.54 cm) (r = −0.27, p < 0.0001), but not correlated with total branches. Height, slenderness, and the count of large living branches (diameter > 2.54 cm) were included in the selected model for AV. Inclusion of dead or small (diameter < 2.54 cm) branches reduced model power. The best model captured 11% of the variation in AV, of which branches explained 5%. We conclude that AV does not appropriately quantify individual tree branchiness, but may be suitable for comparing populations such as families or provenances.
Evaluating the biosusceptibility of natural stone as an supporting tool to prevent Cultural Heritage biodeterioration
Authors: Dias L. , Pires V. , Sitzia F. , Lisci C. , Candeias A. , Caldeira A. T. , Mirão J.
Published: June 2023

Biodeterioration of construction materials is still a major challenge that conservator-restorers face, especially in historic monuments with high cultural value. Natural stone is highly susceptible to deterioration through physical, chemical, and biological ways, whereas biological proliferation may potentiate both chemical and physical deterioration. The composition of the colonizers and their proliferation are highly dependent on climatic parameters like temperature and humidity, which are distinct from place to place. The present work proposes the execution of an innovative methodology that enables the determination of the susceptibility of natural stone to biocolonization, a parameter denominated as biosusceptibility. The study aims to contribute to the creation of models by predicting their deterioration even before the objects’ manufacture, promoting the sustainability of one of the most valuable natural resources. The methodology proposed here was performed on limestones, marbles and slates—exploited in the Portuguese territory—by using colonizing strains typically found on stones exposed to the Mediterranean climate. The results have demonstrated that the stones with higher porosity are less susceptible to epilithic colonization and, consequently, with a moderate alteration of their aesthetic appearance. However, the metabolic activity determined in these stones is higher, which indicates that biocolonization will cause more severe damage to their structure in the future. The first significant changes on the stones’ matrix were assessed one year after the inoculation, using cutting-edge technology of 3D surface micro-reconstruction. Due to its relevance in natural stone deterioration processes, the inclusion of the biosusceptibility information in technical brochures is strongly encouraged.

Graphical Abstract
Conditionally Simulated Nonstationary Multi-point Earthquake Accelerograms Using Regressive Model
Authors: Wen Pan , Zhou Baofeng , Wen Ruizhi
Published: June 2023

A new method is presented that simulates nonstationary multipoint earthquake accelerograms at local field points, when the observed ground motions are specified at several locations. This process effectively avoids the stochastic decomposition of the spectral matrix. In addition, it does not use the target spectrum and spatial coherence function to define the information of each point. First, the observed ground motions are reconstructed using an autoregressive model. Second, a new cross-regressive model is proposed based on the formulation of the auto-regressive model. The cross-regressive model can reconstruct different observed ground motions by using recordings from any nearby area. To consider the nonstationary characteristics and spatial coherence, the ground motions of unobserved points between two observed points can be generated using an interpolation algorithm. This new method simulates the ground motions of target points in the Chiba array using partially observed earthquake accelerograms. The simulated earthquake accelerograms satisfy the nonstationary characteristics and spatial coherence of the Chiba array. This study is promising for engineering applications and hazard analyses.
No-regret Caching via Online Mirror Descent
Authors: Si Salem Tareq , Neglia Giovanni , Ioannidis Stratis
Published: June 2023

We study an online caching problem in which requests can be served by a local cache to avoid retrieval costs from a remote server. The cache can update its state after a batch of requests and store an arbitrarily small fraction of each file. We study no-regret algorithms based on Online Mirror Descent (OMD) strategies. We show that bounds for the regret crucially depend on the diversity of the request process, provided by the diversity ratio
R/h
, where
R
is the size of the batch and
h
is the maximum multiplicity of a request in a given batch. We characterize the optimality of OMD caching policies w.r.t. regret under different diversity regimes. We also prove that, when the cache must store the entire file, rather than a fraction, OMD strategies can be coupled with a randomized rounding scheme that preserves regret guarantees, even when update costs cannot be neglected. We provide a formal characterization of the rounding problem through optimal transport theory, and moreover we propose a computationally efficient randomized rounding scheme.
STAR: A Cache-based Stream Warehouse System for Spatial Data
Authors: Chen Zhida , Cong Gao , Aref Walid G.
Published: June 2023

The proliferation of mobile phones and location-based services has given rise to an explosive growth in spatial data. To enable spatial data analytics, spatial data needs to be streamed into a data stream warehouse system that can provide real-time analytical results over the most recent and historical spatial data in the warehouse. Existing data stream warehouse systems are not tailored for spatial data. In this article, we introduce the
STAR
system.
STAR
is a distributed in-memory data stream warehouse system that provides low-latency and up-to-date analytical results over a fast-arriving spatial data stream.
STAR
supports both snapshot and continuous queries that are composed of aggregate functions and ad hoc query constraints over spatial, textual, and temporal data attributes.
STAR
implements a cache-based mechanism to facilitate the processing of snapshot queries that collectively utilizes the techniques of query-based caching (i.e., view materialization) and object-based caching. Moreover, to speed up processing continuous queries,
STAR
proposes a novel index structure that achieves high efficiency in both object checking and result updating. Extensive experiments over real datasets demonstrate the superior performance of
STAR
over existing systems.
Reports From The Frontier: Overcoming Limitations for Pure-water Anion-exchange-membrane Electrolysis
Authors: Lindquist Grace , Boettcher Shannon
Published: June 2023

Anion-exchange-membrane electrolysis is positioned to play a key role in the predicted exponential growth of green hydrogen technology with essential R&D advances. We reveal key design parameters essential to commercialization. First, stable alkaline oxygen-evolution reaction catalysts with high electronic conductivity and minimal surface reconstruction during operation must be designed. Alkaline catalyst layers must also be applied to the membrane electrode assembly with scalable, industrially relevant techniques. Second, ionomer oxidation mitigation strategies must be developed. This approach could also target other creative catalyst layer design, such as phase-separation control to protect oxidation-prone organic components or catalyst engineering to direct selectivity for hydroxide over polymer oxidation. If competitive efficiency and durability can be achieved in pure water, AEM electrolysis has the potential to become a dominant electrolyzer technology.
The Future of Industrial Electrochemistry & Electrochemical Engineering
Authors: Inman Maria
Published: June 2023

Since its inception, the work of the Industrial Electrochemistry & Electrochemical Engineering (IE&EE) Division has encompassed a broad range of technologies and applications, including mathematical modeling of electrochemical systems, development and optimization of small- and large-scale industrial processes, environmental remediation and electrochemical conversion to produce value-added chemicals. A recent focus has been the creation of innovative technologies that will help to alleviate the climate and environmental crises, to improve sustainability and decarbonize existing technologies.
Carbonation Reaction of Epoxidized Linseed Oil: Comparative Performance of TBABr and TBAI as Catalysts
Authors: Nieto-Alarcón Juan F. , González David A. , Vigueras-Santiago Enrique , Hernández-López Susana
Published: June 2023

Cyclic carbonates are considered to be green nontoxic intermediates with important applications in polymer synthesis and fuel additives and as polar solvents with high boiling points. The carbonation of epoxidized vegetable oils is a very important step in the synthesis of nonisocyanate polyurethane. This reaction is usually performed with carbon dioxide in the presence of an ionic liquid that acts both as solvent and catalyst, with the most studied catalyst being tetra-n-butylammonium bromide (TBABr). Most of the works have reported high yields and good carbonation conversions. In addition, studies with tetra-n-butylammonium iodide (TBAI) as the catalyst have shown it to improve the conversion in the carbonation of short-chain epoxides but not of fatty acid esters and in some vegetable oils. In the current study, the carbonation of epoxidized linseed oil (ELO) (5.8 epoxide group per molecule) was carried out in an autoclave-type reactor under a carbon dioxide atmosphere (60 psi) and the variables evaluated were the reaction temperature (110°C and 140°C), catalyst load (2.5 mol% and 5.0 mol%), reaction time (24 h and 48 h), and catalyst type (TBABr and TBAI). The results of the study showed that the temperature was the most important factor affecting the reaction. However, halohydrins and ketones were also found to have formed from side reactions promoted mainly by TBAI at 140°C and were identified and quantified using FTIR-HATR, 1H-NMR, and 13C-NMR spectroscopy techniques. The best results namely, 100% conversion, 87.9% carbonation, and 87.9% selectivity, with relatively few side reactions (1.7% halohydrins and 1.7% ketones)were: 2.5 mol% of TBABr, a temperature of 110°C, and a reaction time of 24 h. The results also showed that using TBAI as the catalyst increased the frequency of undesirable side reactions during the carbonation of ELO.
Coordinated Variable Speed Limit Control for Consecutive Bottlenecks on Freeways Using Multiagent Reinforcement Learning
Authors: Zheng Si , Li Meng , Ke Zemian , Li Zhibin
Published: June 2023

Most of the current variable speed limit (VSL) strategies are designed to alleviate congestion in relatively short freeway segments with a single bottleneck. However, in reality, consecutive bottlenecks can occur simultaneously due to the merging flow from multiple ramps. In such situations, the existing strategies use multiple VSL controllers that operate independently, without considering the traffic flow interactions and speed limit differences. In this research, we introduced a multiagent reinforcement learning-based VSL (MARL-VSL) approach to enhance collaboration among VSL controllers. The MARL-VSL approach employed a centralized training with decentralized execution structure to achieve a joint optimal solution for a series of VSL controllers. The consecutive bottleneck scenarios were simulated in the modified cell transmission model to validate the effectiveness of the proposed strategy. An independent single-agent reinforcement learning-based VSL (ISARL-VSL) and a feedback-based VSL (feedback-VSL) were also applied for comparison. Time-varying heterogeneous traffic flow stemming from the mainline and ramps was loaded into the freeway network. The results demonstrated that the proposed MARL-VSL achieved superior performance compared to the baseline methods. The proposed approach reduced the total time spent by the vehicles by 18.01% and 17.07% in static and dynamic traffic scenarios, respectively. The control actions of the MARL-VSL were more appropriate in maintaining a smooth freeway traffic flow due to its superior collaboration performance. More specifically, the MARL-VSL significantly improved the average driving speed and speed homogeneity across the entire freeway.
IgE Plasma Cell Leukemia Harboring t(11;14) and 1q Amplification
Authors: Nakahara Wataru , Ogawa Takahito , Matsunaga Hitomi , Iwasa Yuki , Horita Momoka , Ikeda Mako , Asako Mizuki , Iio Sadaharu , Iwama Yuki , Oka Kazumasa , Ueda Shuji
Published: June 2023

IgE plasma cell neoplasm is the rarest subtype of plasma cell neoplasms and is known for its poor prognosis and high incidence of t(11;14). However, t(11;14) has been classified as a standard-risk rather than high-risk cytogenetic abnormality in multiple myeloma. We have been unable to explain the discrepancy that the hallmark of IgE plasma cell neoplasm with a poor prognosis is a standard-risk cytogenetic abnormality. Here, we report a case of IgE primary plasma cell leukemia with extramedullary lesions of the liver, stomach, and lymph nodes. Plasma cell infiltration was pathologically confirmed in each organ. Cytogenetic analysis of plasma cells revealed t(11;14) and amplification of 1q21. Chemotherapy, with immunomodulatory imide drugs, proteasome inhibitors, and CD38 antibodies, was unsuccessful. In IgE plasma cell neoplasm, coexistence of other cytogenetic abnormalities with t(11;14) may be important. Investigating the presence of cytogenetic abnormalities coexisting with t(11;14) is not only useful for evaluating prognosis but also important for understanding the pathogenesis of the disease. Recently, venetoclax, an oral BCL2 inhibitor, has demonstrated promising efficacy in plasma cell neoplasm patients harboring t(11;14). Development of an effective venetoclax-based regimen for treating aggressive IgE plasma cell neoplasm with t(11;14) is expected.
A Novel Extended Power-Lomax Distribution for Modeling Real-Life Data: Properties and Inference
Authors: Qura Maha E. , Alqawba Mohammed , Al Sobhi Mashail M. , Afify Ahmed Z.
Published: June 2023

One of the important features of generalized distribution is its ability and flexibility to model real-life data in several applied fields such as medicine, engineering, and survival analysis, among others. In this paper, a flexible four-parameter Lomax extension called the alpha-power power-Lomax (APPLx) distribution is introduced. The APPLx distribution is analytically tractable, and it can be used quite effectively for real-life data analysis. Key mathematical properties of the APPLx distribution including mode, moments, stress-strength reliability, quantile and generating functions, and order statistics are presented. The APPEx parameters are estimated by using eight classical estimation methods. Extensive simulation studies are provided to explore the performance of the proposed estimation methods and to provide a guideline for practitioners and engineers to choose the best estimation method. Three real-life datasets from applied fields are fitted to assess empirically the flexibility of the APPLx distribution. The APPLx distribution shows greater flexibility as compared to the McDonal–Lomax, Fréchet Topp–Leone Lomax, transmuted Weibull–Lomax, Kumaraswamy–Lomax, beta exponentiated-Lomax, Weibull–Lomax, Burr-X Lomax, Lomax–Weibull, odd exponentiated half-logistic Lomax, and alpha-power Lomax distributions.
Significance of PPARA as a Treatment Target for Chronic Lymphocytic Leukemia
Authors: Xiang Xixi , Li Fu , Zhou Sha , Zeng Yunjing , Deng Xiaojuan , Zhang Hongyang , Li Jiali , Liu Hongyun , Rao Jun , Gao Lei , Zhang Cheng , Wen Qin , Gao Li , Zhang Xi
Published: June 2023

Peroxisome proliferator-activated receptor alpha (PPARA) has been suggested as a therapeutic target for chronic lymphocytic leukemia (CLL). However, the underlying molecular mechanism remains largely unclear. In this study, we analyzed DNA next-generation sequencing (NGS) data and clinical information from 86 CLL patients to identify gene markers related to treatment-free survival (TFS) length. We then constructed a genetic network that includes CLL promoters, treatment targets, and TFS-related marker genes. To assess the significance of PPARA within the network, we utilized degree centrality (DC) and pathway enrichment score (EScore). Clinical and NGS data revealed 10 TFS length-related gene markers, including RPS15, FOXO1, FBXW7, KMT2A, NOTCH1, GNA12, EGR2, GNA13, KDM6A, and ATM. Through literature data mining, 83 genes were identified as CLL upstream promoters and treatment targets. Among them, PPARA exhibited a stronger connection to CLL and TFS-related gene markers, as evidenced by its ranking at No. 13 based on DC, compared to most of the other promoters (>84%). Additionally, PPARA co-functions with 70 out of 92 in-network genes in various functional pathways/gene groups related to CLL pathology, such as regulation of cell adhesion, inflammation, reactive oxygen species, and cell differentiation. Based on our findings, PPARA is considered one of the critical genes within a large genetic network that influences the prognosis and TFS of CLL through multiple pathogenic pathways.
Supplementary Fig. 2 from A Phase 1/2 Multicenter Randomized Trial of Local Ablation plus Toripalimab versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma
Authors: Zhou Chunhui , Li Yan , Li Jiaping , Song Botian , Li Hanfeng , Liang Bin , Gu Shanzhi , Li Haiping , Chen Changyong , Li Sai , Peng Changli , Liu Fei , Xiao Juxiong , Long Xueying , Li Ping , Xiong Zhengping , Yi Xiaoping , Liao Weihua , Shi Liangrong
Published: June 2023

Supplementary Fig. 2 The association of CD8+ TIL density and PD-L1 expression with tumor objective response.
Supplementary Fig. 6 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: June 2023

Supplementary Fig. S6. Detection of short variant gene alterations using the FACT next generation sequencing assay on ctDNA samples from patients dosed at 1400 mg dose (n=23).
Supplementary Fig. 5 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: June 2023

Supplementary Fig. S5. Kaplan-Meier estimate of progression-free survival for patients with and without ESR1 mutations in baseline ctDNA samples collected from the 1400 mg dose group.ESR1 data was available for 36 of 36 patients dosed at 1400 mg.
Supplementary Fig. 4 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: June 2023

Supplementary Fig. S4. ESR1 mutation analysis in ctDNA.
Supplementary Fig. 3 from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: June 2023

Supplementary Fig. S3. Clinical benefit does not correlate with ctDNA ESR1 mutant allele frequency (MAF) baseline levels or dynamics upon treatment, or with baseline ER and PR protein levels by IHC in tumor tissue.
Supplementary Figures 1 from Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors
Authors: de Sousa Luana Guimaraes , McGrail Daniel J. , Lazar Neto Felippe , Li Kaiyi , Marques-Piubelli Mario L. , Ferri-Borgogno Sammy , Dai Hui , Mitani Yoshitsugu , Spardy Burr Nicole , Cooper Zachary A. , Kinneer Krista , Cortez Maria Angelica , Lin Shiaw-Yih , Bell Diana , El Naggar Adel , Burks Jared , Ferrarotto Renata
Published: June 2023

Supplementary Figures
Supplementary Data 1 from Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors
Authors: de Sousa Luana Guimaraes , McGrail Daniel J. , Lazar Neto Felippe , Li Kaiyi , Marques-Piubelli Mario L. , Ferri-Borgogno Sammy , Dai Hui , Mitani Yoshitsugu , Spardy Burr Nicole , Cooper Zachary A. , Kinneer Krista , Cortez Maria Angelica , Lin Shiaw-Yih , Bell Diana , El Naggar Adel , Burks Jared , Ferrarotto Renata
Published: June 2023

Supplementary material including methods, supplementary table 1, supplementary table 2, and supplementary table 3
Data from Spatial Immunoprofiling of Adenoid Cystic Carcinoma Reveals B7-H4 Is a Therapeutic Target for Aggressive Tumors
Authors: de Sousa Luana Guimaraes , McGrail Daniel J. , Lazar Neto Felippe , Li Kaiyi , Marques-Piubelli Mario L. , Ferri-Borgogno Sammy , Dai Hui , Mitani Yoshitsugu , Spardy Burr Nicole , Cooper Zachary A. , Kinneer Krista , Cortez Maria Angelica , Lin Shiaw-Yih , Bell Diana , El Naggar Adel , Burks Jared , Ferrarotto Renata
Published: June 2023

AbstractPurpose:
Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets.
Experimental Design:
Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody–drug conjugate AZD8205 was tested in ACC patient-derived xenografts (PDX).
Results:
RNA deconvolution revealed that most ACCs are immunologically “cold,” with approximately 30% being “hot.” ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX.
Conclusions:
Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.
Data from Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC
Authors: Florou Vaia , Elliott Andrew , Bailey Matthew H. , Stone David , Affolter Kajsa , Soares Heloisa P. , Nevala-Plagemann Chris , Scaife Courtney , Walker Phillip , Korn W. Michael , Lou Emil , Shroff Rachna T. , Hosein Peter J. , Garrido-Laguna Ignacio
Published: June 2023

AbstractBackground:
Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.
Methods:
PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI).
Results:
The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years.
Conclusions:
There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
Supplementary Figure 5 from Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: June 2023

Expression of CD3 and CD8 on CD45+ leukocytes from B16F10-RFLuc-3 tumors. Delta-24-RGDOX was injected into the s.c. tumors on Days 8, 11 and 14. Leukocytes from the tumors were profiled through flow cytometry on Day 18. RGDOX: Delta-24-RGDOX.
Supplementary Figure 3 from Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: June 2023

Survival plots of mice with s.c./s.c. melanomas treated with PBS or wildtype (WT) CD8+ T cells injected into the s.c. Tumor 1. PBS: n=8; WT CTLs: n=5. ns: not significant (p > 0.05). log-rank test.
FIGURE 6 from Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: June 2023

Antigen spread enhanced by combining TAA-specific CTLs and Delta-24-RGDOX in localized intratumoral treatment. Flow cytometry to quantify the density of adoptive TAA-specific pmel-1 T cells (A) or endogenous TAA (OVA)-specific CTLs (B) in treated (Tumor 1) and untreated (Tumor 2) subcutaneous tumors from the indicated treatment groups. Leukocytes were from grouped tissue (4 to 7 mice/group) and processed in triplicate. ELISA assay to show the amount of IFNγ secreted by the splenocytes from the treatment groups stimulated by epitope peptides of TAAs (OVA, gp100, TRP2) and GFP (C), or B16-OVA cells (D). Leukocytes or splenocytes were from grouped tissue (4 to 7 mice/group) and processed in triplicate. The columns in the graphs represent the mean ± SD (n = 3). RGDOX: Delta-24-RGDOX; T cells: pmel-1 T cells. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Two-tailed Student t test.
FIGURE 5 from Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: June 2023

Release of immune suppression of endogenous TAA-specific CTLs from treated (Tumor 1) and untreated (Tumor 2) subcutaneous tumors mediated by Delta-24-RGDOX. PD-1 and TIM3 levels were assessed in CD8+ leukocytes (A), adoptive pmel-1 T cells (B) or endogenous OVA-targeting CTLs (C) from the indicated tumors. Top: Tumor 1; bottom: Tumor 2. A, Left: Representative flow cytometry histograms; Right: Quantification of MFI of PD-1 or TIM3. B and C, Quantification of MFI of PD-1 or TIM3. D and E, Representative flow cytometry dot plots to show relative amount of cell numbers and immune checkpoint protein (PD-1 and TIM3) expression levels between endogenous OVA-specific CTLs and CD8+ leukocytes (D) or OVA-specific CTLs and adoptive pmel-1 T cells (E) from the indicated tumors. Leukocytes from the tumors in the treatment groups as depicted in Fig. 3A were profiled with flow cytometry. Leukocytes were from grouped tissue (4 to 7 mice/group) and processed in triplicate. The columns in the graphs represent the mean ± SD (n = 3). RGDOX: Delta-24-RGDOX; T cells: pmel-1 T cells. ns, not significant (P > 0.05); **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. Two-tailed Student t test.
FIGURE 2 from Adjuvant Therapy with Oncolytic Adenovirus Delta-24-RGDOX After Intratumoral Adoptive T-cell Therapy Promotes Antigen Spread to Sustain Systemic Antitumor Immunity
Authors: Jiang Hong , Shin Dong Ho , Yi Yanhua , Fan Xuejun , Gumin Joy , He Jiasen , Gillard Andrew G. , Lang Frederick F. , Gomez-Manzano Candelaria , Fueyo Juan
Published: June 2023

Systemic tumor regression sustained by combining TAA-specific T cells and Delta-24-RGDOX in localized intratumoral treatment. A, A cartoon depiction of the treatment scheme for schedule (left) and positions of tumor implantation, T-cell and virus injection (right). s.c.: subcutaneously; i.t.: intratumorally. B, Spaghetti plots of the volume of the tumors from the indicated treatment groups. C, Survival plots of the treatment groups. n = 10 except n = 8 for PBS. D, The cell lysates from the indicated cell lines or tumors were analyzed with immunoblotting for OVA (the target of OT-I cells) or gp100. Note that the tumors from PBS or RGDOX group were treated ones collected 8 days after OT-I cell injection; the tumors from OT-I cells group were relapsed tumors collected 32 days after OT-I cell injection. The numbers on the bottom represent relative expression levels of gp100 and OVA normalized against GAPGH. E and F, Survival plots for survivors from combination treatment after being first rechallenged with B16-OVA (D; naïve: n = 4; survivor: n = 6) and then CMT64 (E; naïve: n = 5; survivor: n = 6) cells. RGDOX: Delta-24-RGDOX. ns, not significant (P > 0.05); *, P < 0.05; **, P < 0.01. log-rank test.
Unilateral High Intraocular Pressure, Cataract, and Retinal Detachment in Waardenburg Syndrome
Authors: Al-Najmi Yahya , Abdalla Elsayed Maram E. A. , Alsaggaf Khalid , Alghamdi Albatool , Albeedh Mohammed
Published: June 2023

Waardenburg syndrome was first described in 1951 by Dutch ophthalmologist Petrus Johannes Waardenburg (1886-1979). It is an auditory-pigmentary syndrome that results from a lack of melanocytes in the hair, skin, eyes, or stria vascularis of the cochlea. It accounts for more than 2% of congenitally deaf individuals [Indian J Otolaryngol Head Neck Surg. 2015 Sep;67(3):324–8]. Affected people usually have neurosensory hearing loss, forelock pigmentation loss, iris heterochromia, and medial canthus dystopia, and their first-degree relatives have the same features of this syndrome. The following is a report of an unusual and rare presentation of ocular findings in Waardenburg syndrome. A 25-year-old male presented for eye examination due to gradual loss of his left eye visual acuity over the last few years with characteristic features of Waardenburg syndrome along with high intraocular pressure (IOP), cataract, and retinal detachment (RD) in one eye.
Anterior Chamber Dislocation of Dexamethasone Implant in the Presence of Carlevale Sutureless Scleral Fixation Intraocular Lens
Authors: Stavrakas Panagiotis , Gartaganis Panos , Totou Styliani , Chalkiadaki Evangelia , Manousakis Evangelos , Karmiris Efthymios
Published: June 2023

Dexamethasone intravitreal implant (Ozurdex®; Allergan, Inc., CA, USA) has been proved to be effective in a variety of clinical settings including cases of pseudophakic cystoid macular edema. Uncommonly, this implant can migrate from the vitreous cavity and into the anterior chamber, especially in vitrectomized eyes with lens capsule defects. We report herein a rare case of anterior chamber migration and illustrate the passageway of the dexamethasone intravitreal implant through a new type of scleral fixated lens, the Carlevale IOL (Soleko-Italy). A 78-year-old woman was left aphakic following a complicated right eye hypermature cataract surgery with posterior capsule rupture and zonular dehiscence. Shortly thereafter, she underwent a planned combined pars plana vitrectomy with the placement of a Carlevale sutureless scleral fixated intraocular lens for the treatment of her aphakia. Due to a subsequent persistent cystoid macular edema that was unresponsive to topical treatment and sub-tenon corticosteroids, an intravitreal dexamethasone implant was injected. Eleven days after implantation, the patient presented with a floating implant in the anterior chamber and corneal edema. Following an immediate surgical removal, corneal edema resolved and visual acuity improved. One year later, results remain stable without macular edema recurrence. Anterior chamber migration of the Ozurdex implant is a potential complication in vitrectomized eyes, even when new types which are larger and specially designed for scleral fixation intraocular lenses are utilized. Corneal complications can be reversible following an immediate removal of the implant.
Kt/V or Bicarbonate: What Is More Important for Growth in Pediatric Peritoneal Dialysis Patients?
Authors: Sylvestre Lucimary de Castro , Bernardes Rejane de Paula , Stremel Ribeiro Débora , Diaz-Gonzalez de Ferris Maria Esther , Filler Guido
Published: June 2023

Introduction: Growth retardation is a common problem in pediatric patients with chronic kidney disease. It is unknown if the growth of children on peritoneal dialysis (PD) can be augmented by more dialysis. Methods: We studied the effect of various peritoneal adequacy parameters on delta height standard deviation scores (SDSs) and growth velocity z-scores in 53 children (27 males) on PD, who underwent 2 longitudinal adequacy tests at 9-month intervals. None of the patients were on growth hormone. Intraperitoneal pressure and standard KDOQI guidelines were compared to the outcome measures delta height SDS and height velocity z-scores, using univariate and multivariate tests. Results: At the time of the second PD adequacy test, their mean age was 9.2 ± 5.3 years; mean fill volume was 961 ± 254 mL/m2; and median total infused dialysate volume was 5.26 L/m2/day (range 2.03–15.32 L). The median total weekly Kt/V was 3.79 (range 0.9–9.5), and the median total creatinine clearance was 56.6 (range 7.6–133.48) L/week, higher than previous pediatric studies. The delta height SDS was a median of −0.12 (range −2 to +3.95)/year. The mean height velocity z-score was −1.6 ± 4.0. The only relationships discovered were between the delta height SDS and age, bicarbonate, and intraperitoneal pressure, but not for Kt/V or creatinine clearance. Conclusion: Our findings highlight the importance of normalization of bicarbonate concentrations to improve height z-score.