bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulated Clear-Sky Water Vapor and Temperature Retrievals from PREFIRE Measurements
Authors: Miller Nathaniel B. , Merrelli Aronne , L’Ecuyer Tristan S. , Drouin Brian J.
Published: March 2023

The Polar Radiant Energy in the Far Infrared Experiment (PREFIRE) mission will measure Earth’s emission at wavelengths ranging from 3 to 54 μm. The prelaunch clear-sky retrieval algorithm, evaluated with simulated test data, indicates that PREFIRE measurements will be valuable for retrieving atmospheric water vapor and temperature profiles. Far infrared measurements provide unique retrieval information, indicated by the high ranking of select FIR channels as primary contributors to the total degrees of freedom for signal (DFS). In utilizing all the PREFIRE channels, the average total DFS of 4 test regions ranges from 1.90 to 4.71. The information content increases with higher column water vapor and in the presence of near-surface temperature inversions. Using the DFS profiles for guidance, the retrieval concentrates information into 7 distinct layers to reduce the retrieval uncertainty per layer. Sensitivity tests indicate forward model error due to surface emissivity uncertainty results in about a 9% increase in column water vapor uncertainty. The clear-sky retrieval is sensitive to the presence of undetected ice clouds, especially those with optical depths larger than 0.2. Hence, in addition to a separate PREFIRE cloud mask, optimal estimation retrieval metrics are explored as possible indicators of cloudy scenes.
Ecosystem People, Biosphere People, Ecological Refugees
Authors: Gadgil Madhav
Published: March 2023

One may assign people to three broad categories from an ecological perspective. Ecosystem people meet the bulk of their resource requirements from a limited area near their habitation through gathering or low-input agriculture and animal husbandry. Biosphere people enjoy access to resources garnered from the entire biosphere and made available through markets, while ecological refugees are people that have lost access to their traditional base of natural resources yet have very limited access to resources through markets. In India today the ever-growing pressure of biosphere people is converting an increasingly large proportion of ecosystem people into ecological refugees.
Iron homeostasis governs erythroid phenotype in Polycythemia Vera
Authors: Bennett Cavan , Jackson Victoria E , Pettikiriarachchi Anne , Hayman Thomas , Schaeper Ute , Moir-Meyer Gemma L , Fielding Katherine Louise , Ataide Ricardo , Clucas Danielle , Baldi Andrew James , Garnham Alexandra L , Li-Wai-Suen Connie SN , Loughran Stephen John , Baxter E Joanna , Green Anthony R , Alexander Warren S , Bahlo Melanie , Burbury Kate , Ng Ashley P , Pasricha Sant-Rayn
Published: March 2023

Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
CRISPR/Cas9-mediated Cxcr4 Disease Allele Inactivation for Gene Therapy in a Mouse Model of WHIM Syndrome
Authors: Gao Ji-Liang , Owusu-Ansah Albert , Yang Alexander , Yim Erin , McDermott David H , Jacobs Paejonette , Majumdar Shamik , Choi Uimook , Sweeney Colin L , Malech Harry L , Murphy Philip M
Published: March 2023

WHIM syndrome is an autosomal dominant immunodeficiency disorder caused by gain-of-function mutations in chemokine receptor CXCR4 that promote severe panleukopenia due to bone marrow (BM) retention of mature leukocytes. We previously reported that Cxcr4-haploinsufficient (Cxcr4+/o) hematopoietic stem cells (HSCs) have a strong selective advantage for durable hematopoietic reconstitution over wildtype (Cxcr4+/+) and WHIM (Cxcr4+/w) HSCs, and that a WHIM patient was spontaneously cured by chromothriptic deletion of the disease allele in an HSC, suggesting that WHIM allele inactivation through gene editing may be a safe genetic cure strategy for the disease. We have now developed a two-step preclinical protocol of autologous hematopoietic stem and progenitor cell (HSPC) transplantation towards this goal. First, one copy of Cxcr4 in HSPCs was inactivated in vitro by CRISPR/Cas9 editing with a single guide RNA (sgRNA) that does not discriminate between WHIM and wildtype Cxcr4 alleles. Then, through in vivo natural selection, WHIM allele-inactivated cells were enriched over wildtype allele-inactivated cells. The WHIM allele-inactivated HSCs retained long-term pluripotency and selective hematopoietic reconstitution advantages. To our knowledge this is the first example of gene therapy for an autosomal dominant gain-of-function disease using a disease allele inactivation strategy in place of the less efficient disease allele repair approach.
miR-330 targeting BCO2 is involved in carotenoid metabolism to regulate skin pigmentation in rainbow trout (Oncorhynchus mykiss)
Authors: Wu Shenji , Zhao Lu , Huang Jinqiang , Li Yongjuan , Liu Zhe , Zhang Dongqiang
Published: March 2023

Background

MicroRNAs (miRNAs) play a critical role in regulating skin pigmentation. As a key economic trait, skin color directly affects the market value of rainbow trout (Oncorhynchus mykiss), however, the regulatory mechanism of most miRNAs in fish skin color is still unclear.

Results

In this study, the full-length cDNA sequence of β-carotene oxygenase 2 (BCO2, a key regulator of carotenoid metabolism) from the rainbow trout was obtained using rapid-amplification of cDNA ends (RACE) technology, and qRT-PCR was used to investigate the differential expression of miR-330 and BCO2 in 14 developmental stages and 13 tissues between wild-type rainbow trout (WTrt) and yellow mutant rainbow trout (YMrt). Additionally, the function of miR-330 was verified by overexpression and silencing in vitro and in vivo. The results showed that the complete cDNA sequence of BCO2 was 2057 bp with a 1707 bp ORF, encoding a 568 amino acid protein having a molecular weight of 64.07 kD. Sequence alignment revealed that higher conservation of BCO2 protein amongst fishes than amongst other vertebrates, which was further confirmed by phylogenetic analysis. The analysis of spatial and temporal expression patterns suggested that BCO2 and miR-330 were abundantly expressed from fertilized-stage to multi-cell as well as in the dorsal and ventral skin of WTrt and YMrt, and their expression patterns were opposite in most of the same periods and tissues. In vitro, luciferase reporter assay confirmed that BCO2 was a direct target of miR-330, and transfection of miR-330 mimics into rainbow trout liver cells resulted in a decrease in the expression of BCO2; conversely, miR-330 inhibitor had the opposite effect to the miR-330 mimics. In vivo, miR-330 agomir significantly decreased BCO2 expression in dorsal skin, tail fin, and liver. Furthermore, overexpression of miR-330 could suppress cell proliferation and induce apoptosis.

Conclusion

Our results showed that miR-330 is involved in the regulation of skin pigmentation in rainbow trout by targeting BCO2 and shows its promise as a potential molecular target to assist the selection of rainbow trout with better skin color patterns.
A genetic linkage map and improved genome assembly of the termite symbiont Termitomyces cryptogamus
Authors: Vreeburg Sabine M. E. , Auxier Ben , Jacobs Bas , Bourke Peter M. , van den Heuvel Joost , Zwaan Bas J. , Aanen Duur K.
Published: March 2023

Background

The termite-fungus symbiosis is an ancient stable mutualism of two partners that reproduce and disperse independently. With the founding of each termite colony the symbiotic association must be re-established with a new fungus partner. Complementarity in the ability to break down plant substrate may help to stabilize this symbiosis despite horizontal symbiont transmission. An alternative, non-exclusive, hypothesis is that a reduced rate of evolution may contribute to stabilize the symbiosis, the so-called Red King Effect.

Methods

To explore this concept, we produced the first linkage map of a species ofTermitomyces, using genotyping by sequencing (GBS) of 88 homokaryotic offspring. We constructed a highly contiguous genome assembly using PacBio data and a de-novo evidence-based annotation. This improved genome assembly and linkage map allowed for examination of the recombination landscape and its potential effect on the mutualistic lifestyle.

Results

Our linkage map resulted in a genome-wide recombination rate of 22 cM/Mb, lower than that of other related fungi. However, the total map length of 1370 cM was similar to that of other related fungi.

Conclusions

The apparently decreased rate of recombination is primarily due to genome expansion of islands of gene-poor repetitive sequences. This study highlights the importance of inclusion of genomic context in cross-species comparisons of recombination rate.
A simulation and experiential learning intervention for labor and delivery providers to address HIV stigma during childbirth in Tanzania: study protocol for the evaluation of the MAMA intervention
Authors: Watt Melissa H. , Minja Linda M. , Barabara Mariam , Mlay Pendo , Stephens Maya J. , Olomi Gaudensia , Mlay Janeth , Marchand Virginie , Mmbaga Blandina T. , Hanson Olivia R. , Cohen Susanna R.
Published: March 2023

Background

The experience of HIV stigma during intrapartum care can impact women’s trust in the health care system and undermine their long-term commitment to HIV care engagement. Delivery of respectful maternity care (RMC) to women living with HIV (WLHIV) can improve quality of life and clinical outcomes. The goal of this study is to conduct an evaluation of MAMA (Mradi wa Afya ya Mama Mzazi, Project to Support the Health of Women Giving Birth), a simulation team-training curriculum for labor and delivery providers that addresses providers’ instrumental and attitudinal stigma toward WLHIV and promotes the delivery of evidence-based RMC for WLHIV.

Methods

The MAMA intervention will be evaluated among healthcare providers across six clinics in the Kilimanjaro Region of Tanzania. To evaluate the impact of MAMA, we will enroll WLHIV who give birth in the facilities before (n = 103 WLHIV) and after (n = 103 WLHIV) the intervention. We will examine differences in the primary outcome (perceptions of RMC) and secondary outcomes (postpartum HIV care engagement; perceptions of HIV stigma in the facility; internal HIV stigma; clinical outcomes and evidence-based practices) between women enrolled in the two time periods. Will also assess participating providers (n = 60) at baseline, immediate post, 1-month post training, and 2-month post training. We will examine longitudinal changes in the primary outcome (practices of RMC) and secondary outcomes (stigma toward WLHIV; self-efficacy in delivery intrapartum care). Quality assurance data will be collected to assess intervention feasibility and acceptability.

Discussion

The implementation findings will be used to finalize the intervention for a train-the-trainer model that is scalable, and the outcomes data will be used to power a multi-site study to detect significant differences in HIV care engagement.

Trial Registration

The trial is registered at clinicaltrials.gov, NCT05271903.
Self-management system for postpartum women with hypertension disorders: an eHealth application intervention study
Authors: Chang Chung-Wei , Tsai Yi-Jing , Hsu Yu-Yun , Hou Ting-Wei
Published: March 2023

Background

Hypertension disorders are relatively common in pregnant women and often persist in the postpartum period. Few studies are available regarding the self-management of postpartum hypertension via the eHealth system. This study aimed to develop a self-management eHealth system for women with postpartum hypertension during the postpartum period.

Methods

We adopted a multi-platform system for this research, not only for use on the web interface but also on smartphones. The proposed system possessed three features: (1) the population was limited to postnatal women with hypertension; (2) a self-care record, which allowed postnatal women to keep track of their blood pressure, pulse, weight, medication record, exercise record, and risk factor assessment; and (3) through this system, nurse-midwives could keep track of postnatal women’s health status maintaining the complete record and could communicate directly with the users if their health monitor values reach beyond normal range.

Results

Thirty-nine postnatal women with postpartum hypertension were recruited to the study. A survey to evaluate the usability and satisfaction of the proposed e-health application system was completed by these women. The usability rate of the system reached 92.4% (46.2% satisfied and 46.2% strongly satisfied), which suggested that the system was helpful to the users. The satisfaction rate of the system reached 94.9% (43.6% satisfied and 51.3% strongly satisfied), which suggested that the system was acceptable to the users.

Conclusion

This proposed system has been developed completely with user experience and professional advice from experts. Postnatal women could gain important postpartum-related knowledge and access their related health records and other information easily via their smartphones or computers. During the postpartum period, an eHealth application system can effectively assist women with hypertension to manage their blood pressure and related postnatal healthcare issues.
Outcomes and process evaluation of a cluster-randomised participatory organisational intervention among German healthcare workers
Authors: Montano Diego , Kuchenbaur Marco , Peter Richard
Published: March 2023

Background

In the present investigation the results of the outcome and process evaluation of a participatory workplace intervention are reported. The intervention aimed to increase the workers’ self-assessed physical and mental work ability.

Methods

The intervention was a two-arm, cluster-randomised trial with healthcare workers in 10 hospitals and one elderly care centre in Germany. Outcome data on workers were collected in questionnaires at baseline, and two follow-ups between 2019 and 2021. The intervention consisted of interviews and workshops, in which employees proposed measures for reducing the physical and psychosocial load and strengthening resources at work. Outcome data were analysed with linear-mixed regression models. The process evaluation was based on the thematic criteria proposed in previous literature and the collection of the type of intervention measures and their implementation status.

Results

The regression analysis did not provide evidence of treatment differences or reductions of psychosocial load in the intervention wards. The process evaluation suggested that the measures did not address specifically the self-assessed work ability. In addition, there was no indication that the intervention measures were causally related to the intended goals.

Conclusions

The planning and implementation of organisational interventions require a careful consideration of the definition of intervention goals, the theoretical rationale of the intervention and a project-oriented action plan during the delivery phase.
Urip iku urup (life is lit) by service to others: a qualitative study of frontline healthcare workers’ lived experiences providing patient care in Indonesia’s COVID-19-designated hospital
Authors: Ningrum Ayu Puspita , Missel Malene
Published: March 2023

Background

While COVID-19 affects every walk of human life, it especially implicates healthcare workers at the forefront of the pandemic due to their vulnerable involvement in providing first-line treatment. This study presents the lived experiences of frontline healthcare workers serving in Indonesia’s COVID-19-designated hospital, one of the severely afflicted healthcare settings wherein resource challenges, public health crisis, and political constraints intersect as policy conundrums.

Methods

Using a qualitative exploratory-descriptive approach, this study drew on thirteen in-depth, semi-structured interviews with frontline healthcare workers who have experiences providing first-line COVID-19 patient care in the COVID-19 hospital. The data analysis commenced with the verbatim transcription of the interview data, which was then subjected to a systematic thematic analysis employing hermeneutic phenomenological principles.

Results

The exploration of the participants’ accounts reveals eight interconnected themes: facing resource scarcity and resignation; experiencing service-induced burnout due to occupational workload; encountering fears of being infected and infecting others; engaging in positivity through social connectedness; having dilemmas over healthcare rationing; developing negative emotions during patient interactions; coping through spirituality and religiosity; and embodying a life of service.

Conclusion

Managing healthcare in resource-limited, crisis settings presents multifaceted challenges that exceed mere structural modifications, requiring prioritized public health investment to ensure optimal patient care. Therefore, healthcare policy development and implementation should equally emphasize the well-being of frontline healthcare workers to foster sustainable healthcare delivery and achieve improved patient outcomes.
The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial
Authors: Tang Lin-Quan , Li Xiao-Yun , Li Zhi-Ming , Liu Zhi-Gang , Lin Miao-Zhen , Zhou Huan , Yu Qi-Wen , Zhou Jian , Zhao Chong , Chen Ze-Bin , Wang Xi-Cheng , Peng Jia-Yu , Chen Qiu-Yan , Fang Wen-Feng , Yang Yun-Peng , Zhang Bei , Xia Liang-Ping , Hu Pi-Li , Hu Wei-Han , Li Yi-Jie , Mai Hai-Qiang , Cai Xiu-Yu
Published: March 2023

Background

Previous studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy.

Methods

In this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon’s two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1–14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.

Results

We enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1–52.1) and 85.9% (95% CI, 75.0–93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8–21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0–10.0) and the median OS was 15.7 months (95% CI, 11.3–20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3–4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed.

Conclusions

Apatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity.

Trial registration

Chi-CTR1800017229.
Engaging early career researchers in a global health research capacity-strengthening programme: a qualitative study
Authors: Hawcroft Claire , Rossi Evelina , Tilouche Nerissa , d’Oliveira Ana Flavia , Bacchus Loraine J.
Published: March 2023

Background

Research capacity-strengthening is recognized as an important component of global health partnership working, and as such merits monitoring and evaluation. Early career researchers are often the recipients of research capacity-strengthening programmes, but there is limited literature regarding their experience.

Methods

We conducted a qualitative study as part of an internal evaluation of the capacity-strengthening programme of the international HERA (HEalthcare Responding to violence and Abuse) research group. Semi-structured interviews were conducted with group members, and thematic analysis was undertaken.

Results

Eighteen group members participated; nine of these were early career researchers, and nine were other research team members, including mid-career and senior researchers. Key themes were identified which related to their engagement with and experience of a research capacity-strengthening programme. We explored formal/planned elements of our programme: mentoring and supervision; training and other opportunities; funding and resources. Participants also discussed informal/unplanned elements which acted as important facilitators and/or barriers to engaging with research capacity-strengthening: English language; open relationships and communication; connection and disconnection; and diversity. The sustainability of the programme was also discussed.

Conclusions

Our study gives voice to the early career researcher experience of engaging with a research capacity-strengthening programme in a global health group. We highlight some important elements that have informed adaptations to our programme and may be relevant for consideration by other global health research capacity-strengthening programmes. Our findings contribute to the growing literature and important discussions around research capacity-strengthening and how this relates to the future directions of global health partnership working.
NOMe-HiC: joint profiling of genetic variant, DNA methylation, chromatin accessibility, and 3D genome in the same DNA molecule
Authors: Fu Hailu , Zheng Haizi , Chen Xiaoting , Weirauch Matthew T. , Muglia Louis J. , Wang Li , Liu Yaping
Published: March 2023

Cis-regulatory elements are coordinated to regulate the expression of their targeted genes. However, the joint measurement of cis-regulatory elements’ activities and their interactions in spatial proximity is limited by the current sequencing approaches. We describe a method, NOMe-HiC, which simultaneously captures single-nucleotide polymorphisms, DNA methylation, chromatin accessibility (GpC methyltransferase footprints), and chromosome conformation changes from the same DNA molecule, together with the transcriptome, in a single assay. NOMe-HiC shows high concordance with state-of-the-art mono-omic assays across different molecular measurements and reveals coordinated chromatin accessibility at distal genomic segments in spatial proximity and novel types of long-range allele-specific chromatin accessibility.
Verification of prognostic expression biomarkers is improved by examining enriched leukemic blasts rather than mononuclear cells from acute myeloid leukemia patients
Authors: Pogosova-Agadjanyan Era L. , Hua Xing , Othus Megan , Appelbaum Frederick R. , Chauncey Thomas R. , Erba Harry P. , Fitzgibbon Matthew P. , Jenkins Isaac C. , Fang Min , Lee Stanley C. , Moseley Anna , Naru Jasmine , Radich Jerald P. , Smith Jenny L. , Willborg Brooke E. , Willman Cheryl L. , Wu Feinan , Meshinchi Soheil , Stirewalt Derek L.
Published: March 2023

Background

Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers.

Methods

To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes.

Results

Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells.

Conclusions

This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.
RTiSR: a review-driven time interval-aware sequential recommendation method
Authors: Shi Xiaoyu , Liu Quanliang , Bai Yanan , Shang Mingsheng
Published: March 2023

The emerging topic of sequential recommender (SR) has attracted increasing attention in recent years, which focuses on understanding and learning the sequential dependencies of user behaviors hidden in the user-item interactions. Previous methods focus on capturing the point-wise sequential dependencies with considering the time evenly spaced. However, in the real world, the time and semantic irregularities are hidden in the user’s successive actions. Meanwhile, with the tremendous increase of users and items, the hardness of modeling user interests from spare explicit feedback. To this end, we seek to explore the influence of item-aspect reviews sequence with varied time intervals on sequential modeling. We present RTiSR, a review-driven time interval-aware sequential recommendation framework, to predict the user’s next purchase item by jointly modeling the sequence dependencies from aspect-aware reviews. The main idea is twofold: (1) explicitly learning user and item representation from reviews by assigning different weights, and (2) leveraging a hybrid neural network to capture the collective sequence patterns with a flexible order from aspect-aware review sequences. We conduct extensive experiments on industrial datasets to evaluate the effectiveness of RTiSR. Experimental results demonstrate the superior performance of RTiSR in different evaluation metrics, compared to the state-of-the-art competitors.
Plugged-in electric vehicle-assisted demand response strategy for residential energy management
Authors: Alfaverh Khaldoon , Alfaverh Fayiz , Szamel Laszlo
Published: March 2023

Demand response (DR) management systems are a potentially growing market due to their ability to maximize energy savings by allowing customers to manage their energy consumption at times of peak demand in response to financial incentives from the electricity supplier. Successful execution of a demand response program requires an effective management system where the home energy management system (HEMS) is a promising solution nowadays. HEMS is developed to manage energy use in households and to conduct the management of energy supply, either from the grid or the alternative energy sources like solar or wind power plants. With the increase of vehicle electrification, in order to achieve a more reliable and efficient smart grid (SG), cooperation between electric vehicles (EVs) and residential systems is required. This cooperation could involve not only vehicle to grid (V2G) operation but a vehicle to home (V2H) too. V2H operation is used to transfer the power and relevant data between EVs and residential systems. This paper provides an efficient HEMS enhanced by smart scheduling and an optimally designed charging and discharging strategy for plugged-in electric vehicles (PEVs). The proposed design uses a fuzzy logic controller (FLC) for smart scheduling and to take the charging (from the grid)/discharging (supply the household appliances) decision without compromising the driving needs. Simulations are presented to demonstrate how the proposed strategies can help to reduce electricity costs by 19.28% and 14.27% with 30% and 80% state of charge (SOC) of the PEV respectively compared to the case where G2V operation only used along with the photovoltaic (PV) production, improve energy utilization by smoothing the energy consumption profile and satisfy the user’s needs by ensuring enough EV battery SOC for each planned trip.
Angelica herbal supplement AGN-CognI.Q acute dose safety and pharmacokinetics (PK) dose-response in patients with prostate cancer (PK Dose Trial).
Authors: Joshi Monika , Raman Jay D. , Liu Xin , Shank Doris , Schell Todd D. , Liao Jiangang Jason , Lu Junxuan
Published: March 2023

TPS404

Background: There are currently no FDA approved modalities for intercepting biochemically recurrent prostate cancer (PCa) after standard of care surgery and radiation therapies to delay or prevent the need of androgen deprivation therapy (ADT) for localized disease. Preclinical modeling has suggested herbal alcoholic extracts of Angelica gigas Nakai (AGN) root, their signature pyranocoumarins and metabolite decursinol, as potential novel modalities to address this unmet clinical need. We hypothesize that CognI.Q at the higher doses has an acceptable safety profile in prostate cancer patients and pharmacokinetics (PK) exposure metrics will be increased proportional to dose increment. Methods: This is a single institution, phase 1 PK study, N=12. Primary objective- PK, pharmacodynamic (PD) biomarkers with a single ascending dose (SAD)-PK response design. After a subject is enrolled, a 14-day gap must occur before the next subject can be enrolled. If one subject develops a dose limiting toxicity (DLT) at any dose level, that subject will stop participation; If a 2nd subject develops DLT at the same dose level, the trial will be stopped, and the dose level below will be the maximum tolerated dose (MTD). Any subject at a higher dose level at the time of occurrence of 2nd DLT will also stop participation. All subjects will initially start at the 800 mg x 1dose, with further single dose escalation to 1200mg, 1600mg, 2000mg doses of AGN-CognI.Q; each dose will be 1-2 weeks apart. Inclusion criteria: Treated PCa, not on ADT; no active cancer. Subjects will be assessed for safety- clinical, labs (CBC, CMP, baseline and after 24hrs) and EKGs. PK blood will be taken at hourly intervals from 2-7hrs and 24hrs. Plasma pyranocoumarin content will be measured by LC-MS. Immunophenotyping of NK and T cell subtypes will be assessed at baseline and 24 h. Primary Endpoint: MTD. Secondary Endpoint: PK metrics; genotype CYP 2C19 and 3A4 metabolizer status and explore relationship to PK metrics and safety metrics; NK and inflammatory and immune cytokines as PD biomarkers. Trial is now open to accrual (Clinical trial registration NCT05375539). We anticipate that the acute dose safety and PK/PD information will inform the optimal design and execution of the longer-term safety and efficacy (phase I/II) trials. Research Support: MPI 1R01CA260901-01A. Clinical trial information: Clinical trial registration NCT05375539 .
Pathway Alterations in Stage II/III Primary Melanoma
Authors: Kostrzewa Caroline E. , Luo Li , Arora Arshi , Seshan Venkatraman E. , Ernstoff Marc S. , Edmiston Sharon N. , Conway Kathleen , Gorlov Ivan , Busam Klaus , Orlow Irene , Hernando-Monge Eva , Thomas Nancy E. , Berwick Marianne , Begg Colin B. , Shen Ronglai ,   for InterMEL
Published: March 2023

PURPOSE

Genomic classification of melanoma has thus far focused on the mutational status of BRAF, NRAS, and NF1. The clinical utility of this classification remains limited, and the landscape of alterations in other oncogenic signaling pathways is underexplored.

METHODS

Using primary samples from the InterMEL study, a retrospective cohort of cases with specimens collected from an international consortium with participating institutions throughout the United States and Australia, with oversampling of cases who ultimately died of melanoma, we examined mutual exclusivity and co-occurrence of genomic alterations in 495 stage II/III primary melanomas across 11 cancer pathways. Somatic mutation and copy number alterations were analyzed from next-generation sequencing using a clinical sequencing panel.

RESULTS

Mutations in the RTK-RAS pathway were observed in 81% of cases. Other frequently occurring pathways were TP53 (31%), Cell Cycle (30%), and PI3K (18%). These frequencies are generally lower than was observed in The Cancer Genome Atlas, where the specimens analyzed were predominantly obtained from metastases. Overall, 81% of the cases had at least one targetable mutation. The RTK-RAS pathway was the only pathway that demonstrated strong and statistically significant mutual exclusivity. However, this strong mutual exclusivity signal was evident only for the three common genes in the pathway ( BRAF, NRAS, and NF1). Analysis of co-occurrence of different pathways exhibited no positive significant trends. However, interestingly, a high frequency of cases with none of these pathways represented was observed, 8.4% of cases versus 4.0% expected ( P < .001). A higher frequency of RTK-RAS singletons (with no other pathway alteration) was observed compared with The Cancer Genome Atlas. Clonality analyses suggest strongly that both the cell cycle and RTK-RAS pathways represent early events in melanogenesis.

CONCLUSION

Our results confirm the dominance of mutations in the RTK-RAS pathway. The presence of many mutations in several well-known, actionable pathways suggests potential avenues for targeted therapy in these early-stage cases.
105 Value of Atlas-Based Data and Intraoperative Testing in Deep Brain Stimulation
Authors: Paulo Danika Lea , Narasimhan Saramati , Gonzalez Hernan F. J. , Allen Jackson , Li Rui , Rodriguez William , Konrad Peter , Neimat Joseph , Shah Hamid M. , Bick Sarah K. B. , Dawant Benoit M. , Englot Dario J.
Published: March 2023

INTRODUCTION:

Deep brain stimulation (DBS) is commonly performed awake to collect intraoperative microelectrode recordings (MER) and macrostimulation to optimize efficacy and minimize side effects (Bour et al, 2010). With supplementary information from an atlas-based database (CranialVault), efficacy heat maps guide initial targeting, intraoperative final electrode position (FEP) selection and post-operative programming (D’Haese et al, 2012). A better understanding of how this data is integrated to inform all stages of DBS can assist in reducing OR time, optimizing electrode position, expediting programming, and enhancing patient outcomes.

METHODS:

451 individual patients who underwent DBS for Parkinson’s Disease, Essential Tremor or Dystonia, treated with 822 individual leads, at Vanderbilt University Medical Center between 2011-2021 were included. Intraoperative testing data including MER firing rate, macrostimulation efficacy and coordinates of FEP were retrieved from the CranialVault database. Average coordinates of planned target, midpoint and bottom of FEP, active contact and centroid of heat maps per target in patient space were calculated and visualized. Medical charts were reviewed for 1-year post-operative outcomes.

RESULTS:

The distribution of FEPs per target include 55.2% of leads placed in center track. Average coordinates in patient space of planned target, centroid of heatmap, midpoint and bottom of FEP and active contact were recorded. MER data demonstrates how multiunit activity changes at different depths relative to target, per target. Patients who achieve 4th quartile efficacy intraoperatively are more likely to achieve maximal benefit at 1-year post-op (p = 0.003, chi-squared).

CONCLUSIONS:

Atlas-based data and intraoperative testing is valuable, often leads to changes in FEP and can predict post-operative outcomes.
112 RNA Sequencing Analysis of Endothelium in a Patient-Specific Intracranial Aneurysm Model
Authors: Samarage Hasitha Milan , Kaneko Naoki
Published: March 2023

INTRODUCTION:

Ruptured intracranial aneurysms are responsible for 5-10% of all strokes yet can carry a mortality rate as high as 50%. The growth and rupture of aneurysms is a consequence of complex arterial wall remodeling resulting from complex interactions between cellular biological processes

METHODS:

A total of eight aneurysm casts were created from patients’ 3D rotational angiographic data in our institution's database. Models represented two morphologies (bifurcation and sidewall aneurysms), four locations (middle cerebral artery bifurcation, basilar tip bifurcation, internal cerebral artery-posterior communicating artery sidewall, internal cerebral artery-superior hypophyseal artery sidewall), and two clinical conditions (stable aneurysms and growing aneurysms). The lumen were coated with fibronectin, connected to a pump infusing a cell suspension of HUVEC cells. After culturing to achieve confluence, specimens from the aneurysm and parent artery were separately cut to extract RNA used for sequencing.

RESULTS:

A total of 358 DEGs were identified between aneurysm and parent vessel, 222 DEGs were identified between sidewall and bifurcation aneurysm morphologies and 20437 DEGs were identified between growing and stable aneurysms. Genes such as SYNPO, CHSY3 ALKBH8 were found to be upregulated in endothelial cells within the aneurysms while genes such as FABP4, ANGPT2, SMAD6 and ADAMTS18 were found to be downregulated in comparison with endothelial cells within the parent artery. SERPINB6 was found to be upregulated and FOXN2 was found to be downregulated in growing aneurysms compared to stable aneurysms.

CONCLUSIONS:

We demonstrate the successful development of a patient specific, in-vitro pulsatile intracranial aneurysm cell culture model which can be used to study the complex interactions of endothelial cell biology, specifically the unique transcriptomic profiles of various endothelial cell populations that are subject to varying hemodynamic conditions based on location within the vasculature
125 Survival Analysis by Molecular Subtype for Surgically Treated Breast Cancer Spine Metastases
Authors: Duvall Julia , Massaad Elie , Fourman Mitchell , Siraj Layla , Shankar Ganesh , Shin John H. , Kiapour Ali
Published: March 2023

INTRODUCTION:

Breast cancer spine metastases are a devastating and pervasive clinical problem. Discoveries in tumor biology and the pathophysiology of metastatic disease have expanded systemic treatment options for metastatic breast cancer. The implications of evolving treatment strategies should inform the surgical treatment of spine metastases and the predicted prognosis to guide personalized approaches.

METHODS:

This is a multi-institutional, retrospective, observational cohort study of patients who underwent spine surgery for symptomatic breast cancer spine metastases from 2008-2020. We studied overall survival, stratified by breast cancer molecular subtype and calculated hazard ratios adjusting for demographics, tumor characteristics, treatments, and laboratory values. We tested the performance of established models (Tokuhashi, Bauer, SORG, NESMS) to predict and compare all-cause mortalities using time-dependent performance metrics.

RESULTS:

A total of 98 patients surgically treated for breast cancer spine metastases were identified. The 1-year probabilities of survival for HR+, HR+/HER2+, HER2+, and TNBC were 63%, 83%, 0%, and 12% (P <0.001). Postoperative chemotherapy and endocrine therapy were associated with prolonged survival. The SORG prognostic model had the highest discrimination. The performance of all prognostic scores improved when preoperative molecular data was considered in addition to postoperative systemic treatment data.

CONCLUSIONS:

Advanced HR+, HR+/HER2+ breast cancer portended significantly longer overall survival compared with HER2+ and TNBC tumors after surgery for symptomatic spine metastases. Hormone receptor status and postoperative systemic therapy should be considered in prediction models for a more accurate assessment of prognosis.
126 Objective Functional Outcome Measures Expose Relevant Ceiling Effects Inherent to Subjective Patient-Reported Outcome Measures in Patients Undergoing Surgery for Lumbar Degenerative Disorders
Authors: Maldaner Nicolai , Zeitlberger Anna , Ziga Michal , Bozinov Oliver , Regli Luca , Stienen Martin N.
Published: March 2023

INTRODUCTION:

Patient-reported outcome measures (PROMs) may be subject to relevant floor and ceiling effects which may induce substantial bias to the outcome assessment after spine surgery.

METHODS:

In a prospective study, 50 patients were assessed preoperatively, 6-weeks and 3-months postoperatively for objective functional impairment using the smartphone-based 6-minute walking test (6WT) as well as a set of widely used PROMs. Paired sample t-tests were used to establish significant difference between the changes in raw 6-minute walking distance (6WD) and PROMs at baseline, 6-weeks and 3-months follow-up. Floor and ceiling effect were considered present if >15% achieved the worst and best status. Pearson correlation coefficients were used to define the relationship between 6WT and PROMs at 6-weeks and 3-months.

RESULTS:

The mean 6WD improved from 377 m preoperative to 490 m and 517 m at 6-weeks and 3-months follow-up (p < 0,05). While all PROMs improved from pre- to six-week postoperative, no significant improvement was observed beyond the 6-weeks follow up in the Core Outcome Measure Index (COMI), the Zurich Claudication Questionnaire (ZCQ) Symptoms Severity Scale, the ZCQ Physical Performance Scale, VAS Back and Leg pain. A ceiling effect was observed for the COMI, the ZCQ Symptoms Severity Scale, the ZCQ Physical Performance Scale, VAS back and VAS leg pain in 2%, 4%, 24%, 20% and 16% of patient at the 6-weeks follow up. Correlation between the 6WD and PROMs significantly increased from the 6-weeks to 12-weeks follow up.

CONCLUSIONS:

PROMs reach their best possible score in a relevant number of patients early after surgery for DLD while objective functional outcome continues to improve beyond the 6-weeks follow-up. Objective measures of function may expose relevant ceiling effects observed by PROMs and describe the continued recovery of patient.
127 Modeling Traumatic Brain Injury Using Human Cerebral Organoids
Authors: Tallat Ahmed Mohamed , Beltrán Susana , Bobo Justin , Kodavali Chowdari , Edwards Lincoln , LeDuc Philip , Zinn Pascal O.
Published: March 2023

INTRODUCTION:

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. The ability to model pathophysiological processes through 3D cultures systems may enable new treatments while eliminating the need for animal and human testing. Advances in 3D cell culture systems have resulted in the generation of human cerebral organoids, which to a great extent recapitulate key neural cytoarchitectural features. We currently have no in-vitro human TBI model.

METHODS:

We generated cerebral organoids from human embryonic stem cells. After maturation, the organoids were subjected to a custom-designed Mechanical Excitation Testbed (MET) that delivered compressed the organoid with controlled strain rates and strain for a given number of pulses. We investigated the repercussions of organoid compression by assessing the neuronal function, calcium signaling, and morphological changes, electrophysiology, real-time calcium imaging, and immunohistochemistry. Molecular and gene ontology analysis was also performed using RNA-seq and Ingenuity Pathway Analysis/Gene Set Enrichment.

RESULTS:

Our results demonstrated significant real-time calcium signaling upregulation and altered neuronal activity consistent with TBI severity. Moreover, RNA-seq data demonstrate unsupervised clustering of gene activity of moderate and severe TBI. Furthermore, gene enrichment analysis identified 3 key genes ENO1, CARD9, and FOXP3 which are associated with neuronal development, regulation of cellular apoptosis & IL-17 mediated inflammation pathway, and immunoregulation of T-cells respectively. Finally, TBI response pathways were identified involving stromal elasticity, and extracellular matrix, consistent with TBI.

CONCLUSIONS:

This in-vitro brain organoid TBI model shows strong phenotypic and genetic similarities with TBI patients. Furthermore, This novel TBI model could provide a basis for a high-throughput personalized patient-less model that could be used to study TBIs and test potential therapeutic modalities.
129 Genetically Engineered Exosomes Derived From Mesenchymal Stromal Cells Promote Functional and Structural Recovery in Rats After Traumatic Brain Injury
Authors: Mahmood Asim , Zhang Yanlu , Zhang Yi , Chopp Michael , Xiong Ye
Published: March 2023

INTRODUCTION:

Previous studies have demonstrated that multi-potent mesenchymal stromal cell (MSC)-derived exosomes improve functional recovery after experimental traumatic brain injury (TBI). Our present research focuses on augmenting the beneficial effects of exosomes by transfecting them with microRNAs.

METHODS:

Adult male rats were injured with controlled cortical impact. Animals received a single intravenous injection of MiR-17-92 cluster-enriched exosomes (100 µg/rat) or control exosomes (100 µg/rat) or Vehicle (phosphate-buffered solution) one day after injury. A battery of neurological functional tests was performed after TBI. Spatial learning and memory were measured using the Morris water maze test. All animals were sacrificed five weeks after injury. Their brains were processed for histopathological and immunohistochemical analysis of cell loss, angiogenesis, neurogenesis, and neuroinflammation.

RESULTS:

Compared with control, both Exo-17-92 and Exo-empty treatments significantly improved sensorimotor and cognitive function, reduced neuroinflammation and hippocampal neuronal cell loss, and promoted angiogenesis and neurogenesis (p < 0.05). Moreover, Exo-17-92 treatment exhibited a significantly more robust effect in improving functional recovery and in reducing cell loss, and enhancing angiogenesis and neurogenesis compared to Exo-empty treatment (p<0.05).

CONCLUSIONS:

Exosomes enriched with miR-17-92 cluster have a significantly better effect on improving functional recovery after TBI compared with Exo-empty treatment, likely by enhancing endogenous angiogenesis and neurogenesis. Engineering specific miRNA in exosomes may provide a novel therapeutic strategy for the management of TBI.