tbuckley/cabot-search huggingface dataset:
Late mortality and chronic health conditions in long-term survivors of early-adolescent and young adult cancers: a retrospective cohort analysis from the Childhood Cancer Survivor Study
Authors: Eugene Suh, Kayla L Stratton, Wendy M Leisenring, Paul C Nathan, Jennifer S Ford, David R Freyer, Jennifer L McNeer, Wendy Stock, Marilyn Stovall, Kevin R Krull, Charles A Sklar, Joseph P Neglia, Gregory T Armstrong, Kevin C Oeffinger, Leslie L Robison, Tara O Henderson
Journal: The Lancet Oncology (2020)
Patient and Hospital Factors Associated With Unexpected Newborn Complications Among Term Neonates in US Hospitals
Authors: Mark A. Clapp, Kaitlyn E. James, Sara V. Bates, Anjali J. Kaimal
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Unexpected complications in term newborns have been recently adopted by the Joint Commission as a marker of obstetric care quality. <h3>Objective</h3> To understand the variation and patient and hospital factors associated with severe unexpected complications in term neonates among hospitals in the United States. <h3>Design, Setting, and Participants</h3> This cross-sectional study collected data from all births in US counties with 1 obstetric hospital using county-identified birth certificate data and American Hospital Association annual survey data from January 1, 2015, through December 31, 2017. All live-born, term, singleton infants weighing at least 2500 g were included. The data analysis was performed from December 1, 2018, through June 30, 2019. <h3>Exposures</h3> Severe unexpected newborn complication, defined as neonatal death, 5-minute Apgar score of 3 or less, seizure, use of assisted ventilation for at least 6 hours, or transfer to another facility. <h3>Main Outcomes and Measures</h3> Between-hospital variation and patient and hospital factors associated with unexpected newborn complications. <h3>Results</h3> A total of 1 754 852 births from 576 hospitals were included in the analysis. A wide range of hospital complication rates was found (range, 0.6-89.9 per 1000 births; median, 15.3 per 1000 births [interquartile range, 9.6-22.0 per 1000 births]). Hospitals with high newborn complication rates were more likely to care for younger, white, less educated, and publicly insured women with more medical comorbidities compared with hospitals with low complication rates. In the adjusted models, there was little effect of case mix to explain the observed between-county variation (11.3%; 95% CI, 10.0%-12.6%). Neonatal transfer was the primary factor associated with complication rates, especially among hospitals with the highest rates (66.0% of all complications). The risk for unexpected neonatal complication increased by more than 50% for those neonates born at hospitals without a neonatal intensive care unit compared with those with a neonatal intensive care unit (adjusted odds ratio, 1.55; 95% CI, 1.38-1.75). <h3>Conclusions and Relevance</h3> In this study, severe unexpected complication rates among term newborns varied widely. When included in the metric numerator, neonatal transfer was the primary factor associated with complications, especially among hospitals with the highest rates. Transfers were more likely to be necessary when infants were born in hospitals with lower levels of neonatal care. Thus, if this metric is to be used in its current form, it would appear that accreditors, regulatory bodies, and payers should consider adjusting for or stratifying by a hospital’s level of neonatal care to avoid disincentivizing against appropriate transfers.
Abstract P6-14-06: Prepectoral direct to implant reconstruction following nipple sparing mastectomy using the TiLOOP bra pocket
Authors: Marc Thill, Viviane van Haasteren, Katharina Kelling
Journal: Cancer Research (2020)

Abstract Aim: Evaluation of safety, cosmetic outcome and patients satisfaction following nipple sparing mastectomy with prepectoral direct to implant reconstruction using the TiLOOP® Bra Pocket. Background: TiLOOP® Bra Pocket is a new surgical tool consisting of a large-pore, non-absorbable synthetic mesh made from titanized monofilament polypropylene thread. It is used for immediate prepectoral implant reconstruction to fix the implant on the pectoralis major muscle and to avoid implant rotation. Material and methodes: Between October 2017 and February 2019, 57 patients underwent nipple sparing mastectomy in the certified breast cancer centre, at the AGAPLESION Markus Hospital, Frankfurt, Germany. Data was collected in a prospective registry. All of the patients underwent a prepectoral direct to implant reconstruction using the new TiLOOP® Bra Pocket. We present the first analysis of this prospective unicentric registry. To measure and to analyse the cosmetic outcome and patients’ satisfaction, the BREAST-Q questionnaire was used, an established modular questionnaire to assess patient reported outcome (PRO). Results: All of the 57 patients were available for postoperative analysis. In 35/57 (61%) of the cases a seroma occured and was worth to be punctured. The median number of punctures was 4. The volume was 70 ml in average. Seven patients had a postoperative hematoma and had to undergo another surgical procedure. Three patients developed a skin necrosis or severe wound healing problem due to bad quality of the soft tissue and skin mantle and had to undergo implant explantation. One patient suffered from implant infection but could be treated conservatively. The analysis of patients’ reported outcome via the BREAST-Q resulted in a high satifaction rate regarding the cosmetic outcome. Conclusion: Direct to implant reconstruction with prepectoral implant position by using the TiLOOP® Bra Pocket is a very promising surgical approach. In comparison to a subpectoral implant reconstruction it reduces the duration of surgery, avoids a jumping breast phenomenon and causes less postoperative pain, moreover, it leeds to a high patient satisfaction rate and shows a moderate complication rate. Follow up of our patients will continue. The next analysis will be done after 24 months. Citation Format: Marc Thill, Viviane van Haasteren, Katharina Kelling. Prepectoral direct to implant reconstruction following nipple sparing mastectomy using the TiLOOP bra pocket [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-14-06.
Contribution of Intellectual Disability–Related Genes to ADHD Risk and to Locomotor Activity in <i>Drosophila</i>
Authors: Marieke Klein, Euginia L. Singgih, Anne van Rens, Ditte Demontis, Anders D. Børglum, Nina Roth Mota, Anna Castells-Nobau, Lambertus A. Kiemeney, Han G. Brunner, Alejandro Arias-Vasquez, Annette Schenck, Monique van der Voet, Barbara Franke
Journal: American Journal of Psychiatry (2020)

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster. Methods: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. Results: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. Conclusions: This study reveals that a large set of intellectual disability–related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.
Functional Differences Between EBV‐ and CMV‐Specific CD8<sup>+</sup> T cells Demonstrate Heterogeneity of T cell Dysfunction in CLL
Authors: Tom Hofland, Iris de Weerdt, Sanne Endstra, Aldo Jongejan, Laura Platenkamp, Ester B.M. Remmerswaal, Perry D. Moerland, Ineke J.M. ten Berge, Mark‐David Levin, Arnon P. Kater, Sanne H. Tonino
Journal: HemaSphere (2020)

Acquired T cell dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and is linked to an increased risk of infections, but also reduced immune surveillance and disappointing responses to autologous T cell-based immunotherapy. The mechanisms of T cell dysfunction in CLL are not well understood. Studying immunity against chronic viruses allows for detailed analysis of the effect of CLL on T cells chronically exposed to a specific antigen. Cytomegalovirus (CMV) reactivations are rare in CLL, which corroborates with preserved CMV-specific T cell function. Epstein-Barr virus (EBV) is another herpesvirus that results in chronic infection, but unlike CMV, is characterized by subclinical reactivations in CLL patients. Since both herpesviruses induce strong CD8+ T cell responses, but have different clinical outcomes, studying these specific T cells may shed light on the mechanisms of CLL-induced T cell dysfunction. We first analyzed the phenotype of EBV-specific CD8+ T cells in CLL and healthy controls, and found that in CLL EBV-specific CD8+ T cells are in an advanced differentiation state with higher expression of inhibitory receptors. Secondly, CLL-derived EBV-specific CD8+ T cells show reduced cytotoxic potential, in contrast to CMV-specific T cells. Finally, we performed transcriptome analysis to visualize differential modulation by CLL of these T cell subsets. While T cell activation and differentiation genes are unaffected, in EBV-specific T cells expression of genes involved in synapse formation and T cell exhaustion is altered. Our findings on the heterogeneity of antigen specific T cell function in CLL aids in understanding immune-dysregulation in this disease.
New Therapeutic Strategies for Asthma
Authors: Edward M. Zoratti, George T. O’Connor
Journal: JAMA (2020)

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Abstract P4-06-10: Lentiviral signaling reporters uncover tumor-initiating cell heterogeneity in breast cancer patient-derived xenografts
Authors: John Landua, Ping Gong, Michael Lewis
Journal: Cancer Research (2020)

Abstract Classical markers of tumor-initiating cells (TIC), aldehyde dehydrogenase 1 (ALDH1) activity and the cell-surface markers, CD44pos/CD24low/neg, show insufficient cell type specificity to identify TIC definitively, nor do they allow robust enrichment by FACS. As a consequence, analyses of TIC function and gene expression to date are not definitive. Identification and characterization of the TIC subpopulation is critically important in breast cancer since these cells are thought to mediate treatment resistance, as well as local and distant recurrence. This is particularly critical for “triple negative” breast cancer (TNBC), since currently there are no targeted therapies available for this clinical subtype. Lentiviral signaling reporter vectors allow purification of enriched TIC subpopulations thereby facilitating single cell analyses to identify distinct sets of cells with TIC features. We used a collection of fluorescent lentiviral reporters that enable visualization and flow cytometric enrichment of cells undergoing STAT3-, GLI-, WNT-, or OCT4/SOX2-mediated transcriptional activity. Our collection of patient derived xenograft (PDX) models of TNBC were infected with the lentiviral reporters, re-transplanted, and screened for reporter activity upon regrowth. TIC function of reporter-expressing cells relative to negative cells was assayed by mammosphere formation and limiting dilution transplantation. Reporter expressing cells with enriched TIC function were then analyzed by single cell RNAseq for expression of classical markers to identify the subset of cells most likely to represent the TIC subpopulation. Our results indicate that STAT3 and GLI transcriptional activity can serve as uniquely PDX-dependent indicators for TIC function for a subpopulation of cancer cells. Also, multiple potential TIC signaling pathways, including STAT3, GLI, and OCT4/SOX2, can be active in a single PDX model, but do not necessarily associate with TIC function, indicating TIC diversity in TNBC. These data in conjunction with treatment response and single-cell RNA-seq sheds light on the molecular diversity of TIC populations in TNBC, identifies candidate targets for therapeutic intervention, and will indicate whether TIC diversity is associated with differential response to different chemotherapeutic agents. Citation Format: John Landua, Ping Gong, Michael Lewis. Lentiviral signaling reporters uncover tumor-initiating cell heterogeneity in breast cancer patient-derived xenografts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-10.
Evaluation of the tumor-targeting efficiency and intratumor heterogeneity of anticancer drugs using quantitative mass spectrometry imaging
Authors: Jin Zhang, Qianqian Du, Xiaowei Song, Shanshan Gao, Xuechao Pang, Yan Li, Ruiping Zhang, Zeper Abliz, Jiuming He
Journal: Theranostics (2020)

The development of improved or targeted drugs that discriminate between normal and tumor tissues is the key therapeutic issue in cancer research.However, the development of an analytical method with a high accuracy and sensitivity to achieve quantitative assessment of the tumor targeting of anticancer drugs and even intratumor heterogeneous distribution of these drugs at the early stages of drug research and development is a major challenge.Mass spectrometry imaging is a label-free molecular imaging technique that provides spatial-temporal information on the distribution of drugs and metabolites in organisms, and its application in the field of pharmaceutical development is rapidly increasing.Methods: The study presented here accurately quantified the distribution of paclitaxel (PTX) and its prodrug (PTX-R) in whole-body animal sections based on the virtual calibration quantitative mass spectrometry imaging (VC-QMSI) method, which is label-free and does not require internal standards, and then applied this technique to evaluate the tumor targeting efficiency in three treatment groups-the PTX-injection treatment group, PTX-liposome treatment group and PTX-R treatment group-in nude mice bearing subcutaneous A549 xenograft tumors.Results: These results indicated that PTX was widely distributed in multiple organs throughout the dosed body in the PTX-injection group and the PTX-liposome group.Notably, in the PTX-R group, both the prodrug and metabolized PTX were mainly distributed in the tumor tissue, and this group showed a significant difference compared with the PTX-liposome group, the relative targeting efficiency of PTX-R group was increased approximately 50-fold, leading to substantially decreased systemic toxicities.In addition, PTX-R showed a significant and specific accumulation in the poorly differentiated intratumor area and necrotic area. Conclusion:This method was demonstrated to be a reliable, feasible and easy-to-implement strategy to quantitatively map the absorption, distribution, metabolism and excretion (ADME) of a drug in the whole-body and tissue microregions and could therefore evaluate the tumor-targeting efficiency of anticancer drugs to predict drug efficacy and safety and provide key insights into drug disposition and mechanisms of action and resistance.Thus, this strategy could significantly facilitate the design and optimization of drugs at the early stage of drug research and development.
Kellner’s Symptom Questionnaire, a Highly Sensitive Patient-Reported Outcome Measure: Systematic Review of Clinimetric Properties
Authors: Giada Benasi, Giovanni A. Fava, Chiara Rafanelli
Journal: Psychotherapy and Psychosomatics (2020)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Patient-reported outcomes (PROs) are of increasing importance in clinical medicine. However, their evaluation by classic psychometric methods carries considerable limitations. The clinimetric approach provides a viable framework for their assessment. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; The aim of this paper was to provide a systematic review of clinimetric properties of the Symptom Questionnaire (SQ), a simple, self-rated instrument for the assessment of psychological symptoms (depression, anxiety, hostility, and somatization) and well-being (contentment, relaxation, friendliness, and physical well-being). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; The PRISMA guidelines were used. Electronic databases were searched from inception up to March 2019. Only original research articles, published in English, reporting data about the clinimetric properties of the SQ, were included. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; A total of 284 studies was selected. The SQ has been used in populations of adults, adolescents, and older individuals. The scale significantly discriminated between subgroups of subjects in both clinical and nonclinical settings, and differentiated medical and psychiatric patients from healthy controls. In longitudinal studies and in controlled pharmacological and psychotherapy trials, it was highly sensitive to symptoms and well-being changes and discriminated between the effects of psychotropic drugs and placebo. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The SQ is a highly sensitive clinimetric index. It may yield clinical information that similar scales would fail to provide and has a unique position among the PROs that are available. Its use in clinical trials is strongly recommended.
Contribution of Genome-Wide Significant Single Nucleotide Polymorphisms in Myopia Prediction
Authors: Yanxian Chen, Xiaotong Han, Xiaobo Guo, Yonghui Li, Jonathan Lee, Mingguang He
Journal: Ophthalmology (2019)

To determine the added predictive ability of genome-wide significant single nucleotide polymorphisms (SNPs) in refraction prediction in children and investigate the earliest age threshold for an accurate prediction of high myopia.Prospective longitudinal study.A total of 1063 first-born twins followed annually between 2006 and 2015 in China. The exposures were genetic factors (parental myopia, SNPs) and environmental factors (near work, outdoor activity).Five linear mixed-effect models, consisting of different combinations of age, gender, genetic, and environmental factors, were built to predict myopia development. All predictions were performed on the basis of spherical equivalent (SE) at baseline and the measurements on the second and third visits.The primary outcome measure was SE at the last visit among all subjects, and the secondary outcome measure was the presence of high myopia at the age of 18 years.Mean age of the study population was 10.5±2.2 years (range, 7-15 years) at baseline, and 48.6% were male. In linear mixed-effect models, age, age square, gender, paternal SE, maternal SE, and genetic risk scores (GRSs) showed a significant fixed effect, whereas outdoor and near-work time were not significant to SE at the last visit. Incorporating more follow-up data into the model showed better performance across all models. In the prediction of the presence of high myopia at 18 years of age, the model consisting of only age and gender showed a good performance (area under the curve [AUC] = 0.95), whereas the addition of SNPs did not enhance the model performance significantly. The AUC for predicting high myopia was >0.95 after the age of 13 years for participants with a single visit and after the age of 12 years for those with 1 more visit data.A simple model incorporating age, sex, and relevant refraction data is sufficient to accurately predict high myopia; there was limited improvement in the prediction model after adding genetic information. Furthermore, this prediction on the outcome at 18 years is possible when the child is aged 12 to 13 years.
Development and Validation of a Scoring System, Based on Genetic and Clinical Factors, to Determine Risk of Steatohepatitis in Asian Patients with Nonalcoholic Fatty Liver Disease
Authors: Bo Kyung Koo, Sae Kyung Joo, Donghee Kim, Seonhwa Lee, Jeong Mo Bae, Jeong Hwan Park, Jung Ho Kim, Mee Soo Chang, Won Kim
Journal: Clinical Gastroenterology and Hepatology (2020)