tbuckley/cabot-search huggingface dataset:
Absolute Risk of Adverse Obstetric Outcomes Among Twin Pregnancies After In Vitro Fertilization by Maternal Age
Authors: Yuanyuan Wang, Huifeng Shi, Lian Chen, Danni Zheng, Xiaoyu Long, Yunjun Zhang, Haibo Wang, Ying Shi, Yangyu Zhao, Yuan Wei, Jie Qiao
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Twin pregnancy is a common occurrence in pregnancies conceived with in vitro fertilization (IVF), but the absolute risk of adverse obstetric outcomes stratified by IVF, twin or singleton pregnancy, and maternal age are unknown. <h3>Objective</h3> To estimate the absolute risk of adverse obstetric outcomes at each maternal age among twin pregnancies conceived with IVF. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included pregnant women with infants born from January 1, 2013, to December 31, 2018, based on the Hospital Quality Monitoring System in China. Data were analyzed from September 1, 2020, to June 30, 2021. <h3>Exposures</h3> Twin pregnancy with IVF (IVF-T), singleton pregnancy with IVF (IVF-S), twin pregnancy with non-IVF (nIVF-T), and singleton pregnancy with non-IVF (nIVF-S). <h3>Main Outcomes and Measures</h3> Sixteen obstetric outcomes, including 10 maternal complications (gestational hypertension, eclampsia and preeclampsia, gestational diabetes, placenta previa, placental abruption, placenta accreta, preterm birth, dystocia, cesarean delivery, and postpartum hemorrhage) and 6 neonatal complications (fetal growth restriction, low birth weight, very low birth weight, macrosomia, malformation, and stillbirth). <h3>Results</h3> Among 16 879 728 pregnant women aged 20 to 49 years (mean [SD] age, 29.2 [4.7] years), the twin-pregnancy rates were 32.1% in the IVF group and 1.5% in the non-IVF group (relative risk, 20.8; 95% CI, 20.6-20.9). The most common adverse obstetric outcomes after pregnancy conceived with IVF were cesarean delivery (88.8%), low birth weight (43.8%), preterm birth (39.6%), gestational diabetes (20.5%), gestational hypertension and preeclampsia and eclampsia (17.5%), dystocia (16.8%), and postpartum hemorrhage (11.9%). The absolute risk of most adverse obstetric outcomes in each subgroup presented in 2 dominant patterns: Pattern A indicated the absolute risk ranging from IVF-T to nIVF-T to IVF-S to nIVF-S, and pattern B indicated the absolute risk ranging from IVF-T to IVF-S to nIVF-T to nIVF-S. Both patterns showed an elevated obstetric risk with increasing maternal age in each subgroup. <h3>Conclusions and Relevance</h3> In this cohort study, twin pregnancy, IVF, and advanced maternal age were independently associated with adverse obstetric outcomes. Given these findings, promotion of the elective single embryo transfer strategy is needed to reduce multiple pregnancies following IVF technologies. Unnecessary cesarean delivery shouldh be avoided in all pregnant women.
Residual homing of α4β7-expressing β1<sup>+</sup>PI16<sup>+</sup> regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab
Authors: Emily Becker, Mark Dedden, Christine Gall, Maximilian Wiendl, Arif Bülent Ekici, Anja Schulz-Kuhnt, Anna Schweda, Caroline Voskens, Ahmed Hegazy, Francesco Vitali, Raja Atreya, Tanja Martina Müller, Imke Atreya, Markus F Neurath, Sebastian Zundler
Journal: Gut (2021)

The anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.Regulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-'resistant' α4β7-expressing β1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.Completely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers
Authors: Yu-Yao Huang, Ching-Wen Lin, Nai-Chen Cheng, Shawn M. Cazzell, Hsin-Han Chen, Kuo-Feng Huang, Kwang-Yi Tung, Hsuan-Li Huang, Pao-Yuan Lin, Cherng-Kang Perng, Bimin Shi, Chang Liu, Yujin Ma, Yemin Cao, Yanbing Li, Yaoming Xue, Li Yan, Qiu Li, Guang Ning, Shun-Cheng Chang
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. <h3>Objective</h3> To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. <h3>Design, Setting, and Participants</h3> This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm<sup>2</sup>present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. <h3>Interventions</h3> Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. <h3>Main Outcomes and Measures</h3> The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. <h3>Results</h3> In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm<sup>2</sup>) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84;<i>P</i> &lt; .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. <h3>Conclusions and Relevance</h3> In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, &gt;5 cm<sup>2</sup>; and DFU duration, ≥6 months). <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01898923
Estimated Savings From International Reference Pricing for Prescription Drugs
Authors: Andrew W. Mulcahy, Daniel Schwam, Preethi Rao, Stephanie Rennane, Kanaka Shetty
Journal: JAMA (2021)

Estimated Savings From International Reference Pricing for Prescription DrugsHigh prescription drug prices have important implications for health care spending, 1 patient financial burden, 2 and adherence. 3Prices for brand-name drugs in particular are higher in the US compared with other high-income countries, most of which regulate drug prices.However, inconsistent availability of data on net prices (ie, prices after rebates and other discounts) complicates international comparisons of drug prices.A 2021 study found that US prices for brand-name drugs were 344% of those in other high-income countries at manufacturer ("list") prices, but the difference was smaller (230%) after an adjustment to approximate lower US net prices. 4he Elijah E. Cummings Lower Drug Costs Now Act, HR 3, would allow the US Secretary of Health and Human Services to negotiate prices with drug manufacturers on behalf of Medicare and private insurers, up to a cap of 120% of prices in 6 countries (Australia, Canada, France, Germany, Japan, and the UK).Negotiation would apply to all insulins and at least 25 other single-source, brand-name drugs selected by the secretary in the first year and 50 in the second year.The Congressional Budget Office estimated that this application of international reference pricing, a price control tool used by many other countries, would save $456 billion for Medicare alone over 10 years. 5e estimated what 2020 national US savings would have been at HR 3 maximum international prices rather than US manufacturer and net prices for insulins and 50 top brandname drugs by sales.
Drug Target Identification in Tissues by Thermal Proteome Profiling
Authors: André Mateus, Nils Kurzawa, Jessica Perrin, Giovanna Bergamini, Mikhail M. Savitski
Journal: The Annual Review of Pharmacology and Toxicology (2021)

Drug target deconvolution can accelerate the drug discovery process by identifying a drug's targets (facilitating medicinal chemistry efforts) and off-targets (anticipating toxicity effects or adverse drug reactions). Multiple mass spectrometry–based approaches have been developed for this purpose, but thermal proteome profiling (TPP) remains to date the only one that does not require compound modification and can be used to identify intracellular targets in living cells. TPP is based on the principle that the thermal stability of a protein can be affected by its interactions. Recent developments of this approach have expanded its applications beyond drugs and cell cultures to studying protein-drug interactions and biological phenomena in tissues. These developments open up the possibility of studying drug treatment or mechanisms of disease in a holistic fashion, which can result in the design of better drugs and lead to a better understanding of fundamental biology.
mRNA Export as a Novel Cancer-Specific Dependency
Authors: Eric Wang, Omar Abdel-Wahab
Journal: Cancer Discovery (2021)

In this issue, Malone and colleagues identified the nuclear mRNA export factor NXT1 as a novel genetic dependency in neuroblastoma as well as several additional pediatric cancers. These data highlight potential cell type-specific differences in the nuclear export machinery that may be exploited as cancer therapeutics.See related article by Malone et al., p. 2282.
Acanthamoeba castellanii encephalitis in a patient with AIDS: a case report and literature review
Authors: Gregory L Damhorst, Abigail Watts, Alfonso Hernandez-Romieu, Nonglin Mel, Melody Palmore, Ibne Karim M Ali, Stewart G Neill, Aley Kalapila, Jennifer R Cope
Journal: The Lancet Infectious Diseases (2021)
Concordance of immunological events between intrarectal and intravenous SHIVAD8-EO infection when assessed by Fiebig-equivalent staging
Authors: Joana Dias, Giulia Fabozzi, Kylie March, Mangaiarkarasi Asokan, Cassandra G. Almasri, Jonathan Fintzi, Wanwisa Promsote, Yoshiaki Nishimura, John-Paul Todd, Jeffrey D. Lifson, Malcolm A. Martin, Lucio Gama, Constantinos Petrovas, Amarendra Pegu, John R. Mascola, Richard A. Koup
Journal: Journal of Clinical Investigation (2021)

Primary HIV-1 infection can be classified into six Fiebig stages based on virological and serological laboratory testing, whereas simian-HIV (SHIV) infection in nonhuman primates (NHPs) is defined in time post-infection, making it difficult to extrapolate NHP experiments to the clinics. We identified and extensively characterized the Fiebig-equivalent stages in NHPs challenged intrarectally or intravenously with SHIVAD8-EO. During the first month post-challenge, intrarectally challenged monkeys were up to 1 week delayed in progression through stages. However, regardless of the challenge route, stages I-II predominated before, and stages V-VI predominated after, peak viremia. Decrease in lymph node (LN) CD4+ T cell frequency and rise in CD8+ T cells occurred at stage V. LN virus-specific CD8+ T cell responses, dominated by degranulation and TNF, were first detected at stage V and increased at stage VI. A similar late elevation in follicular CXCR5+ CD8+ T cells occurred, consistent with higher plasma CXCL13 levels at these stages. LN SHIVAD8-EO RNA+ cells were present at stage II, but appeared to decline at stage VI when virions accumulated in follicles. Fiebig-equivalent staging of SHIVAD8-EO infection revealed concordance of immunological events between intrarectal and intravenous infection despite different infection progressions, and can inform comparisons of NHP studies with clinical data.
Corrigendum to “Bi-DTPA as a high-performance CT contrast agent for in vivo imaging” [Biomaterials 203(2019) 1–11]
Authors: Weihua Liao, Peng Lei, Jinbin Pan, Cai Zhang, Xianting Sun, Xuejun Zhang, Chunshui Yu, Shao-Kai Sun
Journal: Biomaterials (2021)
Single-cell exome sequencing reveals multiple subclones in metastatic colorectal carcinoma
Authors: Jie Tang, Kailing Tu, Keying Lu, Jiaxun Zhang, Kai Luo, Haoxuan Jin, Lei Wang, Lie Yang, Weiran Xiao, Qilin Zhang, Xiaoling Liu, Xin yi Ge, Guibo Li, Zongguang Zhou, Dan Xie
Journal: Genome Medicine (2021)

Abstract Background Colorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive. Methods In this study, we characterised the evolutionary pattern of metastatic CRC (mCRC) by analysing bulk and single-cell exome sequencing data of primary and metastatic tumours from 7 CRC patients with liver metastases. Here, 7 CRC patients were analysed by bulk whole-exome sequencing (WES); 4 of these were also analysed using single-cell sequencing. Results Despite low genomic divergence between paired primary and metastatic cancers in the bulk data, single-cell WES (scWES) data revealed rare mutations and defined two separate cell populations, indicative of the diverse evolutionary trajectories between primary and metastatic tumour cells. We further identified 24 metastatic cell-specific-mutated genes and validated their functions in cell migration capacity. Conclusions In summary, scWES revealed rare mutations that failed to be detected by bulk WES. These rare mutations better define the distinct genomic profiles of primary and metastatic tumour cell clones.
Prevalence of SARS-CoV-2 Antibodies From a National Serosurveillance of Kenyan Blood Donors, January-March 2021
Authors: Sophie Uyoga, Ifedayo M. O. Adetifa, Mark Otiende, Christine Yegon, Ambrose Agweyu, George M. Warimwe, J. Anthony G. Scott
Journal: JAMA (2021)

Change in Donor Characteristics and Antibodies to SARS-CoV-2 in Donated Blood in the US, June-August 2020
Mapping the landscape of synthetic lethal interactions in liver cancer
Authors: Chen Yang, Yuchen Guo, Ruolan Qian, Yiwen Huang, Linmeng Zhang, Jun Wang, Xiaowen Huang, Zhicheng Liu, Wenxin Qin, Cun Wang, Huimin Chen, Xuhui Ma, Dayong Zhang
Journal: Theranostics (2021)

Almost all the current therapies against liver cancer are based on the "one size fits all" principle and offer only limited survival benefit. Fortunately, synthetic lethality (SL) may provide an alternate route towards individualized therapy in liver cancer. The concept that simultaneous losses of two genes are lethal to a cell while a single loss is non-lethal can be utilized to selectively eliminate tumors with genetic aberrations. Methods: To infer liver cancer-specific SL interactions, we propose a computational pipeline termed SiLi (statistical inference-based synthetic lethality identification) that incorporates five inference procedures. Based on large-scale sequencing datasets, SiLi analysis was performed to identify SL interactions in liver cancer. Results: By SiLi analysis, a total of 272 SL pairs were discerned, which included 209 unique target candidates. Among these, polo-like kinase 1 (PLK1) was considered to have considerable therapeutic potential. Further computational and experimental validation of the SL pair TP53-PLK1 demonstrated that inhibition of PLK1 could be a novel therapeutic strategy specifically targeting those patients with TP53-mutant liver tumors. Conclusions: In this study, we report a comprehensive analysis of synthetic lethal interactions of liver cancer. Our findings may open new possibilities for patient-tailored therapeutic interventions in liver cancer.
Sympathetic vasoconstrictor activity before and after left ventricular assist device implantation in patients with end‐stage heart failure
Authors: Karsten Heusser, Judith Wittkoepper, Christoph Bara, Axel Haverich, André Diedrich, Benjamin D. Levine, Jan D. Schmitto, Jens Jordan, Jens Tank
Journal: European Journal of Heart Failure (2021)

Sympathetic overactivity, which predicts poor outcome in patients with heart failure, normalizes following cardiac transplantation. We tested the hypothesis that haemodynamic improvement following left ventricular assist device (LVAD) implantation is also associated with reductions in centrally generated sympathetic activity.In eight patients with heart failure (two women, six men, age 44-66 years), we continuously recorded electrocardiogram, beat-to-beat finger blood pressure, respiration, and muscle sympathetic nerve activity (MSNA) before and after implantation of the continuous-flow LVAD devices HeartWare HVAD (n = 4) and HeartMate II (n = 2), and the non-continuous-flow device HeartMate 3 (n = 2). LVAD implantation increased cardiac output by 1.29 ± 0.88 L/min (P = 0.060) and mean arterial pressure by 16.2 ± 7.9 mmHg (P < 0.001), while reducing pulse pressure by 25.3 ± 9.8 mmHg (P < 0.001). LVAD implantation did not change MSNA burst frequency (-1.3 ± 7.5 bursts/min, P = 0.636), total activity (+0.62 ± 1.83 au, P = 0.369), or normalized activity (+0.63 ± 4.23, P = 0.685). MSNA burst incidence was decreased (-7.8 ± 9.3 bursts/100 heart beats, P = 0.049). However, cardiac ectopy altered MSNA bursting patterns that could be mistaken for sympatholysis.Implantation of current design LVAD does not consistently normalize sympathetic activity in patients with end-stage heart failure despite haemodynamic improvement.
Dissecting Response and Resistance to Anti–PD-1 Therapy in Microsatellite-Unstable Gastric Cancer
Authors: Elisa Fontana, Elizabeth C. Smyth
Journal: Cancer Discovery (2021)

Abstract Summary: Most, but not all, patients with microsatellite-unstable gastric cancer respond to anti–PD-1 therapy. In this issue, Kwon and colleagues show, first, that differences in tumor mutation burden (TMB) may drive this variation in outcomes and, second, that treatment with immune checkpoint inhibitors leads to further immunoediting and a reduction in TMB in responding patients. See related article by Kwon et al., p. 2168.
Cytogenetic and molecular abnormalities in <scp>W</scp>aldenström's macroglobulinemia patients: Correlations and prognostic impact
Authors: Daphné Krzisch, Nayara Guedes, Clémentine Boccon‐Gibod, Marine Baron, Clotilde Bravetti, Frédéric Davi, Marine Armand, Luce Smagghe, Jonathan Caron, Olivier A. Bernard, Santos Susin, Elise Chapiro, Véronique Leblond, Florence Nguyen‐Khac, Damien Roos‐Weil
Journal: American Journal of Hematology (2021)

While Waldenström macroglobulinemia (WM) is characterized by an almost unifying mutation in MYD88, clinical presentation at diagnosis and response to therapy can be widely different among WM patients. Current prognostic tools only partially address this clinical heterogeneity. Limited data compiling both molecular and cytogenetic information have been used in risk prognostication in WM. To investigate the clinical impact of genetic alterations in WM, we evaluated cytogenetic and molecular abnormalities by chromosome banding analyses, FISH and targeted NGS in a retrospective cohort of 239 WM patients, including 187 patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two (range, 0-22). Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Complex karyotype (CK) was observed in 15% (n = 31) of cases, including 5% (n = 12) of highly CK (high-CK). TP53 abnormalities (TP53abn) were present in 15% of evaluable patients. TP53abn and del6q were associated with CK/high-CK (p < .05). Fifty-three percent of patients with hyperviscosity harbored CXCR4 mutations. Cytogenetic and molecular abnormalities did not significantly impact time to first treatment and response to therapy. Prognostic factors associated with shorter PFS were del6q (p = .01), TP53abn (p = .002) and high-CK (p = .01). These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (p < .05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.
Adjuvant Immunotherapy after Curative Treatment for Hepatocellular Carcinoma
Authors: Masatoshi Kudo
Journal: Liver Cancer (2021)

Hepatectomy and radiofrequency ablation (RFA) have been established as curative therapies for hepatocellular carcinoma (HCC); however, HCC still has a high recurrence rate after these treatments. A study of HCC pathology has shown that microscopic intrahepatic metastasis occurs in about 10% of tumors ≤2 cm, and microvascular invasion occurs in about 27% of these tumors [1]. Thus, even small HCCs (≤2 cm) have a risk of recurrence. Moreover, intrahepatic metastasis is a major problem for tumors >2 cm because increasing tumor size past this cutoff is correlated with an increased risk of intrahepatic metastasis and microvascular invasion [2]. One reason why the prognosis of HCC is so poor is that patients experience repeated recurrences even after curative treatment, and repeated treatments with RFA, hepatectomy, and transarterial chemoembolization deteriorate liver function in many patients, ultimately resulting in death from liver failure or from tumors that are not amenable to treatment with systemic therapy. This suggests that preventing recurrence of HCC after curative treatment could dramatically improve the prognosis. Several studies on the prevention of recurrence have been conducted to date, but all have failed [3, 4, 5]. Consequently, there currently remains an unmet need for research on adjuvant therapy after curative treatment for HCC.

The most prominent clinical studies of adjuvant therapy for recurrence prevention conducted to date investigated vitamin K [3], retinoids (the NIK-333 study) [4], and sorafenib (the STORM trial) [5]. However, the 1-year recurrence rates were high (25%, 34%, and 42%, respectively) in the control arms of all these studies. Another study showed a 5-year recurrence rate of about 80% after curative treatment for HCC.

Recurrence after curative treatment can occur early or late. Early recurrence is primarily associated with intrahepatic metastasis, whereas late recurrence is often multicentric in origin [6].