tbuckley/cabot-search huggingface dataset:
Multi-omic Analyses Shed Light on The Genetic Control of High-altitude Adaptation in Sheep
Authors: Chao Li, Bingchun Chen, Suo Langda, Peng Pu, Xiaojia Zhu, Shiwei Zhou, Peter Kalds, Ke Zhang, Meenu Bhati, Alexander Leonard, Shuhong Huang, Ran Li, Awang Cuoji, Xiran Wang, Haolin Zhu, Yujiang Wu, Renqin Cuomu, Ba Gui, Ming Li, Yutao Wang, Yan Li, Wenwen Fang, Ting Jia, Tianchun Pu, Xiangyu Pan, Yudong Cai, Chong He, Liming Wang, Yu Jiang, Jian-Lin Han, Yulin Chen, Ping Zhou, Hubert Pausch, Xiaolong Wang
Journal: Genomics Proteomics & Bioinformatics (2024)

Sheep were domesticated in the Fertile Crescent and then spread globally, where they have been encountering various environmental conditions. The Tibetan sheep has adapted to high altitudes on the Qinghai-Tibet Plateau over the past 3000 years. To explore genomic variants associated with high-altitude adaptation in Tibetan sheep, we analyzed Illumina short-reads of 994 whole genomes representing ∼ 60 sheep breeds/populations at varied altitudes, PacBio High fidelity (HiFi) reads of 13 breeds, and 96 transcriptomes from 12 sheep organs. Association testing between the inhabited altitudes and 34,298,967 variants was conducted to investigate the genetic architecture of altitude adaptation. Highly accurate HiFi reads were used to complement the current ovine reference assembly at the most significantly associated β-globin locus and to validate the presence of two haplotypes A and B among 13 sheep breeds. The haplotype A carried two homologous gene clusters: (1) HBE1, HBE2, HBB-like, and HBBC, and (2) HBE1-like, HBE2-like, HBB-like, and HBB; while the haplotype B lacked the first cluster. The high-altitude sheep showed highly frequent or nearly fixed haplotype A, while the low-altitude sheep dominated by haplotype B. We further demonstrated that sheep with haplotype A had an increased hemoglobin-O2 affinity compared with those carrying haplotype B. Another highly associated genomic region contained the EGLN1 gene which showed varied expression between high-altitude and low-altitude sheep. Our results provide evidence that the rapid adaptive evolution of advantageous alleles play an important role in facilitating the environmental adaptation of Tibetan sheep.
The VEGF-Hypoxia Signature Is Upregulated in Basal-like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer
Authors: Yoo Jane Han, Siyao Liu, Ashley Hardeman, Padma Sheila Rajagopal, Jeffrey Mueller, Galina Khramtsova, Ayodele Sanni, Mustapha Ajani, Wendy Clayton, Ian W. Hurley, Toshio F. Yoshimatsu, Yonglan Zheng, Joel Parker, Charles M. Perou, Olufunmilayo I. Olopade
Journal: Clinical Cancer Research (2024)

Black women experience the highest breast cancer mortality rate compared with women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry.
Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer
Authors: Dongbing Ding, Rongpu Liang, Tan Li, Tianyun Lan, Yiquan Li, Shengxin Huang, Guanhui He, Jiannan Ren, Weibo Li, Zongheng Zheng, Tufeng Chen, Jiafeng Fang, Lijun Huang, Xintao Shuai, Bo Wei
Journal: Journal of Controlled Release (2024)
Intranasal delivery of small extracellular vesicles from specific subpopulation of mesenchymal stem cells mitigates traumatic spinal cord injury
Authors: Yi Sun, Jinyun Zhao, Quanbo Liu, Yan Xu, Yiming Qin, Rundong He, Lifu Zheng, Yong Xie, Chengjun Li, Tianding Wu, Yong Cao, Chunyue Duan, Hongbin Lu, Jianzhong Hu
Journal: Journal of Controlled Release (2024)
Centripetal integration of past events in hippocampal astrocytes regulated by locus coeruleus
Authors: Peter Rupprecht, Sian N. Duss, Denise Becker, Christopher M. Lewis, Johannes Bohacek, Fritjof Helmchen
Journal: Nature Neuroscience (2024)

Abstract An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, in contrast, has been described as mostly uncoordinated across cellular compartments without clear central integration. Here we report conditional integration of calcium signals in astrocytic distal processes at their soma. In the hippocampus of adult mice of both sexes, we found that global astrocytic activity, as recorded with population calcium imaging, reflected past neuronal and behavioral events on a timescale of seconds. Salient past events, indicated by pupil dilations, facilitated the propagation of calcium signals from distal processes to the soma. Centripetal propagation to the soma was reproduced by optogenetic activation of the locus coeruleus, a key regulator of arousal, and reduced by pharmacological inhibition of α1-adrenergic receptors. Together, our results suggest that astrocytes are computational units of the brain that slowly and conditionally integrate calcium signals upon behaviorally relevant events.
Interconnecting global threats: climate change, biodiversity loss, and infectious diseases
Authors: Alaina Pfenning-Butterworth, Lauren B Buckley, John M Drake, Johannah E Farner, Maxwell J Farrell, Alyssa-Lois M Gehman, Erin A Mordecai, Patrick R Stephens, John L Gittleman, T Jonathan Davies
Journal: The Lancet Planetary Health (2024)

The concurrent pressures of rising global temperatures, rates and incidence of species decline, and emergence of infectious diseases represent an unprecedented planetary crisis. Intergovernmental reports have drawn focus to the escalating climate and biodiversity crises and the connections between them, but interactions among all three pressures have been largely overlooked. Non-linearities and dampening and reinforcing interactions among pressures make considering interconnections essential to anticipating planetary challenges. In this Review, we define and exemplify the causal pathways that link the three global pressures of climate change, biodiversity loss, and infectious disease. A literature assessment and case studies show that the mechanisms between certain pairs of pressures are better understood than others and that the full triad of interactions is rarely considered. Although challenges to evaluating these interactions—including a mismatch in scales, data availability, and methods—are substantial, current approaches would benefit from expanding scientific cultures to embrace interdisciplinarity and from integrating animal, human, and environmental perspectives. Considering the full suite of connections would be transformative for planetary health by identifying potential for co-benefits and mutually beneficial scenarios, and highlighting where a narrow focus on solutions to one pressure might aggravate another.
Ambient heat exposure and kidney function in patients with chronic kidney disease: a post-hoc analysis of the DAPA-CKD trial
Authors: Zhiyan Zhang, Hiddo J L Heerspink, Glenn M Chertow, Ricardo Correa-Rotter, Antonio Gasparrini, Niels Jongs, Anna Maria Langkilde, John J V McMurray, Malcolm N Mistry, Peter Rossing, Robert D Toto, Priya Vart, Dorothea Nitsch, David C Wheeler, Ben Caplin
Journal: The Lancet Planetary Health (2024)

BackgroundHigher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis.MethodsDAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200–5000 mg/g, and an eGFR of 25–75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150.FindingsClimate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days' heat index of more than 30°C was associated with a –0·6% (95% CI –0·9% to –0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment.InterpretationHigher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression.FundingNone.
Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis
Authors: Soumyajit Roy, Gagan Fervaha, Daniel E. Spratt, Yilun Sun, Amar U. Kishan, Andrew Loblaw, Shawn Malone, Michael Ong, Fred Saad, Christopher J.D. Wallis, Scott C. Morgan
Journal: European Urology (2024)

The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC. Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation. Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51–1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92–1.42). There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.
Navigating the depths: an endoscopic triumph in removing a massive duodenal polyp
Authors: Fatih Aslan, Orhun Cig Taskin, Serhat Ozer, Bahadir Hakan Oguz
Journal: Endoscopy (2024)

Endoscopic submucosal dissection (ESD) is a minimally invasive method for treatment of early gastrointestinal (GI) tumors at any site; however, duodenal ESD is technically challenging because of the anatomic features and high risk of complications, including bleeding and perforation [1]. Here, we report a case of en bloc removal of a distal duodenal polyp of 10 cm in length using ESD, followed by endoscopic closure.
Beyond incrementalism
Authors: None The Lancet Planetary Health
Journal: The Lancet Planetary Health (2024)

Global environmental change, including climate change, biodiversity loss, and pollution pose truly fundamental challenges to the way we collectively think, organise, and govern ourselves, and the resource consequences of these decisions. The existence and increasing urgency of these problems forces a reappraisal of current social, political, and economic norms, not only in relation to how we are damaging our environment but also how many of these same drivers and patterns affect the way we treat each other, leading to chronic poverty, inequality, and injustice.
Endoscopic submucosal dissection for residual gastric lesion made easier thanks to use of adaptative traction device
Authors: Elena De Cristofaro, Pierre Lafeuille, Jérôme Rivory, Jean Grimaldi, Louis Jean Masgnaux, Alexandru Lupu, Mathieu Pioche
Journal: Endoscopy (2024)

European guidelines recommend endoscopic submucosal dissection (ESD) for gastric dysplastic lesions to ensure en bloc resection and for a lower risk of recurrence than endoscopic mucosal resection (EMR) [1]. However, this procedure is considered technically challenging especially for residual lesions in which the fibrosis after previous treatments can be found in the submucosal space and EMR is still performed with a local risk of recurrence. Herein, we report the case of a 66-year-old woman assessed for ESD of a residual dysplastic gastric lesion at the site of previous piecemeal EMR resection (posterior wall of antrum) ([Video 1]).
Case 10-2024: A 46-Year-Old Woman with Hyperglycemia Refractory to Insulin Therapy
Authors: Lindsay T Fourman, Leo L Tsai, Rebecca J Brown, Stephen O'Rahilly
Journal: New England Journal of Medicine (2024)

A 46-year-old woman with type 2 diabetes was admitted to this hospital because of hyperglycemia for which she was receiving over 2000 units of insulin per day. A diagnosis was made.
Pragmatic Trial of Hospitalization Rate in Chronic Kidney Disease
Authors: Miguel A. Vazquez, George Oliver, Ruben Amarasingham, Venkatraghavan Sundaram, Kevin Chan, Chul Ahn, Song Zhang, Perry Bickel, Samir M. Parikh, Barbara Wells, R. Tyler Miller, Susan Hedayati, Jeffrey Hastings, Adeola Jaiyeola, Tuan-Minh Nguyen, Brett Moran, Noel Santini, Blake Barker, Ferdinand Velasco, Lynn Myers, Thomas P. Meehan, Chester Fox, Robert D. Toto
Journal: New England Journal of Medicine (2024)

Despite the availability of effective therapies for patients with chronic kidney disease, type 2 diabetes, and hypertension (the kidney-dysfunction triad), the results of large-scale trials examining the implementation of guideline-directed therapy to reduce the risk of death and complications in this population are lacking.
Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19
Authors: Jennifer Hammond, Robert J Fountaine, Carla Yunis, Dona Fleishaker, Mary Almas, Weihang Bao, Wayne Wisemandle, Mary Lynn Baniecki, Victoria M Hendrick, Veselin Kalfov, J Abraham Simón-Campos, Rienk Pypstra, James M Rusnak
Journal: New England Journal of Medicine (2024)

BackgroundNirmatrelvir in combination with ritonavir is an antiviral treatment for mild-to-moderate coronavirus disease 2019 (Covid-19). The efficacy of this treatment in patients who are at standard risk for severe Covid-19 or who are fully vaccinated and have at least one risk factor for severe Covid-19 has not been established.MethodsIn this phase 2–3 trial, we randomly assigned adults who had confirmed Covid-19 with symptom onset within the past 5 days in a 1:1 ratio to receive nirmatrelvir–ritonavir or placebo every 12 hours for 5 days. Patients who were fully vaccinated against Covid-19 and who had at least one risk factor for severe disease, as well as patients without such risk factors who had never been vaccinated against Covid-19 or had not been vaccinated within the previous year, were eligible for participation. Participants logged the presence and severity of prespecified Covid-19 signs and symptoms daily from day 1 through day 28. The primary end point was the time to sustained alleviation of all targeted Covid-19 signs and symptoms. Covid-19–related hospitalization and death from any cause were also assessed through day 28.Download a PDF of the Research Summary.ResultsAmong the 1296 participants who underwent randomization and were included in the full analysis population, 1288 received at least one dose of nirmatrelvir–ritonavir (654 participants) or placebo (634 participants) and had at least one postbaseline visit. The median time to sustained alleviation of all targeted signs and symptoms of Covid-19 was 12 days in the nirmatrelvir–ritonavir group and 13 days in the placebo group (P=0.60). Five participants (0.8%) in the nirmatrelvir–ritonavir group and 10 (1.6%) in the placebo group were hospitalized for Covid-19 or died from any cause (difference, −0.8 percentage points; 95% confidence interval, −2.0 to 0.4). The percentages of participants with adverse events were similar in the two groups (25.8% with nirmatrelvir–ritonavir and 24.1% with placebo). In the nirmatrelvir–ritonavir group, the most commonly reported treatment-related adverse events were dysgeusia (in 5.8% of the participants) and diarrhea (in 2.1%).ConclusionsThe time to sustained alleviation of all signs and symptoms of Covid-19 did not differ significantly between participants who received nirmatrelvir–ritonavir and those who received placebo. (Supported by Pfizer; EPIC-SR ClinicalTrials.gov number, NCT05011513.) Quick Take Nirmatrelvir for Covid-19 Outpatients 2m 21s
Treating Acute Covid-19 — Final Chapters Still Unwritten
Authors: Rajesh T Gandhi, Martin Hirsch
Journal: New England Journal of Medicine (2024)

treatment with lixisenatide was statistically significant but small.The importance of this finding is not the magnitude of the change but what it portends.Indeed, the primary concern of most patients with Parkinson's disease is not their present condition -it is the fear of progression of the disease.If a three-point improvement in score on the MDS-UPDRS is the most that can be achieved with lixisenatide, then the value of treatment with the drug may be limited (especially in view of the adverse effects).On the other hand, if the benefit of lixisenatide is cumulative, adding another three points each year over a period of 5 to 10 years or more, then this could be a truly transformative treatment.The next step is clearly trials of longer duration to see whether GLP-1 receptor agonists can live up to Dr. Parkinson's prediction.
Biocompatible Electronic Skins for Cardiovascular Health Monitoring
Authors: Yucong Du, Ji Hong Kim, Hui Kong, Anne Ailina Li, Ming Liang Jin, Do Hwan Kim, Yin Wang
Journal: Advanced Healthcare Materials (2024)

Cardiovascular diseases represent a significant threat to the overall well-being of the global population. Continuous monitoring of vital signs related to cardiovascular health is essential for improving daily health management. Currently, there has been remarkable proliferation of technology focused on collecting data related to cardiovascular diseases through daily electronic skin monitoring. However, concerns have arisen regarding potential skin irritation and inflammation due to the necessity for prolonged wear of wearable devices. To ensure comfortable and uninterrupted cardiovascular health monitoring, the concept of biocompatible electronic skin has gained substantial attention. In this review, biocompatible electronic skins for cardiovascular health monitoring are comprehensively summarized and discussed. The recent achievements of biocompatible electronic skin in cardiovascular health monitoring are introduced. Their working principles, fabrication processes, and performances in sensing technologies, materials, and integration systems are highlighted, and comparisons are made with other electronic skins used for cardiovascular monitoring. In addition, the significance of integrating sensing systems and the updating wireless communication for the development of the smart medical field is explored. Finally, the opportunities and challenges for wearable electronic skin are also examined.
Mathematical Model-Driven Deep Learning Enables Personalized Adaptive Therapy
Authors: Kit Gallagher, Maximilian A.R. Strobl, Derek S. Park, Fabian C. Spoendlin, Robert A. Gatenby, Philip K. Maini, Alexander R.A. Anderson
Journal: Cancer Research (2024)

Standard-of-care treatment regimens have long been designed for maximal cell killing, yet these strategies often fail when applied to metastatic cancers due to the emergence of drug resistance. Adaptive treatment strategies have been developed as an alternative approach, dynamically adjusting treatment to suppress the growth of treatment-resistant populations and thereby delay, or even prevent, tumor progression. Promising clinical results in prostate cancer indicate the potential to optimize adaptive treatment protocols. Here, we applied deep reinforcement learning (DRL) to guide adaptive drug scheduling and demonstrated that these treatment schedules can outperform the current adaptive protocols in a mathematical model calibrated to prostate cancer dynamics, more than doubling the time to progression. The DRL strategies were robust to patient variability, including both tumor dynamics and clinical monitoring schedules. The DRL framework could produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing optimal treatment strategies. The DRL framework had no knowledge of the underlying mathematical tumor model, demonstrating the capability of DRL to help develop treatment strategies in novel or complex settings. Finally, a proposed five-step pathway, which combined mechanistic modeling with the DRL framework and integrated conventional tools to improve interpretability compared with traditional "black-box" DRL models, could allow translation of this approach to the clinic. Overall, the proposed framework generated personalized treatment schedules that consistently outperformed clinical standard-of-care protocols.
National Trends in Hospital Performance in Guideline-Recommended Pharmacologic Treatment for Heart Failure at Discharge
Authors: Paul L. Hess, Paula Langner, Paul A. Heidenreich, Utibe Essien, Chelsea Leonard, Stanley A. Swat, Vincenzo Polsinelli, Steven T. Orlando, Gary K. Grunwald, P. Michael Ho
Journal: JACC Heart Failure (2024)
Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension
Authors: Inbal Shafran, Victoria Probst, Adelheid Panzenböck, Roela Sadushi-Kolici, Christian Gerges, Michael Wolzt, Michael J. Segel, David S. Celermajer, Irene Marthe Lang, Nika Skoro-Sajer
Journal: JACC Heart Failure (2024)