tbuckley/cabot-search huggingface dataset:
The alleviation of existential suffering as part of a good death
Authors: Edward Christopher Dee
Journal: The Lancet Healthy Longevity (2021)

In their Review in The Lancet Healthy Longevity, Mehreen Zaman and colleagues1 draw attention to the question: What would it take to die well? To grapple with this question is of fundamental importance because it should influence how we care for our patients at the end of life. In their review of reviews, the authors highlight 11 themes that characterise a good death. Here, I discuss one other aspect of a good death that merits further investigation: the alleviation of existential suffering.
Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice
Authors: Hyung Sik Kim, Min Young Park, Nam Joo Yun, Hye Sun Go, Mi Young Kim, Je Kyung Seong, Minyoung Lee, Eun Seok Kang, Jaewang Ghim, Sung Ho Ryu, Brian A. Zabel, Ara Koh, Yoe-Sik Bae
Journal: The Journal of Experimental Medicine (2021)

Phospholipase D (PLD)2 via its enzymatic activity regulates cell proliferation and migration and thus is implicated in cancer. However, the role of PLD2 in obesity and type 2 diabetes has not previously been investigated. Here, we show that during diet-induced thermogenesis and obesity, levels of PLD2 but not PLD1 in adipose tissue are inversely related with uncoupling protein 1, a key thermogenic protein. We demonstrate that the thermogenic program in adipose tissue is significantly augmented in mice with adipocyte-specific Pld2 deletion or treated with a PLD2-specific inhibitor and that these mice are resistant to high fat diet–induced obesity, glucose intolerance, and insulin resistance. Mechanistically, we show that Pld2 deletion in adipose tissue or PLD2 pharmacoinhibition acts via p62 to improve mitochondrial quality and quantity in adipocytes. Thus, PLD2 inhibition is an attractive therapeutic approach for obesity and type 2 diabetes by resolving defects in diet-induced thermogenesis.
Abstract 9160: Epinephrine-Dominant versus Non-Epinephrine Dominant Resuscitation for In-Hospital Cardiac Arrest
Authors: Jennifer W Chou, Amy Lin, Juan Toledo, Gabriel Wardi, Katrina Derry, Rebecca E Sell
Journal: Circulation (2021)

Introduction: Vasopressors are used during CPR to increase arterial resistance and aortic diastolic pressure, improving coronary perfusion and likelihood of ROSC. In comparison to epinephrine, vasopressin remains effective in an acidemic environment, has favorable cerebral perfusion, and does not directly increase myocardial oxygen demand. Studies comparing epinephrine and vasopressin report variable ROSC, survival, and neurological outcome. Most studies used few vasopressin doses and it is unclear whether greater vasopressin use leads to clinical benefit. Hypothesis: We hypothesized that a non-epinephrine dominant CPR approach with vasopressin would lead to greater ROSC than an epinephrine-dominant approach. Methods: This was a retrospective, single-center study conducted at an 800-bed academic medical center. All first cardiac arrests among adult inpatients between Jan 2018 and Mar 2021 were screened, and those with at least 2 vasopressor doses used were included. Patients who received epinephrine-dominant resuscitation (epinephrine-to-vasopressin dose ratio &gt;2 or CPR using only epinephrine) were compared to patients who received a non-epinephrine dominant approach (epinephrine-to-vasopressin dose ratio ≤2). The incidence of ROSC was analyzed using a Chi-squared test where p &lt;0.05 was considered significant. Secondary outcomes included survival to discharge with favorable neurologic outcome, survival to discharge, and Cerebral Performance Category scores. Results: Of 663 in-hospital cardiac arrests screened, 264 were included. Two hundred twenty-eight (86%) presented with PEA/asystole as the initial rhythm, and the most common etiologies were circulatory (41%) and respiratory (26%). The epinephrine-dominant arm achieved ROSC in 89 (66%) patients compared to 87 (67%) patients in the non-epinephrine dominant arm (RR 0.99, 95% CI 0.84-1.18, p=0.93). Survival to discharge was higher in the epinephrine-dominant arm (25% vs 15%, p=0.04). Conclusion: There was no difference in ROSC between epinephrine-dominant and non-epinephrine dominant resuscitation for adult in-hospital cardiac arrest. Future studies should examine the impact of non-epinephrine dominant CPR on long term neurologic outcomes.
Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial
Authors: Thomas Yau, Joong-Won Park, Richard S Finn, Ann-Lii Cheng, Philippe Mathurin, Julien Edeline, Masatoshi Kudo, James J Harding, Philippe Merle, Olivier Rosmorduc, Lucjan Wyrwicz, Eckart Schott, Su Pin Choo, Robin Kate Kelley, Wolfgang Sieghart, Eric Assenat, Renata Zaucha, Junji Furuse, Ghassan K Abou-Alfa, Anthony B El-Khoueiry, Ignacio Melero, Damir Begic, Gong Chen, Jaclyn Neely, Tami Wisniewski, Marina Tschaika, Bruno Sangro
Journal: The Lancet Oncology (2021)
Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study
Authors: Hessel Peters-Sengers, Joe M. Butler, Fabrice Uhel, Marcus J. Schultz, Marc J. Bonten, Olaf L. Cremer, Brendon P. Scicluna, Lonneke A. van Vught, Tom van der Poll, Friso M. de Beer, Lieuwe D. J. Bos, Gerie J. Glas, Roosmarijn T. M. van Hooijdonk, Janneke Horn, Laura R. A. Schouten, Marleen Straat, Luuk Wieske, Esther Witteveen, Tom D. Y. Reijnders, Alex R. Schuurman, Tjitske S. R. van Engelen, Liza Pereverzeva, Arie J. Hoogendijk, Mischa A. Huson, Maryse A. Wiewel, Peter M. C. Klein Klouwenberg, David S. Y. Ong, Jos F. Frencken, Maria E. Koster-Brouwer, Kirsten van de Groep, Diana M. Verboom
Journal: Intensive Care Medicine (2021)

There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at admission (< 24 h) to the intensive care unit.From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients. In a subgroup (n = 335), blood leukocyte transcriptomes were compared between the sources. Differences in clinical patient profiles and survival were compared in the whole sepsis cohort (n = 2019).The plasma biomarker cohort was categorized into sepsis originating from the respiratory tract (n = 334, 53.8%), abdomen (n = 159, 25.6%), urinary tract (n = 44, 7.1%), cardiovascular (n = 41, 6.6%), central nervous system (CNS) (n = 18, 2.9%), or skin (n = 25, 4%). This analysis revealed stronger inflammatory and cytokine responses, loss of vascular integrity and coagulation activation in abdominal sepsis relative to respiratory. Endothelial cell activation was prominent in urinary, cardiovascular and skin infections, while CNS infection was associated with the least host response aberrations. The leukocyte transcriptional response showed the largest overlap between abdominal and pulmonary infections (76% in common); notable differences between the sources were detected regarding hemostasis, cytokine signaling, innate and adaptive immune, and metabolic transcriptional pathways. After adjustment for confounders, the source of infection remained an independent contributor to 30-day mortality (unadjusted p = 0.001, adjusted p = 0.028).Sepsis heterogeneity is partly explained by source-specific host response dysregulations and should be considered when selecting patients for trials testing immune modulatory drugs.
Abstract 12185: Impact of Cardiac Arrest Centers on the Survival of Nontraumatic Out-of-Hospital Cardiac Arrest Patients: A Systematic Review and Meta-Analysis
Authors: Jun Wei Yeo, Celeste Z Ng, Amelia X Goh, Jocelyn F Gao, Nan Liu, Marcus E Ong, Andrew Ho
Journal: Circulation (2021)

Introduction: The role of cardiac arrest centers (CAC) in out-of-hospital cardiac arrest (OHCA) is uncertain, especially since CACs are inconsistently defined. This study seeks to address knowledge gaps by assessing the impact of CACs on nontraumatic OHCA patients as a whole and among specific subgroups. Methods: In this review, Medline, Embase, and Cochrane CENTRAL were searched from inception to 9 March 2021. Studies were included if they compared CAC vs non-CAC among adult patients with nontraumatic OHCA. CACs were explicitly named by study authors and were capable of appropriate interventions. Data abstraction and quality assessment were independently conducted by two authors, and a third author resolved discrepancies. Main outcomes were survival and survival with favorable neurological outcome at hospital discharge or at 30 days. Meta-analyses were performed for adjusted (aOR) and crude (OR) odds ratios. Sensitivity analyses were conducted for wider definitions of CAC such as high volume centers or improved post-resuscitation care, and subgroups analysed to account for heterogeneity. Results: The search yielded 4544 articles, and 36 were included for analysis. Survival with favorable neurological outcome significantly improved with treatment at CACs (aOR = 1.88, 95% CI 1.53 to 2.31), even when including high volume centers (aOR = 1.68, 95% CI 1.30 to 2.16), or when including improved care centers (aOR = 2.16, 95% CI 1.76 to 2.64) as CACs. Survival significantly increased with treatment at CAC (aOR = 1.92, 95% CI 1.59 to 2.31), even when including high volume centers (aOR = 1.74, 95% CI 1.38 to 2.18), or when including improved care centers (aOR = 1.97, 95% CI 1.71 to 2.26) as CACs. The effect on favorable neurological outcome was more pronounced among patients with shockable rhythm (p = 0.03) and on survival among patients without prehospital ROSC (p = 0.005). Findings were robust to sensitivity analyses, with no publication bias detected. Conclusion: CACs improved survival and neurological outcomes for nontraumatic OHCA patients despite varying definitions of CAC. Patients with shockable rhythms and without prehospital ROSC appeared to yield greater benefit from CACs. Evidence for bypassing hospitals or inter-hospital transfer remains inconclusive.
<i>QuickStats:</i> Age-Adjusted Death Rates* from Heart Disease† Among Adults Aged 45–64 Years, by Urbanization Level§ and Sex — National Vital Statistics System, United States, 2019
Authors: Deepthi Kandi
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Rural Men Both sexes Women Deaths per 100,000 population Abbreviation: MSA = metropolitan statistical area.* Deaths per 100,000 population, age-adjusted to the 2000 U.S. standard population.† Heart disease-related deaths were those with underlying cause of death coded as I00-I09, I11, I13, and I20-I51 in the International Classification of Diseases, Tenth Revision.§ Urbanization level is based on the Office of Management and Budget's February 2013 delineation of MSAs, in which each MSA must have at least one urban area of ≥50,000 inhabitants.Areas with <50,000 inhabitants are grouped into the rural category.In 2019, the age-adjusted death rate from heart disease among adults aged 45-64 years was 121.1 per 100,000 and was higher in rural counties (160.0)than urban counties (114.5).Among men, the age-adjusted death rate from heart disease was 221.4 in rural counties and 165.1 in urban counties.Among women, the age-adjusted death rate from heart disease was 99.5 in rural counties and 66.8 in urban counties.In each urbanization level, the rate was higher for men than for women.
Paracetamol use in pregnancy — caution over causal inference from available data
Authors: Sura Alwan, Elizabeth A. Conover, Lorrie Harris-Sagaribay, Steven H. Lamm, Sharon V. Lavigne, Shari I. Lusskin, Sarah G. Obican, Alfred N. Romeo, Anthony R. Scialli, Katherine L. Wisner
Journal: Nature Reviews Endocrinology (2021)
Defect self-assembly of metal-organic framework triggers ferroptosis to overcome resistance
Authors: Haibao Peng, Xingcai Zhang, Peng Yang, Jiaxu Zhao, Wei Zhang, Nianping Feng, Wuli Yang, Jing Tang
Journal: Bioactive Materials (2021)

The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours. Ferroptosis, resulting from the iron-dependent accumulation of lipid peroxides, has the potential to reverse multidrug resistance. However, simultaneous delivery of the iron sources, ferroptosis inducers, drugs, and enhanced circulation carriers within matrices remains a significant challenge. Herein, we designed and fabricated a defect self-assembly of metal-organic framework (MOF)-red blood cell (RBC) membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer. Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron (III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process. The RBC membrane could camouflage the nanoplatform for longer circulation. Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione, amplify the reactive oxidative species oxidative stress, and enable remarkable anticancer properties. Our work provides an alternative strategy for overcoming multidrug resistance, which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P-glycoprotein protein expression by ferroptosis. This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.
Challenging Traditional Paradigms in Posttraumatic Pulmonary Thromboembolism
Authors: M. Margaret Knudson, Ernest E. Moore, Lucy Z. Kornblith, Amy M. Shui, Scott Brakenridge, Brandon R. Bruns, Mark D. Cipolle, Todd W. Costantini, Bruce A. Crookes, Elliott R. Haut, Andrew J. Kerwin, Laszlo N. Kiraly, Lisa M. Knowlton, Matthew J. Martin, Michelle K. McNutt, David J. Milia, Alicia Mohr, Ram Nirula, Fredrick B. Rogers, Thomas M. Scalea, Sherry L. Sixta, David A. Spain, Charles E. Wade, George C. Velmahos
Journal: JAMA Surgery (2021)

Pulmonary clots are seen frequently on chest computed tomography performed after trauma, but recent studies suggest that pulmonary thrombosis (PT) and pulmonary embolism (PE) after trauma are independent clinical events.To assess whether posttraumatic PT represents a distinct clinical entity associated with the nature of the injury, different from the traditional venous thromboembolic paradigm of deep venous thrombosis (DVT) and PE.This prospective, observational, multicenter cohort study was conducted by the Consortium of Leaders in the Study of Traumatic Thromboembolism (CLOTT) study group. The study was conducted at 17 US level I trauma centers during a 2-year period (January 1, 2018, to December 31, 2020). Consecutive patients 18 to 40 years of age admitted for a minimum of 48 hours with at least 1 previously defined trauma-associated venous thromboembolism (VTE) risk factor were followed up until discharge or 30 days.Investigational imaging, prophylactic measures used, and treatment of clots.The main outcomes of interest were the presence, timing, location, and treatment of any pulmonary clots, as well as the associated injury-related risk factors. Secondary outcomes included DVT. We regarded pulmonary clots with DVT as PE and those without DVT as de novo PT.A total of 7880 patients (mean [SD] age, 29.1 [6.4] years; 5859 [74.4%] male) were studied, 277 with DVT (3.5%), 40 with PE (0.5%), and 117 with PT (1.5%). Shock on admission was present in only 460 patients (6.2%) who had no DVT, PT, or PE but was documented in 11 (27.5%) of those with PE and 30 (25.6%) in those with PT. Risk factors independently associated with PT but not DVT or PE included shock on admission (systolic blood pressure <90 mm Hg) (odds ratio, 2.74; 95% CI, 1.72-4.39; P < .001) and major chest injury with Abbreviated Injury Score of 3 or higher (odds ratio, 1.72; 95% CI, 1.16-2.56; P = .007). Factors associated with the presence of PT on admission included major chest injury (14 patients [50.0%] with or without major chest injury with an Abbreviated Injury Score >3; P = .04) and major venous injury (23 [82.1%] without major venous injury and 5 [17.9%] with major venous injury; P = .02). No deaths were attributed to PT or PE.To our knowledge, this CLOTT study is the largest prospective investigation in the world that focuses on posttraumatic PT. The study suggests that most pulmonary clots are not embolic but rather result from inflammation, endothelial injury, and the hypercoagulable state caused by the injury itself.
Abstract 12051: Impact of COVID-19 on Barriers to Dispatcher-Assisted Cardiopulmonary Resuscitation in Adult Out-of-Hospital Cardiac Arrests in Singapore
Authors: Cherylyn Hui Xin Toh, Shir Lynn Lim, Yazid Muhammad, Nur Shahidah, Qin Xiang Ng, Andrew Ho, Shalini Arulanandam, Benjamin S Leong, Alexander White, Marcus E Ong
Journal: Circulation (2021)

Objective: Reduced rates of bystander cardiopulmonary resuscitation (BCPR) in out-of-hospital cardiac arrest (OHCA) were observed during the Coronavirus Disease-2019 (COVID-19) pandemic in many regions. We investigated the impact of COVID-19 on barriers to Dispatcher-Assisted Cardiopulmonary Resuscitation (DA-CPR) in Singapore. Methods: This nationwide retrospective cohort study involved all calls to our national 995 call center for adult (≥ 18 years old) OHCA not witnessed by Emergency Medical Services. We reviewed audio recordings during the pandemic (January-June 2020) and pre-pandemic (January-June 2019) periods to compare the OHCA characteristics, and the types of “barriers” to DA-CPR — the reason why DA-CPR was not performed. Our primary outcome was the presence/absence of barriers to DA-CPR. Multivariable logistics regression was used to estimate the adjusted odds ratio (aOR) for the likelihood of barriers to DA-CPR accounting for patient and event characteristics. The effect of COVID-19 on DA-CPR rates was evaluated using interrupted time series analysis. Results: There were 1481 OHCA during the pandemic (median age 73 years, 62.7% male), and 1400 prior to the pandemic (median age 72 years, 63.6% male). Residential OHCA and witnessed OHCA increased during the pandemic (78.9% vs 75.5%, p=0.03 and 56.1% vs 39.9%, p&lt;0.01 respectively), but not BCPR and DA-CPR (64.3% vs 65.6%, p=0.44, and 49.1% vs 48.1%, p=0.57 respectively). There were increased barriers to DA-CPR during the pandemic — ‘patient status changed’ (difficulty with recognition) and ‘caller not with patient’ (witnesses calling family rather than 995) doubled in proportion during COVID-19. ‘afraid to do CPR’ fell to 3.8% during the pandemic, while the fear of COVID-19 transmission made up 0.5% of the barriers. Logistic regression showed that females and OHCAs occurring in home residences were more likely to have barriers to DA-CPR (aOR 1.27 and 2.63 respectively). COVID-19 did not have an impact on the trend of DA-CPR rates (p=0.49). Conclusion: COVID-19 did not affect callers’ willingness to perform DA-CPR. Distancing measures led to more residential arrests with an increase in proportion with barriers to DA-CPR, highlighting opportunities for public education and intervention.
Micro-ecology restoration of colonic inflammation by in-Situ oral delivery of antibody-laden hydrogel microcapsules
Authors: Bo Li, Xin Li, Xiaodong Chu, Pengcheng Lou, Yin Yuan, Aoxiang Zhuge, Xueling Zhu, Yangfan Shen, Jinghua Pan, Liyuan Zhang, Lanjuan Li, Zhongwen Wu
Journal: Bioactive Materials (2021)

In-situ oral delivery of therapeutic antibodies, like monoclonal antibody, for chronic inflammation treatment is the most convenient approach compared with other administration routes. Moreover, the abundant links between the gut microbiota and colonic inflammation indicate that the synergistic or antagonistic effect of gut microbiota to colonic inflammation. However, the antibody activity would be significantly affected while transferring through the gastrointestinal tract due to hostile conditions. Moreover, these antibodies have short serum half-lives, thus, require to be frequently administered with high doses to be effective, leading to low patient tolerance. Here, we develop a strategy utilizing thin shell hydrogel microcapsule fabricated by microfluidic technique as the oral delivering carrier. By encapsulating antibodies in these microcapsules, antibodies survive in the hostile gastrointestinal environment and rapidly release into the small intestine through oral administration route, achieving the same therapeutic effect as the intravenous injection evaluated by a colonic inflammation disease model. Moreover, the abundance of some intestinal microorganisms as the indication of the improvement of inflammation has remarkably altered after in-situ antibody-laden microcapsules delivery, implying the restoration of micro-ecology of the intestine. These findings prove our microcapsules are exploited as an efficient oral delivery agent for antibodies with programmable function in clinical application.
Surgical resection of glioblastomas induces pleiotrophin-mediated self-renewal of glioblastoma stem cells in recurrent tumors
Authors: Arnon Møldrup Knudsen, Bo Halle, Oriane Cédile, Mark Burton, Christina Baun, Helge Thisgaard, Atul Anand, Christopher Hubert, Mads Thomassen, Signe Regner Michaelsen, Birgitte Brinkmann Olsen, Rikke Hedegaard Dahlrot, Rolf Bjerkvig, Justin Durla Lathia, Bjarne Winther Kristensen
Journal: Neuro-Oncology (2021)

Glioblastomas are highly resistant to therapy, and virtually all patients experience tumor recurrence after standard-of-care treatment. Surgical tumor resection is a cornerstone in glioblastoma therapy, but its impact on cellular phenotypes in the local postsurgical microenvironment has yet to be fully elucidated.We developed a preclinical orthotopic xenograft tumor resection model in rats with integrated 18F-FET PET/CT imaging. Primary and recurrent tumors were subject to bulk and single-cell RNA sequencing. Differentially expressed genes and pathways were investigated and validated using tissue specimens from the xenograft model, 23 patients with matched primary/recurrent tumors, and a cohort including 190 glioblastoma patients. Functional investigations were performed in vitro with multiple patient-derived cell cultures.Tumor resection induced microglia/macrophage infiltration, angiogenesis as well as proliferation and upregulation of several stem cell-related genes in recurrent tumor cells. Expression changes of selected genes SOX2, POU3F2, OLIG2, and NOTCH1 were validated at the protein level in xenografts and early recurrent patient tumors. Single-cell transcriptomics revealed the presence of distinct phenotypic cell clusters in recurrent tumors which deviated from clusters found in primary tumors. Recurrent tumors expressed elevated levels of pleiotrophin (PTN), secreted by both tumor cells and tumor-associated microglia/macrophages. Mechanistically, PTN could induce tumor cell proliferation, self-renewal, and the stem cell program. In glioblastoma patients, high PTN expression was associated with poor overall survival and identified as an independent prognostic factor.Surgical tumor resection is an iatrogenic driver of PTN-mediated self-renewal in glioblastoma tumor cells that promotes therapeutic resistance and tumor recurrence.
Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing
Authors: Sonia Zambrano, Liqun He, Toshiki Kano, Ying Sun, Emmanuelle Charrin, Mark Lal, Christer Betsholtz, Yusuke Suzuki, Jaakko Patrakka
Journal: Kidney International (2021)