tbuckley/cabot-search huggingface dataset:
Autologous cell replacement: a noninvasive AI approach to clinical release testing
Authors: Budd A. Tucker, Robert F. Mullins, Edwin M. Stone
Journal: Journal of Clinical Investigation (2020)

The advent of human induced pluripotent stem cells (iPSCs) provided a means for avoiding ethical concerns associated with the use of cells isolated from human embryos. The number of labs now using iPSCs to generate photoreceptor, retinal pigmented epithelial (RPE), and-more recently-choroidal endothelial cells has grown exponentially. However, for autologous cell replacement to be effective, manufacturing strategies will need to change. Many tasks carried out by hand will need simplifying and automating. In this issue of the JCI, Schaub and colleagues combined quantitative bright-field microscopy and artificial intelligence (deep neural networks and traditional machine learning) to noninvasively monitor iPSC-derived graft maturation, predict donor cell identity, and evaluate graft function prior to transplantation. This approach allowed the authors to preemptively identify and remove abnormal grafts. Notably, the method is (a) transferable, (b) cost and time effective, (c) high throughput, and (d) useful for primary product validation.
Therapeutic drug monitoring using saliva as matrix: an opportunity for linezolid, but challenge for moxifloxacin
Authors: Simone H.J. van den Elsen, Onno W. Akkerman, Erwin M. Jongedijk, Mireille Wessels, Samiksha Ghimire, Tjip S. van der Werf, Daan J. Touw, Mathieu S. Bolhuis, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2020)

<b>Therapeutic drug monitoring using saliva as matrix is a suitable alternative for serum therapeutic drug monitoring of linezolid, but not for moxifloxacin due to a high variability in saliva-plasma ratios</b>http://bit.ly/2NIYdz7
Prognostic Value of 18F-FDG PET/CT—Metabolic Parameters at Baseline and Interim Assessment in Pediatric Anaplastic Large Cell Lymphoma
Authors: Boon Mathew, Kalasekhar Vijayasekharan, Sneha Shah, Nilendu C. Purandare, Archi Agrawal, Ameya Puranik, Maya Prasad, Gaurav Narula, Shripad Banavali, Venkatesh Rangarajan
Journal: Clinical Nuclear Medicine (2019)

Introduction The event-free survival in pediatric anaplastic large cell lymphoma (ALCL) remains at 70% irrespective of the diverse chemotherapy regimens used. There is lack of valid prognostic factors identifying high-risk patients. We investigated the prognostic value of baseline metabolic parameters and interim response on 18 F-FDG PET/CT in pediatric ALCL patients. Methods We retrospectively reviewed 40 pediatric ALCL patients with paired 18 F-FDG PET/CT and treated uniformly on vinblastine-based institution protocol. The SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis of the lymphomatous lesion were measured. Continuous PET parameters were stratified by their median values. Deauville scoring system was used to assess response to chemotherapy in the interim scan. Prognostic factors for overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Results At median follow-up of 52 months, 13 patients died and 13 had recurrence. On univariate analysis, higher whole-body MTV (WBMTV) and partial response on interim scan were statistically associated with OS. High-risk features, WBMTV, and partial response were statistically associated with DFS. On multivariate analysis combining baseline characteristics and interim response, interim response (hazard ratio, 3.56; P = 0.034) was statistically significant for OS. Multivariate analysis for DFS using only baseline characteristics revealed WBMTV as statistically significant (hazard ratio, 4.08; P = 0.035), but none of the parameters was statistically significant when baseline characteristics and interim response were evaluated together. Conclusions Whole-body tumor burden assessment with MTV and interim response may help to identify high-risk patients who might get benefitted from intensive therapy.
Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity
Authors: Romana R. Gerner, Sophie Macheiner, Simon Reider, Kerstin Siegmund, Felix Grabherr, Lisa Mayr, Bernhard Texler, Patrizia Moser, Maria Effenberger, Hubert Schwaighofer, Alexander R. Moschen, Brigitte Kircher, Herbert Oberacher, Robert Zeiser, Herbert Tilg, David Nachbaur
Journal: Leukemia (2020)
IA08 Mapping Mitochondrial Heterogeneity in Lung Cancer
Authors: M. Momcilovic, M. Han, E. Bushong, L. Stiles, S.M. Dubinett, H. Christofk, O. Shirihai, C.M. Koehler, S. Sadeghi, M. Ellisman, D.B. Shackelford
Journal: Journal of Thoracic Oncology (2020)
Identifying Missing Biosynthesis Enzymes of Plant Natural Products
Authors: Thomas Dugé de Bernonville, Nicolas Papon, Marc Clastre, Sarah E. O’Connor, Vincent Courdavault
Journal: Trends in Pharmacological Sciences (2020)

Elucidating plant-specialized biosynthetic pathways has always constituted a laborious task, notably for natural products with high pharmaceutical values. Here, we discuss emerging omics-based strategies that facilitate the identification of genes from these complex metabolic pathways, paving the way to engineered supplies of these compounds through synthetic biology approaches.
Melanoma Prognosis: Accuracy of the American Joint Committee on Cancer Staging Manual Eighth Edition
Authors: Shirin Bajaj, Douglas Donnelly, Melissa Call, Paul Johannet, Una Moran, David Polsky, Richard Shapiro, Russell Berman, Anna Pavlick, Jeffrey Weber, Judy Zhong, Iman Osman
Journal: JNCI Journal of the National Cancer Institute (2020)

The American Joint Committee on Cancer (AJCC) maintains that the eighth edition of its Staging Manual (AJCC8) has improved accuracy compared with the seventh (AJCC7). However, there are concerns that implementation may disrupt analysis of active clinical trials for stage III patients. We used an independent cohort of melanoma patients to test the extent to which AJCC8 has improved prognostic accuracy compared with AJCC7.We analyzed a cohort of 1315 prospectively enrolled patients. We assessed primary tumor and nodal classification of stage I-III patients using AJCC7 and AJCC8 to assign disease stages at diagnosis. We compared recurrence-free (RFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. We then compared concordance indices of discriminatory prognostic ability and area under the curve of 5-year survival to predict RFS and OS. All statistical tests were two-sided.Stage IIC patients continued to have worse outcomes than stage IIIA patients, with a 5-year RFS of 26.5% (95% confidence interval [CI] = 12.8% to 55.1%) vs 56.0% (95% CI = 37.0% to 84.7%) by AJCC8 (P = .002). For stage I, removing mitotic index as a T classification factor decreased its prognostic value, although not statistically significantly (RFS concordance index [C-index] = 0.63, 95% CI = 0.56 to 0.69; to 0.56, 95% CI = 0.49 to 0.63, P = .07; OS C-index = 0.48, 95% CI = 0.38 to 0.58; to 0.48, 95% CI = 0.41 to 0.56, P = .90). For stage II, prognostication remained constant (RFS C-index = 0.65, 95% CI = 0.57 to 0.72; OS C-index = 0.61, 95% CI = 0.50 to 0.72), and for stage III, AJCC8 yielded statistically significantly enhanced prognostication for RFS (C-index = 0.65, 95% CI = 0.60 to 0.70; to 0.70, 95% CI = 0.66 to 0.75, P = .01).Compared with AJCC7, we demonstrate that AJCC8 enables more accurate prognosis for patients with stage III melanoma. Restaging a large cohort of patients can enhance the analysis of active clinical trials.
Identification of Cartilage Microbial <scp>DNA</scp> Signatures and Associations With Knee and Hip Osteoarthritis
Authors: Christopher M. Dunn, Cassandra Velasco, Alexander Rivas, Madison Andrews, Cassandra Garman, Paul B. Jacob, Matlock A. Jeffries
Journal: Arthritis & Rheumatology (2020)

Objective Alterations of the gut microbiota have been implicated in many forms of arthritis, but an examination of cartilage microbial patterns has not been performed. This study was undertaken to characterize the microbial DNA profile of articular cartilage and determine changes associated with osteoarthritis ( OA ). Methods We performed 16S ribosomal RNA gene deep sequencing on eroded and intact cartilage samples from knee OA patients (n = 21 eroded and 21 intact samples) and hip OA patients (n = 34 eroded and 33 intact samples) and cadaver controls (n = 10 knee samples and 10 hip samples). Microbial DNA diversity was assessed, groups were compared, and metagenomic profiles were reconstructed. Confirmation was performed in an independent cohort by clade‐specific quantitative polymerase chain reaction. Findings in human cartilage were compared to those in cartilage from OA ‐susceptible C57 BL /6 (B6) mice and OA ‐resistant MRL /MpJ ( MRL ) mice. Germ‐free B6 mouse cartilage was analyzed as a methodologic control. Results Alpha diversity was reduced in human OA versus control samples ( P &lt; 0.0001), and in hip versus knee samples ( P &lt; 0.0001). Numerous clades were different in human OA versus control samples, and similar findings were noted in comparisons of murine B6 versus MRL mice. Hip samples were microbiologically distinct from knee samples. OA microbial DNA demonstrated increased gram‐negative constituents ( P = 0.02). Functional analysis demonstrated increases in lipopolysaccharide production ( P = 9.9 × 10 −3 ), phosphatidylinositol signaling ( P = 4.2 × 10 −4 ), and nitrogen metabolism ( P = 8 × 10 −3 ) and decreases in sphingolipid metabolism ( P = 7.7 × 10 −4 ) associated with OA . Conclusion Our study reveals a microbial DNA signature in human and mouse cartilage. Alterations in this signature, including increases in gram‐negative constituents, occur during the development and progression of human OA . Furthermore, our findings indicate that strain‐specific signatures exist within mouse cartilage that mirror human patterns. Further study of the establishment and potential pathogenic role of these DNA signatures is needed.
Establishing high-accuracy biomarkers for colorectal cancer by comparing fecal microbiomes in patients with healthy families
Authors: Jian Yang, Dongfang Li, Zhenyu Yang, Wenkui Dai, Xin Feng, Yanhong Liu, Yiqi Jiang, Pingang Li, Yinhu Li, Bo Tang, Qian Zhou, Chuangzhao Qiu, Chao Zhang, Ximing Xu, Su Feng, Daxi Wang, Heping Wang, Wenjian Wang, Yuejie Zheng, Lin Zhang, Wenjie Wang, Ke Zhou, Shuaicheng Li, Peiwu Yu
Journal: Gut Microbes (2020)

Colorectal cancer (CRC) causes high morbidity and mortality worldwide, and noninvasive gut microbiome (GM) biomarkers are promising for early CRC diagnosis. However, the GM varies significantly based on ethnicity, diet and living environment, suggesting varied GM biomarker performance in different regions. We performed a metagenomic association analysis on stools from 52 patients and 55 corresponding healthy family members who lived together to identify GM biomarkers for CRC in Chongqing, China. The GM of patients differed significantly from that of healthy controls. A total of 22 microbial genes were included as screening biomarkers with high accuracy in additional 46 cases and 40 randomly selected healthy adults in Chongqing (area under the receive-operation curve (AUC) = 0.905, 95% CI 0.832–0.977). The classifier based on the identified 22 biomarkers also performed well in the cohort from Hong Kong (AUC = 0.811, 95% CI 0.715–0.907) and French (AUC = 0.859, 95% CI 0.773–0.944) populations. Quantitative PCR was applied for measuring three selected biomarkers in the classification of CRC patients in independent Chongqing population containing 30 cases and 30 controls and the best biomarker from Coprobacillus performed well with high AUC (0.930, 95% CI 0.904–0.955). This study revealed increased sensitivity and applicability of our GM biomarkers compared with previous biomarkers significantly promoting the early diagnosis of CRC.
Impact of the visceral leishmaniasis elimination initiative on Leishmania donovani transmission in Nepal: a 10-year repeat survey
Authors: Kristien Cloots, Surendra Uranw, Bart Ostyn, Narayan Raj Bhattarai, Epke Le Rutte, Basudha Khanal, Albert Picado, François Chappuis, Epco Hasker, Prahlad Karki, Suman Rijal, Marleen Boelaert
Journal: The Lancet Global Health (2020)

BackgroundNepal launched a visceral leishmaniasis (also known as kala-azar) elimination initiative in 2005. We primarily aimed to assess whether transmission of Leishmania donovani had decreased since the launch of the initiative. We also assessed the validity of the direct agglutination test (DAT) as a marker of infection, in view of future surveillance systems.MethodsWe did a repeat survey in a population aged 2 years and older for whom baseline serological data were available from 2006. Data were from three districts in the eastern region of Nepal. The primary outcome of interest was prevalent infection with L donovani as measured with DAT (cutoff value ≥1:3200). We compared age group-specific and cluster-specific seroprevalences in 2016 with those in 2006, using χ2 tests, with a specific focus on the comparison of seroprevalences in children born between 1996 and 2005, and those born between 2006 and 2015. To estimate the overall adjusted risk ratio for being seropositive in 2016 compared with 2006, we fitted a Poisson model controlling for age, sex, and cluster.FindingsBetween Oct 17, 2016, and Dec 26, 2016, we assessed 6609 individuals. DAT prevalence in children younger than 10 years was 4·1% (95% CI 3·2–5·4) in 2006 versus 0·5% (0·1–1·7) in 2016 (p<0·0001). Seroprevalence was lower in 2016 than in 2006 in all age groups and in all repeated clusters. The overall adjusted risk ratio of being seropositive was 0·44 (95% CI 0·37–0·52) for 2016 compared with 2006, and 0·04 (0·01–0·16) in children younger than 10 years.InterpretationOur findings show that transmission of L donovani in Nepal has decreased significantly between 2006 and 2016, coinciding with the elimination programme. DAT seems useful for monitoring of L donovani transmission.FundingThe Directorate-General for Development Cooperation of Belgium.
When Intensive Care Becomes Good End-of-Life Care
Authors: Hannah Wunsch
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

When Intensive Care Becomes Good End-of-Life Care Years ago, I began a research project with colleagues to demonstrate that physicians receive different, and arguably better, endof-life care because of our greater knowledge about dying.We hypothesized, as had others, that physicians would be more likely to die at home, would be less likely to die in an ICU, and would generally receive less "aggressive" care.It took years to complete the study.The findings were not what we had expected: Physicians did receive more palliative care, but they also were more likely to die in an ICU and, among those with cancer, more likely to receive chemotherapy in the last 6 months of life; it was more of everything (1).The work by Rolnick and colleagues (2) in this issue of the Journal (pp.832-839), demonstrating that family satisfaction with end-of-life care for patients dying in the hospital is higher for patients who have received intensive care, is aligned with our findings, and it challenges the general belief regarding what constitutes a "good" death.The study forces us to reevaluate what we strive for as caregivers when we have conversations with patients and families, helping them to navigate the complex decision-making regarding where to go in the hospital for care.This finding regarding greater satisfaction was true among medical and surgical subgroups, as well as when focused on those with severe, life-limiting illnesses.Whether these responses were a reaction to intensive monitoring and invasive support or, as I suspect is often the case, to the reassurance of skilled caregivers is not answered by these data.Although overall satisfaction with care was high, a notable (and very concerning) finding was that only 50% of individuals believed that pain was well controlled.As a physician who is responsible for determining which patients should or should not be admitted to an ICU, I have had my share of frustration admitting patients I believe I cannot help, that my efforts have been wasted because the patient will not leave the hospital or even the ICU.I have felt resentment toward patients and families who have insisted on coming to the ICU because I viewed intensive care primarily through the lens of what I and the rest of the team could do in terms of providing lifesaving therapies.However, that has changed.The man I married just 6 years ago died in June 2019.He was diagnosed with metastatic cancer less than 2 years after our wedding and died 4 years after that.He received palliative care but also chemotherapy in his last week of life and died in the ICU; we were both intensive care physicians, and the story was exactly as told writ large in my own study.There was clearly a comfort in the ICU-the knowledge that excellent nurses and doctors were always available.A symptom such as dyspnea is scary, either to experience oneself or to watch
Anti-CD30 chimeric antigen receptor T cell therapy for relapsed/refractory CD30+ lymphoma patients
Authors: D. Wang, C. Zeng, B. Xu, J.-H. Xu, J. Wang, L.-J. Jiang, Q.-X. Wang, C.-R. Li, N. Wang, L. Huang, Y.-C. Zhang, Y. Xiao, J.-F. Zhou
Journal: Blood Cancer Journal (2020)
David Oliver: The risks of discharging patients early against doctors’ judgment
Authors: David Oliver
Journal: BMJ (2020)

On 13 January the BBC reported the contents of an internal email to doctors from the medical director and chief nursing officer at the Royal Cornwall Hospital.1 In response to “significant pressure,” and to free up bed capacity, the email urged doctors to discharge patients “earlier than some clinicians would like.”

Last month the Guardian had carried a similar story from Norfolk and Norwich University Hospital, reporting internal memos urging senior doctors to find the “least unsafe option” in identifying patients to discharge.2

No doubt, senior operational and clinician managers at those trusts face an almost impossible balancing act. I’m sure that you’d find similar emails in dozens of acute hospitals around the NHS, given that they start each day in negative bed equity, with patients queuing in the emergency department, sometimes on trolleys in corridors.

What struck me about both cases was that the …
Abstract 14739: The Role of Mitochondrial Stress and the Late Sodium Current in Ibrutinib-Mediated Atrial Fibrillation
Authors: Ambili Menon, Liang Hong, Brandon Chalzan, Arvind Sridhar, Meihong Zhang, Christopher Gans, Jalees Rehman, Dawood Darbar
Journal: Circulation (2018)

Background: Ibrutinib (a Bruton’s tyrosine kinase inhibitor, BTKI) is rapidly becoming the treatment of choice for many B-cell malignancies, but its proarrhythmic effects may limit its use. Ibrutin...
A trial‐based cost‐effectiveness analysis of topical 5‐fluorouracil vs. imiquimod vs. ingenol mebutate vs. methyl aminolaevulinate conventional photodynamic therapy for the treatment of actinic keratosis in the head and neck area performed in the Netherlands
Authors: M.H.E. Jansen, J.P.H.M. Kessels, I. Merks, P.J. Nelemans, N.W.J. Kelleners‐Smeets, K. Mosterd, B.A.B. Essers
Journal: British Journal of Dermatology (2020)

Actinic keratosis (AK) is a common premalignant skin condition that might have the ability to progress into squamous cell carcinoma. Due to the high incidence of AK, treatment of this disease significantly impacts healthcare spending. To determine which commonly prescribed field‐directed treatment is the most cost‐effective, when comparing 5‐fluorouracil (5‐FU) 5%, imiquimod (IMQ) 5%, ingenol mebutate (IM) 0·015% and methyl aminolaevulinate photodynamic therapy (MAL‐PDT) for AK in the head and neck region. We performed an economic evaluation from a healthcare perspective. Data were collected alongside a single‐blinded, prospective, multicentre randomized controlled trial with 624 participants in the Netherlands. The outcome measure was expressed as the incremental cost‐effectiveness ratio, which is the incremental costs per additional patient with ≥ 75% lesion reduction compared with baseline. This trial was registered at ClinicalTrials.gov, number NCT02281682. The trial showed that 5‐FU was the most effective field treatment for AK in the head and neck region. Twelve months post‐treatment, the total mean costs for 5‐FU were significantly lower (€433) than the €728, €775 and €1621 for IMQ, IM and MAL‐PDT, respectively. The results showed that 5‐FU was a dominant cost‐effective treatment (more effective and less expensive) compared with the other treatments, 12 months post‐treatment. Based on these results, we consider 5‐FU 5% cream as the first‐choice treatment option for multiple AKs in the head and neck area. What's already known about this topic? Due to the increasing incidence of actinic keratosis (AK), the recommended treatment results in a considerable socioeconomic burden for (dermatological) healthcare. Although cost‐effectiveness modelling studies have been performed in which different treatments for AK were compared, a prospective clinical trial comparing four frequently prescribed treatments on effectiveness and resource consumption within a time horizon of 12 months has never been conducted. What does this study add? This is the first study examining the cost‐effectiveness of 5‐fluorouracil 5% cream, imiquimod 5% cream, ingenol mebutate 0·015% gel and methyl aminolaevulinate photodynamic therapy, with data collected in a randomized controlled trial over a time horizon of 12 months. We found that 5‐fluorouracil was a dominant cost‐effective treatment (more effective and less costly), based on data from the Netherlands. Linked Comment:Steeb et al. Br J Dermatol 2020; 183:612.
Recurrence at Nipple-Areola Complex and Safety of Nipple-Sparing Mastectomy—Reply
Authors: Zhen-Yu Wu, BeomSeok Ko
Journal: JAMA Surgery (2020)

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