tbuckley/cabot-search huggingface dataset:
Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance
Authors: Mariann Gyöngyösi, Dominika Lukovic, Katrin Zlabinger, Andreas Spannbauer, Alfred Gugerell, Noemi Pavo, Denise Traxler, Dietmar Pils, Gerald Maurer, Andras Jakab, Martin Riesenhuber, Andreas Pircher, Johannes Winkler, Jutta Bergler-Klein
Journal: Cardiovascular Research (2019)

The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
Population Health Management: Saving Lives and Saving Money?
Authors: Ashish K. Jha
Journal: JAMA (2019)

Marc N. Gourevitch, MD, MPH; Lesley H. Curtis, PhD; Maureen S. Durkin, PhD, DrPH; Angela Fagerlin, PhD; Annetine C. Gelijns, PhD, JD; Richard Platt, MD, MSc; Belinda M. Reininger, DrPH; Judith Wylie-Rosett, EdD, RD; Katherine Jones, MA; William M. Tierney, MD
Persistence and effectiveness of systemic therapies for psoriasis
Authors: K.J. Mason, S. Williams, Z.Z.N. Yiu, K. McElhone, D.M. Ashcroft, C.E. Kleyn, Z.K. Jabbar‐Lopez, C.M. Owen, N.J. Reynolds, C.H. Smith, N. Wilson, R.B. Warren, C.E.M. Griffiths
Journal: British Journal of Dermatology (2019)

The health watchdog NICE recommends that patients with moderate‐to‐severe psoriasis should try at least two non‐biologic systemic therapies before they are eligible for biologic drugs. Unfortunately, there are few studies which compare different drugs and give information about how long they are effective. The authors, based in several major centres in the UK, performed a systematic review (a type of high quality way of reviewing the scientific research) of the major non‐biologic drugs used in psoriasis, using databases including MEDLINE, PubMed and Embase. They identified 411 studies, of which 8 had recruited more than 100 patients who were included in the study, representing 4624 patients. Discontinuation because of adverse events (unwanted side effects) was commoner with treatments called fumaric acid esters (43‐46%) than with methotrexate (22%). In one study, 50% remained on methotrexate, 42% on acitretin but only 22% on ciclosporin after one year; however, this may reflect the fact that ciclosporin is generally used in short courses because of increased toxicity in long term use. In other studies, the mean time for discontinuing methotrexate ranged from 7.7 to 22.3 months, whereas for fumaric acid esters it was 28 to 50 months. 76% of patients on fumaric acid esters and 59% on methotrexate achieved a reduction in Psoriasis Area and Severity Index (PASI score) of greater than 75%. PASI is used to record the redness, thickness and scaling of a patient's psoriasis and to measure how well a treatment works, as a reduction in the PASI score means a reduction in these symptoms; for example PASI 75 means the patient has a 75% or more reduction in their PASI score from the start. The authors concluded that it was difficult to compare the available studies because they used different methods of analysis, and stressed the need for long term observational studies (i.e. where researchers observe the effect of a treatment without trying to change who is or isn't exposed to it) of good quality.
Serum-sodium as an independent prognostic factor in metastatic renal cell carcinoma
Authors: A. N. Jeppesen, H. K. Jensen, F. Donskov, N. Marcussen, H. von der Maase
Journal: Journal of Clinical Oncology (2009)

5102 Background: Recently, low serum sodium has been associated with poor disease-free and overall survival in localized renal cell carcinoma (RCC) (Vasudev, Clin Can Res. 2008). The present study investigated the prognostic impact of serum-sodium values below normal in patients with metastatic RCC (mRCC). Methods: A cohort of 120 consecutive patients with mRCC received subcutaneous, low-dose Interleukin-2 and Interferon-α at Dept. of Oncology, Aarhus University Hospital, from 2002 to 2004 (Cohort A). Baseline variables were collected retrospectively. Follow up was at least 4 years. Potential prognostic factors were analyzed by univariate and multivariate analyses. Endpoint was overall survival. An independent cohort of 120 consecutive patients with mRCC was used for validation. These patients were treated with interleukin-2 based regimens at the same institution from 1999 to 2002 (Cohort B). Data in this cohort were prospectively collected. Results: In cohort A, the estimated 5-year survival rate was 15% and the median survival was 15.1 months. Serum-sodium ranged between 126 and 144 mmol/l. Twenty-four patients (20%) had serum-sodium levels below normal range (&lt;136 mmol/l). In the multivariate analysis, significant independent risk factors of short survival were serum-sodium below normal value (HR 1.90, CI 1.1–3.2, p = 0.014), high neutrophile count (&gt;7) (HR 1.75, CI 1.1–2.8, p = 0.018), lactate dehydrogenase &gt;1.5 upper normal level (HR 2.09, CI 1.3–3.3, p = 0.002), and number of sites (+3) (HR 1.92; CI 1.3–2.9, p = 0.003). In cohort B, the observed 5-year survival rate was 15% and the median survival was 15 months. Serum-sodium ranged between 128 mmol/l and 146 mmol/l. Seventeen patients (14%) had sodium levels below normal range. In the multivariate analysis, serum-sodium was validated as an independent prognostic factor (HR 2.98, CI 1.54–5.77, p = 0.001). Conclusions: Low serum-sodium is a new, validated, independent prognostic factor in patients with metastatic RCC. No significant financial relationships to disclose.
Dynamic real-time imaging of marrow-resident neutrophils interacting with human mesenchymal stem cells during systemic lipopolysaccharide challenge.
Authors: Alex Yee-Chen Huang, Jay T. Myers, Deborah Sim Barkauskas
Journal: Journal of Clinical Oncology (2013)

e22158 Background: Human mesenchymal stem cells (hMSCs) have gained intense interest due to their immune-modulatory, tissue differentiating and homing properties to sites of inflammation and tumor microenvironment, as evidenced by more than 200 ongoing clinical trials using hMSCs in a variety of clinical settings. Despite evidence demonstrating the bio-distribution of infused hMSCs in target organs using static fluorescence imaging or whole-body imaging techniques, there is controversy regarding how hMSCs exert their biological effects, and very little is known about how they behave dynamically within host tissues on a single-cell level in vivo. Methods: We infused fluorescently labeled clinical-grade hMSCs into immune-competent mice in which neutrophils and monocytes express a second fluorescent marker under the Lysozyme M (LysM) promoter. The recipient mice were then subjected to serial 4-D (xyzt) imaging of the bone marrow cavity with intravital two-photon microscopy (TPM) during acute systemic Lipopolysaccharide (LPS) challenges to observe changes in MSC and neutrophil migration behavior. Results: We were able, for the first time, to capture dynamic interactions between and migration pattern of hMSCs and LysM + granulocytes in the bone marrow of live mice during systemic LPS challenge. Contrary to some published reports, many of the infused hMSCs remained intact despite repeated cellular contacts with host neutrophils. However, we also observed the destruction and subsequent phagocytosis of some hMSCs by surrounding granulocytes. Conclusions: Our imaging platform provides opportunities to gain insight into the biology and therapeutic mechanisms of hMSCs in vivo at a single-cell level within live hosts.
Influenza vaccine effectiveness against laboratory-confirmed influenza in hospitalised adults aged 60 years or older, Valencia Region, Spain, 2017/18 influenza season
Authors: Ainara Mira-Iglesias, F Xavier López-Labrador, Víctor Baselga-Moreno, Miguel Tortajada-Girbés, Juan Mollar-Maseres, Mario Carballido-Fernández, Germán Schwarz-Chavarri, Joan Puig-Barberà, Javier Díez-Domingo
Journal: Eurosurveillance (2019)

Introduction Influenza immunisation is recommended for elderly people each season. The influenza vaccine effectiveness (IVE) varies annually due to influenza viruses evolving and the vaccine composition. Aim To estimate, in inpatients ≥ 60 years old, the 2017/18 trivalent IVE, overall, by vaccine type and by strain. The impact of vaccination in any of the two previous seasons (2016/17 and 2015/16) on current (2017/18) IVE was also explored. Methods This was a multicentre prospective observational study within the Valencia Hospital Surveillance Network for the Study of Influenza and Respiratory Viruses Disease (VAHNSI, Spain). The test-negative design was applied taking laboratory-confirmed influenza as outcome and vaccination status as main exposure. Information about potential confounders was obtained from clinical registries and/or by interviewing patients; vaccine information was only ascertained by registries. Results Overall, 2017/18 IVE was 9.9% (95% CI: −15.5 to 29.6%), and specifically, 48.3% (95% CI: 13.5% to 69.1%), −29.9% (95% CI: −79.1% to 5.8%) and 25.7% (95% CI: −8.8% to 49.3%) against A(H1N1)pdm09, A(H3N2) and B/Yamagata lineage, respectively. For the adjuvanted and non-adjuvanted vaccines, overall IVE was 10.0% (95% CI: −24.4% to 34.9%) and 7.8% (95% CI: −23.1% to 31.0%) respectively. Prior vaccination significantly protected against influenza B/Yamagata lineage (IVE: 50.2%; 95% CI: 2.3% to 74.6%) in patients not vaccinated in the current season. For those repeatedly vaccinated against influenza A(H1N1)pdm09, IVE was 46.4% (95% CI: 6.8% to 69.2%). Conclusion Our data revealed low vaccine effectiveness against influenza in hospitalised patients ≥60 years old in 2017/18. Prior vaccination protected against influenza A(H1N1)pdm09 and B/Yamagata-lineage.
Which operation is most effective for complete rectal prolapse?
Authors: Stella Maye Dilke, Claire Becker, Phillip James Tozer, Carolynne Vaizey
Journal: BMJ (2019)

### What you need to know

Rectal prolapse affects about 2.5 per 100 000 people each year in the United Kingdom.1 It is more common in women.2 Risk factors include multiple deliveries, straining, anorexia, traumatic vaginal delivery, and old age.3 Protrusion of the rectum through the anal canal can be distressing for the patient, causing discomfort and embarrassment. Complications include bleeding, constipation, incontinence, rectal ulcers, and, rarely, rectal ischaemia, which is an emergency.

Complete (full thickness) rectal prolapse involves protrusion containing all the layers of the rectal wall through the anus (fig 1). A mucosal prolapse occurs when mucosa alone protrudes through the anus. Internal intussusception is a prolapse of the rectum into the distal rectum or anal canal but without protrusion outside the anus.



Fig 1 
Full thickness rectal prolapse (reproduced with permission of Societe Nationale Francaise de Colo-Proctologie)



Surgery is the definitive treatment and can provide complete resolution of full thickness rectal prolapse.4 Some patients, however, experience recurrence and complications such as constipation and faecal incontinence and may require further surgery.3 A minority of patients prefer symptom control, or are unfit for surgery, and are treated with laxatives and manual reduction.

In this article we focus on surgical management of full thickness rectal prolapse. There are a range of surgical techniques available (box 1),23 but there is no consensus on which is the most effective.5 Traditionally, the open abdominal procedure was reserved for younger, fitter patients, …
What to Tell a Parent Who Worries a Young Child Has Autism
Authors: Annette Estes, Tanya St. John, Stephen R. Dager
Journal: JAMA Psychiatry (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Abstract 15911: Reduced Senescence and Enhanced Proliferation of Human Cardiac Progenitor Cells Isolated and Expanded Under Reduced Oxygen Tension
Authors: Huamei He, Hui Xiong, Thomas O’Malley, Beisi Ji, Elizabeth G Favre, Francis X McGowan
Journal: Circulation (2015)

Background: Oxygen availability at the cellular level in vivo is significantly lower (~1-7%) than that used for typical ambient cell culture conditions (21%). Here we investigated whether prolonged culture at reduced O2 concentrations affected proliferation, senescence and oxidative stress of human cardiac progenitor cells (hCPCs). Methods: hCPCs positive for c-kit and negative for lineage markers (ckit+/Lin-) were isolated from right atrial tissues obtained from five infants during repair of congenital heart defects and expanded for a maximum of 10 passages in varying O2 concentrations (1, 5, and 21%); all manipulations were performed at the target O2 in a hypoxic chamber. Cellular phenotype was confirmed by ICC staining and flow cytometry. Doubling time, oxidative stress (8-OH-deoxyguanosine [8OHdG], protein carbonyl formation) and senescence markers (telomere length, telomerase activity, P16ink4a staining) were measured. Results: Reducing ambient O2 from 21% to 1% did not alter cell surface marker expression. Culture and expansion at 21% O2 markedly accelerated hCPC senescence compared to 1% or 5% O2, as indicated by increased P16ink4a positive hCPCs and greater loss of telomere length and telomerase activity; much of this damage appeared to occur during early passage and expansion. Both protein carbonyl and 8OHdG formation progressively increased in 21% O2, whereas these oxidative injury markers showed little change at 1 and 5% O2 concentrations. hCPCs that were cultured at either 5% or 1% O2 demonstrated shorter doubling times with resultant higher cell yields during in vitro expansion. Conclusion: Culturing ckit+/Lin- hCPCs at lower oxygen tension minimizes oxidative damage, reduces senescence, and enhances proliferative potential during long-term culture; expansion at 1% ambient O2 appeared to be most effective. This relatively straightforward modification may further understanding of the biology of CPCs and their regenerative potential.
The "real life" impact of adding bevacizumab to first-line treatment of metastatic colorectal cancer: A retrospective large database study.
Authors: Ariel Hammerman, Sari Greenberg-Dotan, Erez Battat, Haim Bitterman, Baruch Brenner
Journal: Journal of Clinical Oncology (2013)

e14571 Background: Bevacizumab is included in the Israeli National List of Reimbursed Drugs (NLRD) for 1 st line treatment of all metastatic colorectal cancer (mCRC) patients since 7/2006. This study evaluates the "real life" impact of adding bevacizumab to 1 st line treatment of mCRC by comparing patients' outcomes before and after the drug's availability in the NLRD. Methods: We conducted a retrospective database study ,using the computerized databases of Clalit Health Services' (CHS), Israel's largest health care provider, to compare two cohorts: (A) all CHS' patients diagnosed with mCRC between 1/2000-12/2004 that received 1 st line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced), and (B) all CHS's patients that started 1 st line treatment with irinotecan or oxaliplatin-based combination chemotherapy and bevacizumab between 7/2006 and 8/2009 (allowing a minimum follow-up of 3 years). The primary endpoint was overall survival (OS) and the secondary endpoints were 1 st line progression free survival (PFS) and metastatectomy rates. Since data on actual progression status was unavailable, PFS was defined as the duration of 1 st line treatment. As CHS covers more than 50% of the Israeli population, our study may represent the general care received by Israeli patients with mCRC. Results: The study population included 1,739 patients: 1,052 in cohort A and 687 in cohort B. Patient demographics were similar between the cohorts. Median OS was 15.0 months for cohort A (95% CI: 13.4–16.6) and 23.0 months for cohort B (95% CI: 21.7–24.3), with an unadjusted hazard ratio (HR) of 0.71 (95% CI: 0.64-0.80, p&lt;0.0001). Median PFS was 9.8 months (95% CI: 9.0–10.5) for cohort A and 14.0 months (95% CI: 13.0-15.0) for cohort B, with a HR of 0.80 (95% CI: 0.71-0.87, p&lt;0.0001). The rate of metastatectomies was significantly higher in cohort B (8.1% vs. 3.9%; P = 0.001). Conclusions: In this retrospective database analysis, OS, PFS and metastatectomy rates of 1 st line treatment of mCRC were significantly higher in the later period of the study. The addition of bevacizumab to standard treatment of mCRC may have had a major contribution to this improvement.
Optimal combination therapy for advanced colorectal cancer: An examination of synergy and antagonism with EGFR inhibition.
Authors: Nilesh Vora, Steven Evans, Paula J Bernard, Federico Francisco, Robert Alan Nagourney
Journal: Journal of Clinical Oncology (2012)

e14075 Background: While FOLFOX +/- Bevacizumab is the most widely used combination in colorectal cancer (CRC), the EGFr antagonists Cetuximab &amp; Panitumumab have not further enhanced activity. On the contrary, the addition of EGFR inhibitors to Irinotecan-based regimens at 1st &amp; 2nd line has improved response and both progression freel &amp; overall survival (Van Cutsem. 2010; Peeters. 2010.) Methods: We applied the ex vivo analysis of programmed cell death (EVA-PCD) (Nagourney, Curr Treat Opt Onc 2006) to examine interactions between EGFr antagonists and Irinotecan or FOLFOX in 534 human tumor primary culture microspheroids isolated from CRC surgical specimens or cytologically (+) fluids. Gefitinib was used as a surrogate for Cetuxima/Panitumumab activity. Tissue samples exposed to Oxaliplatin, 5FU, Irinotecan, and Oxaliplatin &amp; 5FU (FOLFOX) provided dose response curves with and without Gefitinib for formal synergy analysis by median effect (Chou &amp; Talalay). Results: Shown in table below. Conclusions: Results indicate superiority for Irinotecan combination with the EGFr antagonist Gefitinib. The percentage of synergistic interactions for Irinotecan &amp; Gefitinib (41%) is demonstrably higher than that associated with FOLFOX &amp; Gefitinib (4%). This suggests distinct modes of interaction between these classes of agents favoring Irinotecan and could have an impact upon future clinical trial designs. Recognizing the importance of Kras mutation, additional studies are underway to examine the impact of Kras mutation upon synergy. However, as wild-type and mutant samples would be expected to be equally distributed, subset analyses may reveal quantitative (higher % synergy) rather than qualitative differences (relative activity of Irinotecan vs FOLFOX). Results of these analyses will be reported. Supported in part by the Vanguard Cancer Foundation. [Table: see text]
Risk Factors for Physical Disability in Patients With Leprosy
Authors: Hidyanara L. de Paula, Carlos D. F. de Souza, Sara R. Silva, Paulo R. S. Martins-Filho, Josafá G. Barreto, Ricardo Q. Gurgel, Luis E. Cuevas, Victor S. Santos
Journal: JAMA Dermatology (2019)

The World Health Organization (WHO) 2016-2020 Global Leprosy Strategy aims to reinvigorate efforts to control leprosy and avert leprosy disability to less than 1 per million population.To systematically identify clinical factors associated with physical disability in patients with leprosy.Searches were conducted in Scopus, PubMed, and Web of Science databases to identify studies published from January 23, 1988, to May 23, 2018, using the keywords leprosy and physical disability and related terms.Studies that evaluated patients using the WHO leprosy disability grading system and reported the number of patients with and without disability by clinical characteristics were included.The odds ratio (OR) was used as a measure of association between the clinical features and physical disability. Summary estimates were calculated using random-effects models.The primary outcome was physical disability according to the WHO disability classification. The association between clinical features and physical disability was evaluated.The search identified 2447 reports. After screening titles and abstracts, 177 full-text articles were assessed for eligibility, and 32 studies were included in the systematic review; 24 of the 32 studies included sex information (39 571 patients), of whom 24 218 (61.2%) were male. Male patients with leprosy were more likely to have physical disability than female patients with leprosy (pooled OR, 1.66; 95% CI, 1.43-1.93; I2, 81.3%; P < .001). Persons with multibacillary leprosy were 4-fold more likely to have physical disability than those with paucibacillary leprosy (pooled OR, 4.32; 95% CI, 3.37-5.53; I2, 88.9%, P < .001). Patients having leprosy reactions were more likely to have disability (pooled OR, 2.43; 95% CI, 1.35-4.36; I2, 92.1%; P < .001). Patients with lepromatous leprosy experienced 5- to 12-fold higher odds of disability.This systematic review and meta-analysis confirms the association between the presence of physical disabilities and male sex, multibacillary leprosy, leprosy reactions, and lepromatous presentation. These findings can guide the development of targeted interventions for early identification of individuals at greater risk of developing physical disabilities and education campaigns to promote early consultation to institute treatment for leprosy reactions and prevent physical disability.