tbuckley/cabot-search huggingface dataset:
Palliative Care Interventions for Surgical Patients
Authors: Elizabeth J. Lilley, Kashif T. Khan, Fabian M. Johnston, Ana Berlin, Angela M. Bader, Anne C. Mosenthal, Zara Cooper
Journal: JAMA Surgery (2015)

<h3>Importance</h3> Inpatient palliative care improves symptom management and patient satisfaction with care and reduces hospital costs in seriously ill patients. However, the role of palliative care in the treatment of patients undergoing surgery (surgical patients) remains poorly defined. <h3>Objective</h3> To characterize the content, design, and results of interventions to improve access to palliative care or the quality of palliative care for surgical patients. <h3>Evidence Review</h3> This systematic review was conducted according to PRIMSA guidelines. Articles were identified through searches of PubMed, PsycINFO, EMBASE, and CINAHL as well as manual review of references. Eligible articles included experimental, quasi-experimental, and observational studies published in English from January 1, 1994, through October 31, 2014, in which patient outcomes of palliative care interventions for adult surgical patients were reported. Data on the study setting, design, intervention, participants, and results were extracted from the final study set and analyzed from December 22, 2014, to February 7, 2015. <h3>Findings</h3> A total of 3838 abstracts were identified and screened by 2 reviewers, 77 articles were reviewed in full text, and 25 articles (22 unique interventions involving 8575 unique patients) met the study criteria. Interrater agreement was good (κ = 0.78). Nine single-institution retrospective cohort studies, 7 single-institution prospective cohort studies, 7 single-institution randomized clinical studies, and 2 multicenter randomized clinical studies were included. Nineteen of the 23 single-site studies were performed at academic hospitals. Given the heterogeneity of study methods and measures, meta-analysis was not possible. Preoperative decision-making interventions were associated with decreased mortality in 4 studies. Three studies reported improved quality of communication; 4, improved symptom management; and 7, decreased use of health care resources and decreased cost. However, many studies were small, performed in academic settings, and methodologically flawed and did not measure clinically meaningful outcomes. <h3>Conclusions and Relevance</h3> The sparse evidence regarding interventions to introduce or improve palliative care for surgical patients is further limited by methodologic flaws. Rigorous evaluations of standardized palliative care interventions measuring meaningful patient outcomes are needed.
MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis
Authors: Pedro M Machado, Xenofon Baraliakos, Désirée van der Heijde, Jürgen Braun, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2015)

To study the sequential relationship between MRI vertebral corner inflammation (VCI), vertebral corner fat deposition (VCFD) and the development/growth of radiographic syndesmophytes at the same vertebral corner (VC).Baseline, 24 and 102 weeks spinal MRIs were assessed for the presence/absence of VCI and VCFD. Anterior VCs of lateral radiographs of the cervical and lumbar spine (baseline and 102 weeks) were assessed for the development of new bone (syndesmophyte formation or syndesmophyte formation/growth combined). Data from 161 to 177 patients were analysed at the VC level using two-way and multilevel analyses adjusting for within-patient correlation and MRI reader (generalised estimating equations for binomial outcomes).The presence of VCI (adjusted (adj) OR 1.75 to 1.98) as well as the presence of VCFD (adjOR 1.60 to 2.32) at any time point (TP) were significantly associated with the development of new bone. The combination of VCI and VCFD at the same VC increased the strength of the association, both for the sequential or simultaneous presence of VCI and VCFD across the three TPs (adjOR 2.12 to 2.73), as well as for the development of new VCFD preceded by VCI at a previous TP (adjOR 2.12 to 3.01). The complete absence of both VCI and VCFD across the three TPs 'protected' against new bone formation (adjOR 0.45 to 0.62). However, 40-66% of new bone still developed in VCs without MRI inflammation or fat degeneration at any of the three TPs.Both VCI and VCFD contribute to new bone formation in ankylosing spondylitis (AS), especially if VCI precedes VCFD. However, VCI, VCFD and this particular sequence of events only partially explain the development of new bone in AS.
Grieve's Modern Musculoskeletal Physiotherapy (Fourth edition)
Authors: Fiona Wilson
Journal: British Journal of Sports Medicine (2015)

<h3>Abstract</h3> Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in brute-force association testing without incorporating prior knowledge is challenging due to limited statistical power and effects of linkage disequilibrium. Sequence variants affecting transcription factor (TF) binding at CRMs have a strong potential to influence gene regulatory function, which provides a motivation for prioritising such variants in association testing. Here, we generate an atlas of CRMs showing predicted allelic variation in TF binding affinity in human lymphoblastoid cell lines (LCLs) and test their association with the expression of their putative target genes inferred from Promoter Capture Hi-C and immediate linear proximity. We reveal over 1300 CRM TF-binding variants associated with target gene expression, the majority of them undetected with standard association testing. A large proportion of CRMs showing associations with the expression of genes they contact in 3D localise to the promoter regions of other genes, supporting the notion of ‘epromoters’: dual-action CRMs with promoter and distal enhancer activity.
Implementing a Trauma-Informed Approach in Pediatric Health Care Networks
Authors: Meghan L. Marsac, Nancy Kassam-Adams, Aimee K. Hildenbrand, Elizabeth Nicholls, Flaura K. Winston, Stephen S. Leff, Joel Fein
Journal: JAMA Pediatrics (2015)

Pediatric health care networks serve millions of children each year. Pediatric illness and injury are among the most common potentially emotionally traumatic experiences for children and their families. In addition, millions of children who present for medical care (including well visits) have been exposed to prior traumatic events, such as violence or natural disasters. Given the daily challenges of working in pediatric health care networks, medical professionals and support staff can experience trauma symptoms related to their work. The application of a trauma-informed approach to medical care has the potential to mitigate these negative consequences. Trauma-informed care minimizes the potential for medical care to become traumatic or trigger trauma reactions, addresses distress, provides emotional support for the entire family, encourages positive coping, and provides anticipatory guidance regarding the recovery process. When used in conjunction with family-centered practices, trauma-informed approaches enhance the quality of care for patients and their families and the well-being of medical professionals and support staff. Barriers to routine integration of trauma-informed approaches into pediatric medicine include a lack of available training and unclear best-practice guidelines. This article highlights the importance of implementing a trauma-informed approach and offers a framework for training pediatric health care networks in trauma-informed care practices.
Uncoupling Caveolae From Intracellular Signaling In Vivo
Authors: Jan R. Kraehling, Zhengrong Hao, Monica Y. Lee, David J. Vinyard, Heino Velazquez, Xinran Liu, Radu V. Stan, Gary W. Brudvig, William C. Sessa
Journal: Circulation Research (2016)

Rationale: Caveolin-1 (Cav-1) negatively regulates endothelial nitric oxide (NO) synthase–derived NO production, and this has been mapped to several residues on Cav-1, including F92. Herein, we reasoned that endothelial expression of an F92ACav-1 transgene would let us decipher the mechanisms and relationships between caveolae structure and intracellular signaling. Objective: This study was designed to separate caveolae formation from its downstream signaling effects. Methods and Results: An endothelial-specific doxycycline-regulated mouse model for the expression of Cav-1-F92A was developed. Blood pressure by telemetry and nitric oxide bioavailability by electron paramagnetic resonance and phosphorylation of vasodilator–stimulated phosphoprotein were determined. Caveolae integrity in the presence of Cav-1-F92A was measured by stabilization of caveolin-2, sucrose gradient, and electron microscopy. Histological analysis of heart and lung, echocardiography, and signaling were performed. Conclusions: This study shows that mutant Cav-1-F92A forms caveolae structures similar to WT but leads to increases in NO bioavailability in vivo, thereby demonstrating that caveolae formation and downstream signaling events occur through independent mechanisms.
Diagnosis and Prevention of Postoperative Deep-Vein Thrombosis
Authors: L P Le Quesne
Journal: Annual Review of Medicine (1975)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
German drug industry says pricing law is restricting access to some drugs
Authors: N. Stafford
Journal: BMJ (2015)

<b>Background:</b> The American College of Sports Medicine recommends 20–60 minutes of aerobic exercise three to five days a week at an intensity of 40/50–85% of maximal aerobic power (Vo<sub>2</sub>max) reserve, expending a total of 700–2000 kcal (2.93–8.36 MJ) a week to improve aerobic power and body composition. <b>Objective:</b> To ascertain the minimum effective dose of exercise. <b>Methods:</b> Voluntary, healthy, non-obese, sedentary, postmenopausal women (n = 121), 48–63 years of age, were randomised to four low dose walking groups or a control group; 116 subjects completed the study. The exercise groups walked five days a week for 24 weeks with the following intensity (% of Vo<sub>2</sub>max) and energy expenditure (kcal/week): group W1, 55%/1500 kcal; group W2, 45%/1500 kcal; group W3, 55%/1000 kcal; group W4, 45%/1000 kcal. Vo<sub>2</sub>max was measured in a direct maximal treadmill test. Submaximal aerobic fitness was estimated as heart rates at submaximal work levels corresponding to 65% and 75% of the baseline Vo<sub>2</sub>max. The body mass index (BMI) was calculated and percentage of body fat (F%) estimated from skinfolds. <b>Results:</b> The net change (the differences between changes in each exercise group and the control group) in Vo<sub>2</sub>max was 2.9 ml/min/kg (95% confidence interval (CI) 1.5 to 4.2) in group W1, 2.6 ml/min/kg (95% CI 1.3 to 4.0) in group W2, 2.4 ml/min/kg (95% CI 0.9 to 3.8) in group W3, and 2.2 ml/min/kg (95% CI 0.8 to 3.5) in group W4. The heart rates in standard submaximal work decreased 4 to 8 beats/min in all the groups. There was no change in BMI, but the F% decreased by about 1% unit in all the groups. <b>Conclusions:</b> Walking (for 24 weeks) at moderate intensity 45% to 55% of Vo<sub>2</sub>max, with a total weekly energy expenditure of 1000–1500 kcal, improves Vo<sub>2</sub>max and body composition of previously sedentary, non-obese, postmenopausal women. This dose of exercise apparently approaches the minimum effective dose.
The Role of Chromosomal Translocations in B- and T-Cell Neoplasia
Authors: L C Showe, C M Croce
Journal: Annual Review of Immunology (1987)

At the turn of the century, Boveri (1) suggested that abnormal chro­ mosomal patterns in tumor samples reflect the processes responsible for the development of the malignant phenotype. However, the first demonstrated association of a consistent chromosomal rearrangement with a specifi c disease did not occur until 1960 when a marker chromosome, the Phi­ ladelphia chromosome (Ph +), was discovered to be consistently associated with chronic myelogenous leukemia (CML) (2). The Ph+ chromosome was subsequently shown to result from a reciprocal translocation between chromosomes 9 and 22 (3). Due to the introduction of new techniques for high resolution ban­ ding-analysis of chromosomes, a large majority of human cancer cells are now known to carry clonal cytogenetic changes (4). This has been most clearly demonstrated for the hematopoietic malignancies and has resulted in a renewed focus on chromosomal rearrangements as a causative factor in malignant transformation. While this view was originally not widely accepted outside of the discipline of cytogenetics, the painstaking efforts to observe and catalogue these rearrangements have now been justifi ed. The application of the new technologies of molecular biology and somatic cell genetics have allowed the characterization of a variety of chromosomal abnormalities, and in particular chromosomal translocations, at the mol-
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Authors: Michael I Love, Wolfgang Huber, Simon Anders
Journal: Genome biology (2014)

In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html .
Pharmacokinetics and Pharmacodynamics of Biosimilar Insulins: Is Clamp Technology Fit for Purpose?
Authors: Philip Home
Journal: Diabetes Care (2015)

The euglycemic glucose clamp was first used to assess the new human insulins in the early 1980s by comparing pharmacodynamics (PD) of square-wave intravenous infusions in terms of the clamp glucose infusion rate (1). Shortly afterward, the technique was adapted to study the profile of action of subcutaneously injected insulin (2) and in people with type 1 diabetes rather than people without diabetes. One major advantage of the clamp is that it allows the study at the same time of both the pharmacokinetics (PK), the plasma concentration absorption profile of injected insulin, and PD in terms of measures such as onset, peak, peak:trough ratio, duration, and area under the curve (Table 1). Attractively, the time-action profiles can be visualized. Although initially used for mealtime insulins, the technique was soon applied to extended-acting insulins, comparing insulin-action profiles of nominally similar insulins (NPH preparations) from different manufacturers (3).

View this table:

Table 1 
Some glucose clamp advantages and limitations in the study of subcutaneous injection profiles of insulin preparations



Mealtime insulins can be compared, to a useful extent, in people with type 1 diabetes (C-peptide negative) using standardized or usual meals on a background of steady-state basal insulin or infusion (4). Such an option is not available for long-acting insulins, so glucose clamp studies are particularly important for assessing and comparing these. Thus, while general guidelines for comparing a biosimilar medication (a copy) with the original product emphasize PK/PD studies (5,6), specific guidelines for insulin as drawn up by the European regulators go into considerable detail on glucose clamp studies (7). In …
Identifying Non–Duchenne Muscular Dystrophy–Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs
Authors: Michele A. Gatheridge, Jennifer M. Kwon, Jerry M. Mendell, Günter Scheuerbrandt, Stuart J. Moat, François Eyskens, Cheryl Rockman-Greenberg, Anthi Drousiotou, Robert C. Griggs
Journal: JAMA Neurology (2015)

Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients.To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings).Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015.The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD.Screening for DMD will result in identification of other muscle diseases. Future screening protocols should include infants of both sexes and include follow-up testing algorithms to evaluate patients who do not have DMD gene mutations but may have another muscle disorder associated with elevated neonatal creatine kinase levels. These programs will need to be aware that false-negative results are a possibility.
Convergence of Acquired Mutations and Alternative Splicing of <i>CD19</i> Enables Resistance to CART-19 Immunotherapy
Authors: Elena Sotillo, David M. Barrett, Kathryn L. Black, Asen Bagashev, Derek Oldridge, Glendon Wu, Robyn Sussman, Claudia Lanauze, Marco Ruella, Matthew R. Gazzara, Nicole M. Martinez, Colleen T. Harrington, Elaine Y. Chung, Jessica Perazzelli, Ted J. Hofmann, Shannon L. Maude, Pichai Raman, Alejandro Barrera, Saar Gill, Simon F. Lacey, Jan J. Melenhorst, David Allman, Elad Jacoby, Terry Fry, Crystal Mackall, Yoseph Barash, Kristen W. Lynch, John M. Maris, Stephan A. Grupp, Andrei Thomas-Tikhonenko
Journal: Cancer Discovery (2015)

The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor-armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.
Abstract 4673: Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration
Authors: Arunkumar Arumugam, Ramadevi Subramani, Sushmita Nandy, Duy Do, Rajkumar Lakshmanaswamy
Journal: Cancer Research (2015)

Abstract Early pregnancy is the only natural phenomenon known to confer protection against breast cancer. We have earlier demonstrated that short-term treatment with pregnancy levels of estradiol (STET) is very effective in preventing mammary carcinogenesis. The underlying mechanisms behind the protective effect of parity and STET remain unclear. In the current study, we attempted to delineate the influence of the mammary gland microenvironment on mammary carcinogenesis among parous and STET compared to age matched virgin rats. Parous, STET, and virgin (control) Sprague Dawley rats were administered N-methyl-N-nitrosourea (50mg/kg BW) at 15 weeks of age. Mammary cancer development was monitored by weekly palpations for 9 months post carcinogen treatment. A subset of rats (n = 4) were euthanized five weeks post carcinogen treatment. Mammary gland samples were surgically excised and used for histological and molecular analysis. Our analysis demonstrated that parity and STET resulted in reduced expression of cell survival markers (pAKT, pmTOR), extracellular matrix mediated signaling proteins (ERK1/2, pFAK, Itgb1) hormonal (ER, PR, GHR) and growth factor receptors (pEGFR, pIGFR1) compared to age matched virgin group. Further, expression of EMT markers and regulators of cell migration were significantly reduced in parous and STET mammary glands. MicroRNA analysis disclosed that both parity and STET differentially regulated the expression of 23 microRNAs. Among these 18 microRNAs were down regulated and 5 microRNAs were up regulated in both parous and STET treatment. In silico analysis revealed that several of the differentially regulated microRNAs are direct regulators of the cell survival and cell migratory proteins. Parity and STET by altering microRNA expression influences cell survival, cell migration and cell death signaling pathways reduces the cancer promoting microenvironment in the mammary gland. Citation Format: Arunkumar Arumugam, Ramadevi Subramani, Sushmita Nandy, Duy Do, Rajkumar Lakshmanaswamy. Parity and short-term estradiol treatment confers protection against breast cancer by suppressing cell survival and migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2015-4673
Molecular Mechanisms and Therapeutic Approaches to the Treatment of African Trypanosomiasis
Authors: C C Wang
Journal: The Annual Review of Pharmacology and Toxicology (1995)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More