tbuckley/cabot-search huggingface dataset:
Comparative Outcomes After Percutaneous Coronary Intervention Among Black and White Patients Treated at US Veterans Affairs Hospitals
Authors: Taisei Kobayashi, Thomas J. Glorioso, Ehrin J. Armstrong, Thomas M. Maddox, Mary E. Plomondon, Gary K. Grunwald, Steven M. Bradley, Thomas T. Tsai, Stephen W. Waldo, Sunil V. Rao, Subhash Banerjee, Brahmajee K. Nallamothu, Deepak L. Bhatt, A. Garvey Rene, Robert L. Wilensky, Peter W. Groeneveld, Jay Giri
Journal: JAMA Cardiology (2017)

Current comparative outcomes among black and white patients treated with percutaneous coronary intervention (PCI) in the Veterans Affairs (VA) health system are not known.To compare outcomes between black and white patients undergoing PCI in the VA health system.This study compared black and white patients who underwent PCI between October 1, 2007, and September 30, 2013, at 63 VA hospitals using data recorded in the VA Clinical Assessment, Reporting, and Tracking System for Cardiac Catheterization Laboratories (CART-CL) program. A generalized linear mixed model with a random intercept for site assessed the relative difference in odds of outcomes between black and white patients. The setting was integrated institutionalized hospital care. Excluded were all patients of other races or those with multiple listed races and those with missing data regarding race or the diagnostic cardiac catheterization. The dates of analysis were January 7, 2016, to April 17, 2017.Percutaneous coronary intervention at a VA hospital.The primary outcome was 1-year mortality. Secondary outcomes were 30-day all-cause readmission rates, 30-day acute kidney injury, 30-day blood transfusion, and 1-year readmission rates for myocardial infarction. In addition, variations in procedural and postprocedural care were examined, including the use of intravascular ultrasound, optical coherence tomography, fractional flow reserve measurements, bare-metal stents, postprocedural medications, and radial access.A total of 42 391 patients (13.3% black and 98.4% male; mean [SD] age, 65.2 [9.1] years) satisfied the inclusion and exclusion criteria. In unadjusted analyses, black patients had higher rates of 1-year mortality (7.1% vs 5.9%, P < .001) as well as secondary outcomes of 30-day acute kidney injury (20.8% vs 13.8%, P < .001), 30-day blood transfusion (3.4% vs 2.7%, P < .01), and 1-year readmission rates for myocardial infarction (3.3% vs 2.7%, P = .01) compared with white patients. After adjustment for demographics, comorbidities, and procedural characteristics, odds for 1-year mortality (odds ratio, 1.04; 95% CI, 0.90-1.19) were not different between black and white patients. There were also no differences in secondary outcomes with the exception of a higher rate of adjusted 30-day acute kidney injury (odds ratio, 1.22; 95% CI, 1.10-1.36).While black patients had a higher rate of mortality than white patients in unadjusted analyses, race was not independently associated with 1-year mortality among patients undergoing PCI in VA hospitals.
A Phase II Study of Tacrolimus and Thymoglobulin, As Graft-Versus-Host-Disease Prophylaxis in Patients Undergoing Related Donor Allogeneic Hematopoietic Cell Transplantation
Authors: Dipenkumar Modi, Wei Chen, Jang Hyejeong, Abhinav Deol, Lois Ayash, Alavi Asif, Divaya Bhutani, Kendra Mellert, Voravit Ratanatharathorn, Joseph P. Uberti
Journal: Blood (2016)
Plasma, tissue and tumor disposition of STEALTH® liposomal CKD-602 (S-CKD602) and non-liposomal CKD-602, a camptothecin analogue, in mice bearing A375 human melanoma xenografts
Authors: Sandra Strychor, Julie L. Eiseman, Erin Joseph, Margaret E. Tonda, Nu Y. Ying, Charles Engbers, William C. Zamboni
Journal: Cancer Research (2006)

3064   Introduction: S-CKD602 is a STEALTH® liposomal formulation of CKD-602, a camptothecin (CPT) analogue. The cytotoxicity of CPT analogues is related to duration of exposure (Zamboni, et.al., Clin Cancer Res 1998). STEALTH® liposome (SL) formulations contain lipid conjugated to polyethylene glycol and have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. The disposition of SL-encapsulated drug is dictated by the liposome, which alters the plasma pharmacokinetic (PK) profile and tissue distribution of the drug. The objectives of this study were to evaluate the plasma, tissue and tumor disposition of drug after S-CKD602 and non-liposomal CKD-602 administration. Methods: S-CKD602 at 1mg/kg (∼1/2 of the maximum tolerated dose [MTD]) or non-liposomal CKD-602 at 30mg/kg (∼MTD) was administered IV x 1 via a tail vein to mice bearing A375 human melanoma xenografts. The A375 xenograft was used based on previous antitumor activity (Yu et al., AACR;05, #2396). Mice (n=3) were euthanized at 0.083 to 24 h, 48 h, and 72 h after S-CKD602 and from 0.083 to 24 h after non-liposomal CKD-602. Plasma, tumor, liver, spleen, kidney, and brain samples were processed to measure sum total (encapsulated + released) CKD-602. An LC-MS assay was used to measure the total (sum of lactone and hydroxyl acid) CKD-602. The area under the concentration versus time curves (AUC) from 0 to infinity, maximum conc (C max ), time of C max  (T max ), and time of last detectable conc (T last ) were estimated. Results: PK parameters are summarized in the table. Conclusions: The prolonged exposure of CKD-602 in tumor, liver, and spleen after administration of S-CKD602 is consistent with SL. S-CKD602 provides PK advantages in plasma and tumor compared to non-liposomal CKD-602 at 1/30 th  of the dose, which is consistent with the improved antitumor efficacy of S-CKD602 in preclinical studies. The greater exposure of CKD-602 in the brain after S-CKD602 compared with CKD-602 and activity of CPT analogues in patients with brain tumors suggest S-CKD602 should be evaluated in this patient population. Sponsored by ALZA Corporation.
An Incidental Hypervascular Retroperitoneal Mass
Authors: Patricia W. Costacurta, Aaron C. Shaver, Kamran Idrees
Journal: JAMA Surgery (2017)

A 69-year-old man presented with an incidental right infrarenal, retroperitoneal mass measuring 9.7 × 7.7 × 9.1 cm. The mass was supplied from a hypertrophied lumbar artery and from a branch of the internal iliac artery. What is your diagnosis?
The role of hMLH1 splice variants in childhood acute lymphoblastic leukemia (ALL)
Authors: Amy Peasland, Elizabeth C. Matheson, Andrew G. Hall, Julie A. Irving
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1220 

The mismatch repair (MMR) system plays an important role in the maintenance of the integrity of the genome by eliminating sequence errors from the newly synthesized strand during DNA replication. hMLH1 forms part of the MutL complex with hPMS2, which is recruited to the repair pathway by the MutSα or MutSβ mismatch recognition complex. The 19 exons of hMLH1 encode an 85KDa protein. The N-terminus has an ATP-binding domain and the C-terminus is required for hPMS2 interaction, hence C-terminal truncations often eliminate MMR activity. Abnormalities in proteins involved in the MMR system have been detected in a variety of hematological malignancies and may cause resistance to drugs used in their treatment. As well as base-base mismatches and insertion-deletion loops, MMR recognises chemotherapeutic lesions introduced by some drugs used to treat ALL (e.g. mercaptopurines and thioguanines). Therefore, loss of MMR leads to resistance to these agents. Alternative splicing is a means of generating functionally diverse protein forms from a single gene. Alternatively spliced forms of hMLH1 have been investigated in a variety of normal and tumour tissues, particularly lymphocytes, and are tissue-specific. Variant hMLH1 transcripts have recently been shown to be up regulated in response to mercaptopurine in vivo (Cheok et al. 2003). Their effect on MMR and drug sensitivity is undetermined. Splice variants of hMLH1 have been identified using RT-PCR, with overlapping primers spanning the whole transcript. Bone marrow samples from children with ALL at presentation and relapse have been screened, along with peripheral blood mononuclear cells (PBMNC) from normal controls and a range of leukemic cell lines. Transcripts lacking exons 6, 9, 9-10, 10-11, 9-11, 12, 16 and 17 were identified in all patient samples and PBMNC, although levels varied amongst patients. Some patients expressed greater proportions of variant transcripts than of full-length transcript. This was reflected in the varying levels of full-length protein in patient samples, as visualised by Western blotting. The transcripts identified are predicted to encode truncated or internally deleted proteins of uncertain functional role. The most abundant alternatively spliced form, hMLH1Δ9/10, has been shown to be expressed in patient cells by Western blotting. Alternatively spliced isoforms of DNA repair proteins have been reported to exert a dominant-negative modulatory effect in the nucleotide excision repair pathway (Khan et al. 2002). An assay has been developed in which MMR-proficient cells have been transfected with variant hMLH1 to assess the effects of variant protein expression on repair activity and drug sensitivity. This should reveal whether variant isoforms of hMLH1 act as dominant negative proteins in the MMR pathway, and thereby modulate MMR function and thioguanine sensitivity.
Diagnosis and Management of Asthma in Adults
Authors: Jennifer L. McCracken, Sreenivas P. Veeranki, Bill T. Ameredes, William J. Calhoun
Journal: JAMA (2017)

<h3>Importance</h3> Asthma affects about 7.5% of the adult population. Evidence-based diagnosis, monitoring, and treatment can improve functioning and quality of life in adult patients with asthma. <h3>Observations</h3> Asthma is a heterogeneous clinical syndrome primarily affecting the lower respiratory tract, characterized by episodic or persistent symptoms of wheezing, dyspnea, and cough. The diagnosis of asthma requires these symptoms and demonstration of reversible airway obstruction using spirometry. Identifying clinically important allergen sensitivities is useful. Inhaled short-acting β<sub>2</sub>-agonists provide rapid relief of acute symptoms, but maintenance with daily inhaled corticosteroids is the standard of care for persistent asthma. Combination therapy, including inhaled corticosteroids and long-acting β<sub>2</sub>-agonists, is effective in patients for whom inhaled corticosteroids alone are insufficient. The use of inhaled long-acting β<sub>2</sub>-agonists alone is not appropriate. Other controller approaches include long-acting muscarinic antagonists (eg, tiotropium), and biological agents directed against proteins involved in the pathogenesis of asthma (eg, omalizumab, mepolizumab, reslizumab). <h3>Conclusions and Relevance</h3> Asthma is characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. Management of persistent asthma requires avoidance of aggravating environmental factors, use of short-acting β<sub>2</sub>-agonists for rapid relief of symptoms, and daily use of inhaled corticosteroids. Other controller medications, such as long-acting bronchodilators and biologics, may be required in moderate and severe asthma. Patients with severe asthma generally benefit from consultation with an asthma specialist for consideration of additional treatment, including injectable biologic agents.
“Independent” reanalysis of landmark starch solutions trial was published by original authors
Authors: Peter Doshi
Journal: BMJ (2017)

Academics who refused calls to share the data underlying their landmark trial that triggered the downfall of starches for fluid resuscitation have announced an “independent reanalysis,” which confirms their original findings.1

However, they have not made their data available to the wider scientific community—a key element of transparent research practice and what other academics have been calling for.23

The 7000 patient trial, CHEST (Crystalloid versus Hydroxyethyl Starch Trial),4 is one of the most important pieces of evidence concerning the effects of hydroxyethyl starch solutions for increasing intravascular volume in patients in intensive care.

Published in the New England Journal of Medicine in 2012, CHEST reported that the hydroxyethyl starch investigated, Voluven, was no different than saline in terms of mortality but led to greater use of renal replacement therapy. The trial helped persuade drug regulators in Europe and the US to issue safety warnings in 2013.

In February the US health watchdog Public Citizen sent a petition to the Food and Drug Administration calling for hydroxyethyl starch intravenous solutions to be removed from the market,5 a move supported by CHEST’s lead author, John Myburgh.6

But the global healthcare company Fresenius Kabi, which makes Voluven and was a major funder (€3.5m (£3.15m; $4m)) of the trial, has long contended that the study was improperly reported.2 Before the trial the company took the unusual step of signing away all rights to the data, a decision it later came to regret. In 2014 it sought the assistance of The BMJ to intervene with the CHEST investigators. It then asked the Yale Open Data Access Project (YODA) to serve as an independent intermediary between the CHEST investigators and a reanalysis team to be determined, but the academic investigators rejected YODA’s offer.2

The latest “independent analysis” is …
Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
Authors: Sanjeev Shukla, Sanjay Gupta
Journal: Cancer Research (2007)

1576  Cancer prevention is profoundly dependent on the p53 tumor suppression protein as it functions in regulating growth and protecting cells from malignant transformation. The ability of p53 in providing prevention against cancer lies in the elimination of damaged or infected cells by causing cell cycle arrest and/or apoptosis. Several studies have demonstrated the anti-tumor activity of p53 and in fact, p53 is the most frequently altered protein in human cancer. Approximately, 50% of all human malignancies harbor mutations or deletions in the TP53 gene that disable the tumor suppressor function of the encoded protein. The other half of human tumors expresses wild type protein and encodes further defects in the p53 signaling pathway playing critical role in tumorigenesis. Agents which can differentially activate wild-type p53 in cancer cells could be develop for chemoprevention. Apigenin (4’,5,7-trihydroxyflavone) is one such agent that potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild type p53, to growth suppressive concentration (10-80 μM) of apigenin resulted in i) stabilization of p53 by phosphorylation on critical serine sites, ii) p14/ARF-mediated downregulation of murine double minute (MDM) 2 protein, and iii) induction of WAF1/p21 in dose- and time- dependent manner. Apigenin, at these doses resulted in reactive oxygen species (ROS) generation which was accompanied by disruption of mitochondrial membrane potential, cytosolic release of cytochrome C and apoptosis. Interestingly, we observed accumulation of p53 to the mitochondria which was rapid and occurred between 1-3 h after apigenin treatment. All these effects were significantly blocked by pretreatment with antioxidant, N-acetylcystiene, and a well known p53 inhibitor, pifithrin. Apigenin-mediated p53 activation and apoptosis was further attenuated by p53 anti-sense treatment. Exposure of cells to apigenin further led to decrease in Bcl-2 expression and increase in Bax thereby shifting the Bax/Bcl-2 in favor of apoptosis. This altered expression of Bcl-2 family members triggered activation of the initiator caspases 9 and 8 followed by activation of effector caspase 3. Treatment of 22Rv1 cells with general caspase inhibitor, Z-VAD-FMK and a specific caspase-3 inhibitor, DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. Taken together, the present study indicates that apigenin-induced apoptosis in 22Rv1 cells is mediated by ROS-dependent disruption of the mitochondrial membrane potential and stabilization of p53.
Blended CBT Controls Anxiety in Cancer Survivors
Authors: Anita Slomski
Journal: JAMA (2017)

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Child treated for HIV in infancy has been healthy for nine years
Authors: Sophie Cousins
Journal: BMJ (2017)

A South African child who was infected with HIV at birth and given a short course of treatment at nine weeks old has remained healthy for the past nine years without further intervention, according to research presented at the International AIDS Society Conference on HIV Science in Paris.

The child, who was diagnosed with HIV at one month, began antiretroviral therapy (ART) at nine weeks of age for 40 weeks …
Authors’ reply to Spiegel and colleagues
Authors: Gary Evoniuk, Bernadette Mansi, Barbara DeCastro, Jennie Sykes
Journal: BMJ (2017)

We agree with Spiegel and colleagues that our findings are not broadly generalisable1 since, as we noted,2 they relate to a single sponsor whose policy is to publish all human drug trials regardless of outcome. Although we hypothesised there would be no submission bias (according to the policy), it was not a given that policy would translate into practice. By sharing our data we hope to …
Comparative effectiveness of adjuvant chemotherapy in surgically resected non-small cell lung cancer.
Authors: Sara Mariam Ali, Juan P. Wisnivesky, Cardinale B. Smith, Grace Mhango
Journal: Journal of Clinical Oncology (2016)

e20000 Background: Current guidelines recommend the use of adjuvant platinum-based chemotherapy as the standard of care for patients with stages IB-IIIA ( ≥ 4cm) NSCLC who have undergone resection. However, there have been no randomized trials comparing the effectiveness of newer versus older chemotherapeutic agents when combined with platinum agents. The objective of this study was to compare survival outcomes and toxicity in the use of platinum based combinations using novel agents (pemetrexed) and older agents (gemcitabine, taxanes, vincas, and etoposide). Methods: Using the Surveillance, Epidemiology and End Results (SEER)–Medicare linked database we identified 871 patients with stage IB-IIIA non-squamous NSCLC (tumor size ≥ 4 cm) who received adjuvant platinum-based chemotherapy between 2009 and 2012. Overall survival and rates of serious adverse events (defined as those requiring admission to hospital) were compared between patients treated with different platinum-based adjuvant chemotherapy regimens including platinum-taxanes (PT), platinum–pemetrexed (PP), platinum-vin-alkaloids (PV), platinum-gemcitabine or etoposide (PGE). Kaplan–Meier curves were used to compare survival of patients receiving platinum-pemetrexed (PP) to those receiving the other platinum based combinations. Cox regression analysis was used to identify potential mediators of the association between PP and survival. Results: We identified 871 patients. Of these, 17% got PT, 12% PV, 53% PGE and 17% PP (p = .01). In bivariate analysis toxicity was significantly less in the PP group; any toxicity (p = .01), infection rates (p = .03), abnormal electrolytes and dehydration (p = .01).In unadjusted analysis, overall survival was significantly improved in the PP group (p = .01). After adjusting for baseline characteristics there was no difference in overall survival among groups. Conclusions: PP did not demonstrate significant improvement in overall survival when compared to older chemotherapy agents. However, PP demonstrated an improved toxicity profile.These study findings should be confirmed in prospective studies.
David Oliver: NHS doctors’ licence to challenge
Authors: David Oliver
Journal: BMJ (2017)

BerkshireImagine that you're a head teacher at a state school.You have a professional obligation to give children the best education you can with the resources you have.They have no second chance.Whatever you may think about workforce gaps, dilapidated buildings, curriculum changes, class sizes, testing, inspection, you strive to deliver maximum value to the students.You are on the public payroll.If you don't like it you can leave, and plenty do.None of this is incompatible with a simultaneous right and duty to highlight all of the problems you believe compromise teachers' jobs and children's education.Similar considerations apply in emergency services, social work, the military, local government, and criminal justice.They surely also apply to state employed NHS clinicians.We get on with the job as best we can because patients need us.Why should this preclude simultaneously challenging our political leadership, incompetent or unfair inspection and regulation, underfunding, understaffing, unsafe conditions, unevidenced initiatives, or misleading spin?George Bernard Shaw was surely right in arguing that "progress depends on the unreasonable man"
Population of Ethiopia
Journal: New England Journal of Medicine (1963)

Population growth in Ethiopia is attributed to declining mortality and high fertility.  Poverty war and famine have contributed to economic decline and overpopulation.  These conditions are associated with low levels of education and health weak infrastructure and low agricultural and industrial production.  Ethiopia has the second largest population in Africa after Nigeria.  Population is estimated at 50 million in 1990.  Rural highland densities are highest in the ensete cultivation areas of southern Ethiopia.  Pastoral nomads populate the less dense southern lowlands.  82% of total population in 1984 lived in highlands. Population has been shifting to the agricultural lowlands and urban areas since the 1960s.  Urbanization entails numerous small size settlements and a large population concentration in Addis Ababa.  About 93% of the population speaks one of 14 main languages.  Ethiopias diversity is represented by the 70-80 languages spoken.  Over 66% of the population speaks either Orominya Amharic or Tigrinya.  Distribution of the population by religion educational level or ethnic group varies among the awrajas and regions.  Religious minorities cluster in urban areas.  Ethiopia was one of the first African countries with a writing system but only 32% of males and 22% of females attended primary schools during 1986-88.  63% of the total population was literate in 1985.  In 1984 46.5% of the total population was aged under 15 years.  Marriage is early and universal.  The singulate mean age of marriage among rural females was 17.5 years in 1984.  Divorce and widowhood are common.  Female life expectancy at birth in 1971 is estimated to have been 45.2 years.  About 20% of female deaths occur during the childbearing years.  Fertility increased to 6.62 children per woman in 1984.  Contraceptive use is low.  The most popular modern method is the pill.  There are social barriers to contraceptive use and lower fertility.