tbuckley/cabot-search huggingface dataset:
Characteristics of Clinical Trials to Support Approval of Orphan vs Nonorphan Drugs for Cancer
Authors: Aaron S. Kesselheim
Journal: JAMA (2011)

The Orphan Drug Act incentivizes medication development for rare diseases, offering substantial financial benefits to the manufacturer. Orphan products constitute most new drug approvals in oncology, but safety and efficacy questions have emerged about some of these agents.To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs.We identified all new orphan and nonorphan drugs approved between 2004 and 2010 to treat cancer. We then collected data on key development variables from publicly available information on the US Food and Drug Administration's Web site and in the Code of Federal Regulations.We assessed clinical testing dates, approved indications, and regulatory characteristics (regular vs accelerated review, advisory committee review, postmarketing commitments). We then compared design features (randomization, blinding, primary end point) of pivotal trials supporting approval of orphan and nonorphan drugs and rates of adverse safety outcomes (deaths not attributed to disease progression, serious adverse events, dropouts) in pivotal trials.Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66-152] vs 290 [IQR, 185-394] patients exposed to the drug; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02-2.92; P = .04).Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.
Review: Oral drugs for type 2 diabetes, alone or in combination, have different relative benefits and harms for surrogate endpoints
Authors: Juan Pablo Domecq, Gabriela Prutsky, Victor M. Montori
Journal: Annals of Internal Medicine (2011)

Source Citation Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. 2011;154:602-13. 21403054
Relationship Between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men
Authors: Frances Hayes
Journal: Diabetes Care (2006)

I thank Drs. Kaplan and Crawford (1) for their kind remarks on our article (2) on the relationship between testosterone levels and insulin sensitivity in men and for their thoughtful comments on the optimal form of androgen replacement for older men.

While the standard form of androgen replacement for hypogonadal men is testosterone, the authors express concern about its use in older men, given that it results …
The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation
Authors: S Thepot, J Zhou, A Perrot, M Robin, A Xhaard, R P de Latour, L Ades, P Ribaud, A D Petropoulou, R Porcher, G Socié
Journal: Leukemia (2010)
The Relationship between Housing and Health: Children at Risk
Authors: Patrick Breysse, Nick Farr, Warren Galke, Bruce Lanphear, Rebecca Morley, Linda Bergofsky
Journal: Environmental Health Perspectives (2004)

In November 2002, the National Center for Healthy Housing convened a 2-day workshop to review the state of knowledge in the field of healthy housing. The workshop, supported with funds from the U.S. Centers for Disease Control and Prevention's National Center for Injury Prevention and Control and National Center for Environmental Health, was unique in that it focused solely on the effect of housing on children's health and the translation of research findings into practical activities in home construction, rehabilitation, and maintenance. Participants included experts and practitioners representing the health, housing, and environmental arenas. Presentations by subject-matter experts covered four key areas: asthma, neurotoxicants, injury, and translational research. Panel discussions followed the presentations, which generated robust dialogue on potential future research opportunities and overall policy gaps. Lack of consensus on standard measurements, incomplete understanding about the interaction of home hazards, inadequate research on the effectiveness of interventions, and insufficient political support limit current efforts to achieve healthy housing. However, change is forthcoming and achievable.
Protamine Insulin
Authors: Philip Felig
Journal: JAMA (1984)

The epoch-making discovery of insulin by Banting and Best led to an appropriate euphoria among physicians treating diabetic patients. Death due to diabetic coma (diabetic ketoacidosis) was largely eliminated. Life expectancy in the child with newly discovered diabetes was increased from two years to 30 years or more, and severely restrictive dietary regimens that bordered on starvation were no longer necessary for the prolongation of the life of the diabetic. 1 Nevertheless, within a few years of the inception of insulin treatment, the limitations in its clinical effectiveness became increasingly apparent.  Improvements in the extraction and commercial preparation of insulin eliminated the impurities that often resulted in localized burning sensations, irritations, and even sterile abscesses at the site of injection. However, as the purity of the preparations increased, the duration of action of the injected hormone decreased. 2 As a consequence, an increasing number of patients required multiple injections through
(Not such) good fortune
Authors: T. Dalrymple
Journal: BMJ (2010)

Towards the end of his Memoirs of His Life and Writings , published two years after his death, Edward Gibbon (1737-94) expatiates, sincerely, on his good fortune in a way that is surely most uncommon, especially now that once again there is a fashion for romantic agony as a sign of superior sensibility: “When I contemplate the common lot of mortality, I must acknowledge that I have drawn a high prize in the lottery of life.”

Even the fact that he had reached what would now be considered middle age was fortunate: “The general probability is about three to one that a new-born infant will not live to complete …
FIRST-PASS PULMONARY EXTRACTION STUDIES IN HUMANS
Authors: R C Verma, M Gan, L Bennett, K Lin, C Schiepers, M Basic, A Go, J Sabbe, C Wynn, N Feldman, J Touya, S-C Huang, H Flaster, J Rahimian, N Mankovich
Journal: Clinical Nuclear Medicine (1993)

Verma, R C; Gan, M; Bennett, L; Lin, K; Schiepers, C; Basic, M; Go, A; Sabbe, J; Wynn, C; Feldman, N; Touya, J; Huang, S-C; Flaster, H; Rahimian, J; Mankovich, N Author Information
537 RESTORATION OF THE L-ARGININE:ADMA RATIO BY L-ARGININE TREATMENT IN BILE DUCT LIGATED RATS RESULTS IN SIGNIFICANT LOWERING OF PORTAL PRESSURE
Authors: V. Sharma, V. Balasubramaniyan, N.A. Davies, G. Mehta, A. Habtesion, R. Jalan, R.P. Mookerjee
Journal: Journal of Hepatology (2010)
The definition and diagnostic testing of physical and cholinergic urticarias – EAACI/GA<sup>2</sup>LEN/EDF/UNEV consensus panel recommendations
Authors: M. Magerl, E. Borzova, A. Giménez‐Arnau, C. E. H. Grattan, F. Lawlor, P. Mathelier‐Fusade, M. Metz, A. Młynek, M. Maurer
Journal: Allergy (2009)

The recommendations for the definition and diagnosis presented in this position paper are the result of a panel consensus meeting held in December 2008 in Berlin. This consensus meeting was a joint initiative of EAACI (European Academy of Allergology and Clinical Immunology) Dermatology Section, the EU-funded network of excellence, GA(2)LEN (Global Allergy and Asthma European Network), the EDF (European Dermatology Forum) and UNEV (urticaria network e.V.). The aim of these recommendations is to improve the diagnosis and management of patients with physical urticaria or cholinergic urticaria and to promote research and a better understanding of these diseases. Our recommendations used the paper produced by a 1996 expert meeting (1) and they acknowledge the latest changes in our understanding of physical urticarias and cholinergic urticaria as well as the recent development of novel diagnostic tools. In addition, this consensus paper highlights areas of need for further research.
Reducing the toll of road traffic accidents
Authors: A K Adams
Journal: Journal of the Royal Society of Medicine (2004)

No doubt I shall not be the only person to rise to John Bache's bait (December 2003 JRSM1). He gives an unsubstantiated opinion that elderly drivers are a serious cause of accidents because their reaction times, memories, concentration and visual acuity are poor. May I give an equally unsubstantiated alternative view? I suggest that elderly people might not cause more accidents, because they drive more slowly, take fewer risks, are less prone to `road rage' or being provoked by it and have a life-time's driving experience behind them. Furthermore, the elderly have learned not to mix drink, drugs and driving and the drugs they take may be less hazardous than so-called recreational ones. Physical frailty is not a problem with modern cars, except for getting in and out of them (why are car doors not made hinged from the rear, as in London taxis?). I agree that requirements for driving licences need changing; for example, visual fields are as important as visual acuity, at all ages.

The only hard evidence I know of to support my view is that insurance premiums are not universally loaded against the old as they are against the young, and insurers are very knowledgeable about risk.

Conflict of interest I am 80 years of age. I try to avoid driving after dark.
SOME REFLECTIONS UPON CELLULAR PHYSIOLOGY AND PATHOLOGY.
Authors: AUGUSTUS A. ESHNER
Journal: JAMA (1899)

Modern research and investigation have shed much light on the intimate nature of disease processes, but there is a good deal of virgin soil yet to be tilled. Life may be looked upon as a manifestation of the activity of the cell (or of an aggregation of cells), which, if expended in a proper manner, represents the condition of health. Perversion of this activity, through influences acting from either within or without, leads to disease; while permanent inhibition (destruction) results in death. Normal cellular activity (function) implies a proper relation between waste (catabolism) and repair (anabolism), the replacement of used-up and worn-out material by fresh nutritive pabulum, together with the elimination of the products of disintegration—normal metabolic or nutritional equilibrium. Failure in either of these processes, as well as defect in quality of the nutritive pabulum, gives rise to derangement of this metabolic equilibrium, resulting in the one instance in
Impact of Providing Fee Data on Laboratory Test Ordering
Authors: Leonard S. Feldman, Hasan M. Shihab, David Thiemann, Hsin-Chieh Yeh, Margaret Ardolino, Steven Mandell, Daniel J. Brotman
Journal: JAMA Internal Medicine (2013)

Inpatient care providers often order laboratory tests without any appreciation for the costs of the tests.To determine whether we could decrease the number of laboratory tests ordered by presenting providers with test fees at the time of order entry in a tertiary care hospital, without adding extra steps to the ordering process.Controlled clinical trial.Tertiary care hospital.All providers, including physicians and nonphysicians, who ordered laboratory tests through the computerized provider order entry system at The Johns Hopkins Hospital.We randomly assigned 61 diagnostic laboratory tests to an "active" arm (fee displayed) or to a control arm (fee not displayed). During a 6-month baseline period (November 10, 2008, through May 9, 2009), we did not display any fee data. During a 6-month intervention period 1 year later (November 10, 2009, through May 9, 2010), we displayed fees, based on the Medicare allowable fee, for active tests only.We examined changes in the total number of orders placed, the frequency of ordered tests (per patient-day), and total charges associated with the orders according to the time period (baseline vs intervention period) and by study group (active test vs control).For the active arm tests, rates of test ordering were reduced from 3.72 tests per patient-day in the baseline period to 3.40 tests per patient-day in the intervention period (8.59% decrease; 95% CI, -8.99% to -8.19%). For control arm tests, ordering increased from 1.15 to 1.22 tests per patient-day from the baseline period to the intervention period (5.64% increase; 95% CI, 4.90% to 6.39%) (P < .001 for difference over time between active and control tests).Presenting fee data to providers at the time of order entry resulted in a modest decrease in test ordering. Adoption of this intervention may reduce the number of inappropriately ordered diagnostic tests.
Diagnosis and Management of Pneumonia in the Aged
Authors: J. J. Flanagan
Journal: BMJ (1966)

the one described above.Through the good offices of Dr. J. A. Boycott, serum specimens collected from the patient on 23 September and 12 October were sent to the other of us (H.S.) for examination for cytomegalovirus antibodies.The complement-fixing antibody titres were found to be 8 and 512 respectively.A further serum taken on 1 February 1966 had a titre of 256; urine specimens collected at this time were examined for virus excretion but without success.The clinical course and laboratory findings of our patient closely followed the pattern described by the Finnish workers, and we would agree with their conclusion that cyto- megalovirus infection must be considered as a possible cause of atypical, Paul-Bunnellnegative, infectious mononucleosis.-Weare, Xetc.,
Will ductal carcinoma in situ defeat breast cancer screening?
Authors: J. R Benson
Journal: BMJ (2009)

<h3>Abstract</h3> Expression of the unconventional myosin, Myosin-1e (Myo1e), has been shown to contribute to tumor progression in the MMTV-PyMT mouse model of mammary tumorigenesis and is associated with poor outcome in breast cancer patients. However, the specific effects of Myo1e expression on the mammary tumor cells remain unidentified. Here, we used Myo1e-KO and wild-type (WT) MMTV-PyMT mice on a pure genetic background to further investigate the molecular and cellular effects of Myo1e expression. Myo1e-WT tumors were characterized by an increased abundance of intra-epithelial macrophages and lower amounts of the extracellular matrix. Transcriptomic profiling of WT and Myo1e-KO tumors identified a pattern of differential expression of tumor suppressor and tumor-promoting genes that was consistent with the observed differences in tumor progression and morphology between the genotypes, and also revealed differential expression of genes associated with secretion and cell-cell adhesion. In agreement with the RNA-seq findings, Myo1e-expressing tumor cells exhibited increased proliferation and elevated nuclear enrichment of YAP1 transcriptional activator compared to Myo1e-KO tumor cells. To investigate tumor cell-autonomous effects of Myo1e expression, we used the epithelial cell line PY-230 derived from the MMTV-PyMT-induced mouse tumor to create Myo1e-depleted cells by Crispr-mediated genome editing. Cells deficient in Myo1e had increased expression of genes encoding milk components compared to the wild-type cells. Electric cell-substrate impedance sensing (ECIS) measurements showed that depletion of Myo1e in PY-230 cells resulted in increased resistance to electrical current indicating enhanced epithelial barrier function. Overall, we find that Myo1e expression biases tumors towards a less-differentiated, pro-tumorigenic state, and that depletion of Myo1e is associated with a pro-secretory, more differentiated state.
S45 How Successful Are Medical Thoracoscopists At Predicting Malignancy?
Authors: R. Hallifax, J. Corcoran, I. Psallidas, N. Rahman
Journal: Thorax (2014)

<h3>Introduction</h3> Use of medical thoracoscopy by physicians to diagnose malignant pleural disease is increasing. Thoracoscopy is also used therapeutically to pleurodese (talc poudrage), at the time of biopsy, to minimise pleural effusion recurrence. However, this relies on the physician being confident of their diagnosis macroscopically. A survey was conducted of regular thoracoscopists to establish the current practise related to medical thoracoscopy and a video of previous thoracoscopies (with known histology) was used to assess the accuracy of macroscopic evaluation of pleural disease. <h3>Methods</h3> 20 video clips recorded during thoracoscopy in Oxford were combined into a short video (30 s per clip): including a selection of cases with malignant (13) and benign disease (7), intentionally including some cases which were deemed "unclear". A survey of thoracoscopists was conducted via email. Respondents were asked to state whether each clip showed malignant or benign disease, scoring their confidence in their diagnosis (out of 10), whether they predict trapped lung and if they would perform pleurodesis. Gold standard of diagnosis was the histology result. <h3>Results</h3> Procedural survey: 16 physicians responded from 12 tertiary referral centres: 13 consultants and 3 specialist registrars. 15 (94%) had performed &gt;30 thoracoscopies each. Four institutions (25%) perform between &gt;10 thoracoscopies per month; 12 (75%) between 1–10 per month. Only 6 (38%) perform thoracoscopies as day cases. All perform rigid rather than flexible thoracoscopies. Video survey: Of the 20 video clips, the mean number of correct answers was 12.4 (62%). Respondents were more confident of their answers (out of 10) when correct (7.1/10) than incorrect (6.1/10). In cases deemed malignant, 69% would have performed talc pleurodesis; however, 17% would have pleurodesed patients who had benign disease (See Table). Respondents only correctly predicted trapped lung in 2.6/20 cases (13%). <h3>Conclusion</h3> Despite being experienced thoracoscopists, only 62% correctly diagnosed malignant or benign on video clips. The majority would appropriately perform pleurodesis, but 17% may have inappropriately pleurodesed benign disease. There are limitations to this small survey using short thoracoscopy clips, but this data suggests caution is required when considering making diagnosis on macroscopic appearance and deciding whether the lung is trapped.
THE TREATMENT OF ACNE VULGARIS WITH EPIOESTRIOL (ACTRIOL).
Authors: R. J. RUSHTON
Journal: British Journal of Dermatology (1962)

Journal Article THE TREATMENT OF ACNE VULGARIS WITH EPIOESTRIOL (ACTRIOL). Get access R. J. RUSHTON, M.B., B.Chir. R. J. RUSHTON, M.B., B.Chir. Registrar, Rupert Hallam Department of Dermatology, Royal Infirmary, Sheffield Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 74, Issue 3, 1 March 1962, Pages 91–93, https://doi.org/10.1111/j.1365-2133.1962.tb13462.x Published: 01 March 1962
Cerebral Blood Volume in Man
Authors: Richard D. Penn
Journal: JAMA (1975)

Cerebral blood volume in man can be measured by subtracting computerized axial tomogram density measurements taken before from those taken after an intravascular marker is infused into the blood. The average blood volume is 3.0 ml/100 ml of brain tissue, with a range of 2.4 to 4.25. This method can be applied in studying cerebral pathologic conditions. Areas of cerebral edema, surrounding a tumor, have a decreased blood volume.
Managing peanut allergy
Authors: H. A Sampson
Journal: BMJ (1996)

Liuzzo et al found that 24% of patients with myocardial infarction did not have raised C reactive protein values on admission.2We are undertaking a prospective multicentre study of 2000 patients with unstable angina sponsored by the Italian National Research Council to assess the incremental prognostic value of markers of the acute phase response and their cor- relation with conventional risk factors and with the mechanisms that lead to enhanced production of C reactive protein.This study should improve our understanding of the role of inflammation.In the meantime what conclusions can we draw from available evidence about the usefulness of C reactive protein measurements?Blood concentrations of C reactive protein (and possibly of serum amyloid A protein) may provide useful information beyond that available from the clinical presentation and other tests in two conditions.In patients presenting with unstable angina C reactive protein concentrations greater than 3 mg/Il, and especially greater than 10 mg/l, predict a poor response to intensive medical treatment and indicate high risk of myocardial infarction.Such patients should be given intensive medical treatment but also be considered for urgent revascularisation.In patients with chronic ischaemic heart disease C reactive protein measurements identify a gradient of risk for myocardial infarction or cardiovascular death.The risk of these outcomes over three years rises from 0% in patients in the upper third of cholesterol concentrations (> 263 mg/dl) but the lower third of C reactive protein and fibrinogen concentrations to 10% in patients in the highest third of both cholesterol and C reactive protein and fibrinogen values.In this second, high risk, group reducing cholesterol concentra- tions may have a much greater effect in reducing the incidence of events than in the first group, who appear to be at a consid- erably lower risk.
Prophylactic Cesarean Section at Term?
Authors: George B. Feldman, Jennie A. Freiman
Journal: New England Journal of Medicine (1985)

A 40-year-old nullipara with an uncomplicated antepartum course entered labor spontaneously at 41 weeks' gestation. During early labor, the placenta suddenly detached. An emergency cesarean section was started less than 10 minutes after the onset of fetal bradycardia, but the baby's condition was depressed at birth, and eventually there was profound, permanent neurologic damage. The family initiated a malpractice suit.This patient and her baby experienced an unpredictable disaster. The medical response her physicians initiated was appropriate but ineffective. After a lengthy trial, the court concurred in this assessment of events, and the malpractice charge was dismissed.During the course . . .