tbuckley/cabot-search huggingface dataset:
Statistical issues and challenges in immuno-oncology
Authors: Tai-Tsang Chen
Journal: Journal for ImmunoTherapy of Cancer (2013)

<h3>Background</h3> The development of immuno-oncologic agents poses unique challenges, namely that both efficacy and safety profiles differ from previously characterized cytotoxic and pathway-specific agents. In addition, exponential distribution is usually assumed in study designs with time-to-event endpoints such as overall survival or progression-free survival. This assumption might lead to wrong estimates of study duration and statistical power if the phenomena of long term survival and delayed clinical effects are present. The aim here was to evaluate the magnitude of the impact caused by the violation of this assumption, and to describe new ways of analyzing efficacy and safety of immuno-oncologic agents. <h3>Methods</h3> Monte Carlo simulation was implemented to explore the impact of long term survivors and delayed treatment effect on study power and trial duration. Scenarios with various combinations of long term and delayed treatment effects were considered. Study power and duration were evaluated based on 10000 randomly generated trial data sets. The utility of group sequential study designs was discussed. A new set of immune-related response criteria (irRC) was considered for efficacy analysis. Two new methods for identifying adverse events, termed immune-related adverse events (irAE) and immune-mediated adverse reactions (imAR) were described. The key features of the safety profiles derived using these two methods were similar. Both methods were aimed at identifying inflammatory adverse events caused by immunotherapies. <h3>Results</h3> The presence of long term survivors usually lengthened the study duration. Depending on the treatment effect post survival curve separation, delayed clinical effect in general led to a loss of power. The irRC offered a new way of identifying clinical responses. Both safety analyses demonstrated higher sensitivity of identifying adverse events of immune system origin. <h3>Conclusion</h3> This simulation study showed the importance of accounting for the delayed treatment effect and long term survivors when these phenomena were expected. Interim analyses for the purpose of stopping the study for either positive or futile outcome should be implemented with caution in immuno-oncology trials. The new efficacy analysis offered a potential new way of assessing signs of activity in immunotherapies. While the irAE method facilitated prompt and effective management of adverse events, the imAR method captured truly immune-related events.
Abnormal hormone responses of an adrenocortical cancer adenyl cyclase
Authors: Immanuel Schorr, Robert L. Ney
Journal: Journal of Clinical Investigation (1971)

Properties of adenyl cyclase of normal adrenals and of a corticosterone-producing adrenal cancer of the rat have been compared. Enzyme activity was found in all particulate fractions of both tissues. The cyclase of the tumor as well as of the adrenals was stimulated by adrenocorticotropic hormone (ACTH) over similar concentration ranges. Unexpectedly, the tumor enzyme was also stimulated by epinephrine, norepinephrine, and thyroid-stimulating hormone (TSH). These hormones produced a dose-related effect over a concentration span that was comparable with that for ACTH. The tumor cyclase was not responsive to angiotensin Il, vasopressin, glucagon, insulin, growth hormone, parathyroid hormone, and thyrocalcitonin. ACTH was the only hormonal preparation that stimulated normal adrenal cyclase. These findings are compatible either with the possibility that the adenyl cyclase receptor of the tumor has undergone structural alteration with a consequent loss of specificity for ACTH or with the possibility that the tumor possesses several cyclase regulatory receptors.
The dependence of the time constant of left ventricular isovolumic relaxation (tau) on pericardial pressure.
Authors: M A Frais, D W Bergman, I Kingma, O A Smiseth, E R Smith, J V Tyberg
Journal: Circulation (1990)

The purpose of this study was to investigate the dependence of tau, the time constant of left ventricular (LV) isovolumic relaxation, on pericardial pressure and to compare values of tau as determined by the methods of previous investigators and by a standard exponential curve fit. All of the more recent methods involve an additional parameter--the pressure to which the exponential relaxation finally declines (PB, the pressure intercept in the method of Craig and Murgo and the asymptote in the exponential fits). An additional purpose of the study was to determine the relation of these parameters to pericardial pressure. In eight closed-chest anesthetized dogs, tau was calculated from intracavitary (Plv) and transmural LV pressure (Plv = Plv-Pper) by each method as pericardial (Pper) and LV end-diastolic pressure were changed by pericardial infusion and intravenous volume loading. The time constant determined by the method of Weiss et al was dependent on pericardial pressure; the time constants determined by the other methods were not. PB and the asymptotes were found to be similar and to increase almost equally with pericardial pressure. When pericardial pressure was zero, these values were approximately -20 mm Hg. Thus, both these parameters seem to indicate the same baseline pressure, a pressure that increases pari passu with pericardial pressure. Reported changes in the value of tau calculated from intracavitary LV pressure by the method of Weiss et al may reflect factors other than changes in LV diastolic function.
Psychology and Psychosomatic Illness: Reflections on Theory and Research Methodology
Authors: J.C. Nemiah
Journal: Psychotherapy and Psychosomatics (1973)

The term 'denial', as commonly used in respect to patients with psychosomatic disorders, implies that the widely observed absence of affect and fantasy, in such patients, is the result of psychological defense mechanisms. Careful observation of the mental functioning of those with psychosomatic disorders discloses a basic incapacity in patients with these illnesses to experience or express affect and related fantasies that is different from that seen in patients with psychoneuroses, in whom psychological defense mechanisms are clearly operating. It is suggested that the phenomena seen in psychosomatic patients are not primarily the result of psychodynamic conflicts but can be better understood in neurophysiological concepts, and that further understanding of psychosomatic processes is to be sought for in an increased knowledge of brain function.
SPIROCHETES IN HODGKIN'S DISEASE.PRELIMINARY COMMUNICATION.
Authors: WILLIAM CHARLES WHITE
Journal: JAMA (1907)

Having noticed the frequency with which spirochetal infections are attracted to the lymphatic tissue, for example<i>Spirochæta pallida</i>to lymph glands,<i>Spirochæta obermeieri</i>to the spleen, and knowing the frequency with which spirillar forms are present in the mouth and familiar with the frequent history of enlarged tonsils preceding Hodgkin's disease, I was tempted to apply the specific stains for spirochetes to the glands in Hodgkin's disease. This seemed the more likely to give results by coupling the observation of the peculiar giant cell formation described by Reed and by Longcope in the glands of Hodgkin's disease with the observation of Benda that the giant cell formation in syphilitic children's livers was made up of pale spirochetes. With these thoughts in mind, I sent to a number of laboratories a request for glands of Hodgkin's disease which had been hardened in formalin. Dr. W. G. MacCallam, of Johns Hopkins, Baltimore,
Wake up and smell the coffee
Authors: A. A. Pierry
Journal: BMJ (2012)

<h3>ABSTRACT</h3> Here we present a generalized method of guide RNA “tuning” that enables Cas9 to discriminate between two target sites that differ by a single nucleotide polymorphism. We employ our methodology to generate a novel <i>in vivo</i> mutation prevention system in which Cas9 actively restricts the occurrence of undesired gain-of-function mutations within a population of engineered organisms. We further demonstrate that the system is scalable to a multitude of targets and that the general tuning and prevention concepts are portable across engineered Cas9 variants and Cas9 orthologs. Finally, we show that the designed mutation prevention system maintains robust activity even when placed within the complex environment of the mouse gastrointestinal tract.
Doctors and patients confuse cervical screening with diagnostic tests
Authors: M. McCartney
Journal: BMJ (2014)

Campaigns backed by patients and families to lower the age at which women are eligible for cervical screening are understandable. They present screening to the UK public as a logical, clear headed, and obvious health need. 

The age at which cervical screening starts was raised from 20 to 25 in England after a recommendation from the advisory committee on cervical cancer screening in 2003.1 Northern Ireland followed in 2011,2 and Scotland will from 2015.3 I suspect that many campaigners saw this merely as rationing. If you believe that screening would have saved a 22 year old woman’s life, and it were available in Scotland but not in England, a natural conclusion is …
Failure of Tuberculosis Control
Authors: Eran Bellin
Journal: JAMA (1994)

The dramatic increase in tuberculosis (TB) incidence<sup>1</sup>is testimony to the failure of the United States to coordinate its medical care provision, disease surveillance, and societal will to consistently provide TB therapy and monitor TB control.<sup>2</sup>In this issue ofThe Journal, Bloch and colleagues<sup>3</sup>demonstrate a remarkable shift in the epidemiology of TB in the United States. In the 1970s, US health officials believed that indigenous TB was coming under control, its ultimate elimination possible with only an occasional case reactivating in the elderly. Transient increases in TB incidence were attributed to immigrants, such as the Indochinese refugees in the mid 1970s<sup>4</sup>and Philippine national World War II veterans in Hawaii in the 1990s.<sup>5</sup>These foreign cases brought with them the peril of drug resistance as a result of the indiscriminate and inconsistent use of TB medications in the immigrants' countries of origin. Bloch
THE PHYSIOLOGIC BASIS OF THE NEUROGENIC BLADDER
Authors: JOSEPH P. EVANS
Journal: JAMA (1941)

The propriety of presenting yet another paper dealing with the physiology of micturition might well be questioned since the literature on the subject has become so voluminous as to be repetitious. The presentation of significant new data or the pointing out of new problems would be adequate justification. In this instance, however, I shall attempt so to strip the subject of its physiologic and neurologic complexities as to provide a useful working concept of bladder activity which the practitioner can utilize in handling his everyday problems. The authoritative work of Denny-Brown and Robertson<sup>1</sup>and of Langworthy, Kolb and Lewis<sup>2</sup>may be referred to for detailed presentation and analysis of the experimental and clinical evidence. There are several basic anatomic and physiologic facts that are a prerequisite to an understanding of the problem. Briefly they are as follows: The bladder is made up of smooth or involuntary musculature. The
Population study of tender point counts and pain as evidence of fibromyalgia
Authors: P Croft, J Schollum, A Silman
Journal: BMJ (1994)

<h3>Abstract</h3> <b>Objective</b>: To determine the relation between tender points, complaints of pain, and symptoms of depression, fatigue, and sleep quality in the general population. <b>Design</b>: Two stage cross sectional study with an initial questionnaire about pain to classify those eligible for an examination of tender points. <b>Setting</b>: Two general practices in north west England. <b>Subjects</b>: Stratified random sample of adults from age-sex registers. Of the responders, 250 were selected for examination of tender points on the basis of their reported pain complaints; 177 subsequently participated. Main outcome measures - Tender point count (0 to 18) grouped into four categories with the highest (&gt;=11) corresponding to the criteria of the American College of Rheumatology for fibromyalgia. Assessment of pain (chronic widespread, regional, none). Measures of depression, fatigue, and difficulty with sleeping. <b>Results</b>: Women had a higher median tender point count (six) than did men (three). Counts were higher in those with pain than in those who had no pain and in those with widespread compared with regional pain. Most subjects with chronic widespread pain, however, had fewer than 11 tender points (27/45; 60%). Two people with counts of 11 or more were in the group reporting no pain. Mean symptom scores for derpession, fatigue, and sleep problems increased as the tender point count rose (P value for trend &lt;0.001). The trends were independent of pain complaints. <b>Conclusions</b>: Tender points are a measure of general distress. They are related to pain complaints but are seperately associated with fatigue and depression. Sleep problems are associated with tender points, although prospective studies are needed to determine whether they cause tenderness to develop. Fibromyalgia does not seem to be a distinct disease entity.
Cancer risk is higher in relatives of women with early breast cancer
Authors: Roger Dobson
Journal: BMJ (2006)

Male and female relatives of women who receive a diagnosis of breast cancer before the age of 50 are at a higher risk of developing a number of malignancies, a new study has found.

The study, which looked at cancer in first degree relatives of women with early onset breast cancer, showed a higher rate of cancers of the breast, ovaries, and cervix among the relatives than national rates, adjusted for age, sex, and time. Among relatives aged under 50 the risk of cancers of the colon and gall bladder were higher, says the study, which was published online ahead of print publication in the European Journal of Cancer on …
Severe Motility Disturbance after Small Doses of Prochlorperazine
Authors: C. D. Christian, George Paulson
Journal: New England Journal of Medicine (1958)

PROCHLORPERAZINE,‡ a phenothiazine derivative, has been shown to be an effective antiemetic and antinauseant in dosages approximately half those of chlorpromazine1 and is being used in many conditions in which nausea and vomiting are problems. Motor symptoms of a bizarre dystonic type resembling Parkinson's disease and including spasm of the neck muscles, extensor rigidity of the back muscles, carpopedal spasm, trismus and difficulty in swallowing have been reported2 , 3 as untoward side effects of prochlorperazine therapy, but such effects are generally considered to be mild and to be associated with the higher dosages of the medication (exceeding 60 mg. daily).2 In . . .
The National Health Service Corps and Inner-City Hospitals
Authors: Fitzhugh Mullan
Journal: New England Journal of Medicine (1997)

The looming surplus of physicians in the United States has given new life to the long-standing national debate about the training of physicians, subsidies for such training, and the large numbers of graduates of foreign medical schools in residency programs. There have been many proposals to limit federal funding for graduate medical education in order to reduce the incentives hospitals now have to hire residents.15 A consensus statement on decreasing the number of residency positions was recently issued by a consortium of leaders in medicine.6 The Health Care Financing Administration has approved a demonstration program in New York City . . .
Blair throws down challenge to GPs over NHS changes
Authors: L. Beecham
Journal: BMJ (2000)

<b>Objective:</b> Multicenter randomized phase III trial (NCT01780675) to investigate memory functioning and safety after PCI with or without hippocampus sparing in Small Cell Lung Cancer (SCLC) (25 Gy/ 10 fractions) using the Hopkins Verbal Learning Test-Revised (HVLT-R). We here report on the differences between localized (stage I-III) vs. metastatic (stage IV) patients. <b>Methods:</b> Primary endpoint: decline in HVLT-R total recall at 4 months. Decline of 5 or more out of a possible 36 points was considered a failure. <b>Results:</b> 168 patients were randomized. Median follow-up: 24.6 months. Median age: 64 years, 51% female, performance score WHO 0-1: 93%. Stage distribution: 70% localized, 30% metastatic. Localized disease: at 4 months, 27 % in both treatment arms had a decline of ≥ 5 points of HVLT-R total recall (p=1.00); at 8 months: 34 % and 22 % in PCI and HA-PCI (p=0.40). Metastatic disease: at 4 months, 33 % in both treatment arms had a decline of ≥ 5 points (p=1.00); at 8 months: 33 % and 50 % in PCI and HA-PCI (p=1.00). No difference in the incidence of brain metastases between PCI and HA-PCI in localized or metastatic SCLC were observed. No patients developed isolated brain metastases in the hippocampal avoidance region. There were no statistically significant differences in the overall survival (OS) between PCI and HA-PCI, neither in localized, nor in metastatic disease. <b>Conclusion:</b> HA-PCI did not affect neuro-cognitive decline compared to standard PCI, both in localized and in metastatic SCLC. No increase in brain metastases was observed. Regular PCI remains the standard of care.
Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT)
Authors: T Fischer, C Reifenrath, GR Hess, MT Corsetti, S Kreil, J Beck, P Meinhardt, G Beltrami, B Schuch, H Gschaidmeier, R Hehlmann, A Hochhaus, A Carella, C Huber
Journal: Leukemia (2002)
Abstract 4486: Stent Thrombosis After Drug-Eluting Stent Implantation: Incidence, Timing and Relation to Discontinuation of Clopidogrel Therapy Over a 4-Year Period
Authors: Stefanie Schulz, Julia Ellert, Julia Goedel, Robert A Byrne, Raisuke Iijma, Olga Bruskina, Jürgen Pache, Julinda Mehilli, Deutsches Herzzentrum München, Albert Schömig, Adnan Kastrati, Deutsches Herzzentrum München
Journal: Circulation (2008)

To assess the incidence, timing and relation of drug-eluting stent thrombosis (ST) to discontinuation of clopidogrel therapy. This prospective observational cohort study includes 6816 consecutive patients that underwent a successful drug-eluting stent (DES) implantation between July 2002 through December 2006 in 2 tertiary, high-volume percutaneous coronary intervention (PCI) centers in Germany. The primary end point was definite ST (ARC definition). During 4-year follow-up, 4.2% of the patient population incurred a myocardial infarction (MI), 8.6% had died and 3.1% had experienced a bleeding complication. Definite ST was observed in 73 patients, corresponding to a cumulative incidence of 1.2% at 4 years. Cumulative incidence of ST was 0.5% at 30 days and 0.8% at 1 year. In comparison to patients without ST, patients with ST carried a higher risk of MI (93% versus 3%; OR 48.5 [41.3 to 57.1]) and death (42% versus 8%; OR 5.2 [3.6 to 7.6]). Figure 1 shows the number of patients with ST in each time interval from discontinuation of clopidogrel therapy. Figure 2 depicts the cumulative incidence of ST in patients who were on clopidogrel therapy and in those who discontinued clopidogrel. The 4-year incidence of ST after DES implantation is low in high-volume PCI centers. A relevant number of ST occur early after discontinuation of clopidogrel therapy. The dependence of ST on discontinuation of clopidogrel therapy is evident during the first 6 months but not thereafter.
Airway reflexes, autonomic function, and cardiovascular responses.
Authors: J Widdicombe, L Y Lee
Journal: Environmental Health Perspectives (2001)

In this article, we review the cardiovascular responses to the inhalation of irritants and pollutants. Many sensory receptors in the respiratory system, from nose to alveoli, respond to these irritants and set up powerful reflex changes, including those in the cardiovascular system. Systemic hypotension or hypertension, pulmonary hypertension, bradycardia, tachycardia, and dysrhythmias have all been described previously. Most of the experiments have been acute and have been performed on anesthetized experimental animals. Experiments on humans suggest we have similar sensory systems and reflex responses. However, we must use caution when applying the animal results to humans. Most animal experiments, unlike those with humans, have been performed using general anesthesia, with irritants administered in high concentrations, and often to a restricted part of the respiratory tract. Species differences in the response to irritants are well established. We must be even more careful when applying the results of acute experiments in animals to the pathophysiologic changes observed in prolonged exposure to environmental pollution in humans.
A critical role for DAP10 and DAP12 in CD8+ T cell–mediated tissue damage in large granular lymphocyte leukemia
Authors: Xianghong Chen, Fanqi Bai, Lubomir Sokol, Junmin Zhou, Amy Ren, Jeffrey S. Painter, Jinhong Liu, David A. Sallman, Y. Ann Chen, Jeffrey A. Yoder, Julie Y. Djeu, Thomas P. Loughran, Pearlie K. Epling-Burnette, Sheng Wei
Journal: Blood (2008)
[288] THE LIVER-SPECIFIC PROMOTER OF COLLAGEN XVIII IS A FUNCTIONAL TARGET OF THE C/EBPB TRANSCRIPTION FACTOR IN HUMAN LIVER
Authors: L. Armelin-Correa, A. Fautrel, E. Lavergne, D. Quelard, D. Bonnier, N. Theret, B. Turlin, M.R. Passos Bueno, B. Clement, O. Musso
Journal: Journal of Hepatology (2007)
NATIONAL LICENSURE FOR PHYSICIANS IN THE FEDERAL SERVICE
Authors: Donald Brown
Journal: JAMA (1918)

To the Editor:  —I wish to voice the opinion of almost every physician with whom I have conversed on the granting of national licensure to all physicians in the medical service of the U. S. Army or Navy, enlisted in the Medical Reserve Corps, National Guard or regular Medical Corps. These men should be granted the privilege of practicing medicine in any place in the United States at the end of the war, without taking a state board examination. In my conversation with officers some say that they do not know whether or not they will go back to the place from which they came. Others, younger men, argue that they had not been given the time to take their state board examinations in the state in which they want to practice, but took them where they were taking their internship, and that that state does not reciprocate with their
A Transgenic Marker for Mouse B Lymphoid Precursors
Authors: Inga-Lill Mårtensson, Fritz Melchers, Thomas H. Winkler
Journal: The Journal of Experimental Medicine (1997)

Three lines of transgenic mice have been generated which express human CD25 under the control of the 722-base pair region located immediately 5′ of the precursor (pre)–B cell–specific λ5 gene. All three strains express human CD25 in parallel to endogenous λ5 on pre–B cells, but not on mature B lymphocytes or other blood cell lineages. High expression of human CD25 on B lineage cells of transgenic mice has allowed the identification of a new B220+CD19−λ5+ precursor of the B220+CD19+λ5+ c-kit+ pre-BI cells. Both types of precursors are clonable on stromal cells in the presence of interleukin-7. The CD19− precursors have a sizeable part of their immunoglobulin heavy chain gene loci in germline configuration, while the CD19+ pre–BI cells are predominantly DJH rearranged. The results indicate that random integration of the 722-bp 5′ region of the λ5 gene into the mouse genome confers tissue and differentiation stage–specific expression of a transgene.
Re: Fritz H. Schröder, Karl-Heinz Kurth, Sophie D. Fossa, et al. Early Versus Delayed Endocrine Treatment of T2-T3 pN1-3 M0 Prostate Cancer Without Local Treatment of the Primary Tumour: Final Results of European Organisation for the Research and Treatment of Cancer Protocol 30846 After 13 Years of Follow-up (A Randomised Controlled Trial). Eur Urol 2009;55:14–22
Authors: Tomasz Drewa
Journal: European Urology (2008)