tbuckley/cabot-search huggingface dataset:
Clinical endpoints in trials of drugs for cancer: time for a rethink?
Authors: P P Koopmans
Journal: BMJ (2002)

There is a continual debate between health authorities, doctors, researchers, the pharmaceutical industry, and regulatory authorities over the question of when a new drug should be admitted to the market and when it should be prescribed or reimbursed.1 Divergent interests often obscure the scientific debate, but it is in the interest of all parties that valuable and effective drugs should be licensed without undue delay. 2 3 Yet it may take many years (mostly 10-15) from the time when a clinical development plan for a drug (mapping out how to investigate it) is established to its being prescribed for patients. This is frustrating for all drugs but is particularly so for drugs for fatal diseases such as cancer. I argue here that the process can be improved and focus particularly on three issues: the endpoints, side effects, and more collaboration between the parties, and especially the participation of patients.

#### Summary points

The introduction to market of drugs for lethal diseases such as cancer can be improved

More attention should be given to clinical symptoms and quality of life and less to survival

Surrogate endpoints and biomarkers should be used as support for proof of effectiveness

Clinical endpoints such as survival can be investigated after the drug's introduction

Licensing authorities, pharmaceutical companies, and patients should agree in advance the relevant endpoints and desired effect sizes

The major points at issue in drugs for cancer are the desired endpoint and the degree of change required over existing treatment.4 Licensing authorities require that drugs have a clinically meaningful effect. In the case of cancer drugs this is often translated as meaning an increase in survival compared with standard treatment. In potentially lethal diseases, however, waiting to assess these clinical endpoints (for example, the effect on five year survival) poses a dilemma as the …
Modeling marrow damage from response data: evolution from radiation biology to benzene toxicity.
Authors: D T Jones, M D Morris, J S Hasan
Journal: Environmental Health Perspectives (1996)

Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between 5 and 30 days. Mortality data from 27 experiments with 851 dose-response groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals: 12,827 mice, 2925 rats, 1676 sheep, 829 swine, 479 dogs, and 204 burros. Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is critical to hematopoietic recovery does not resemble stemlike cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in fitting of model coefficients.
Nutritional Issues in Nursing Home Care
Authors: John E. Morley
Journal: Annals of Internal Medicine (1995)

The most common nutritional problems in nursing home residents are weight loss and concomitant protein energy undernutrition. Although the causes of weight loss in these patients can usually be treated, they are rarely identified in the nursing home. Depression and adverse drug effects are the most common causes of weight loss. We discuss the appropriate use of feeding tubes in the nursing home and the early use of enteral feeding to prevent the development of severe protein energy undernutrition. Vitamin deficiencies, especially folate and pyridoxine deficiencies, frequently develop in nursing home residents. Hip fractures are often associated with vitamin D deficiency. Trace mineral deficiencies (for example, zinc deficiency) can aggravate immune deficiency and slow wound healing. Inadequate fluid intake leads to dehydration, hypotension, and, in persons with diabetes mellitus, hyperosmolarity. Finally, food intake itself can cause postprandial hypotension (which in turn may precipitate falls), produce electrolyte shifts, and result in aspiration pneumonia. Physical activity programs are an important component of nursing home care that may have an effect on nutritional status, and simple, cost-effective programs may be as beneficial as high-technology programs. Careful attention to the nutritional intake of nursing home residents is both a clinical and a quality-of-life issue.
More review content in TMM 2003
Authors: A.Romina Emilianus
Journal: Trends in Molecular Medicine (2003)

This new section, at the front of TMM, will contain Research Focus articles as well as Letters:•Research Focus (formerly Research News) articles discuss recent papers from the primary literature. These articles are shorter than Reviews or Opinions and the authors focus on the importance of the new papers, briefly setting them in context and explaining their significance for a wide audience.•Letters usually discuss a recent article in TMM or, very occasionally, a matter of general interest. Letters should be no more than 400 words long and, where they discuss a TMM article, the author of that article will normally be invited to reply.
Update on Statins: 2003
Authors: Carl J. Vaughan, Antonio M. Gotto
Journal: Circulation (2004)

T he number of significant developments in the years since the first version of this review has made necessary an update about the evolving role of 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, in the management and prevention of cardiovascular disease. 1 Two contrasting events have dominated the statin field in the last 3 years.First, the withdrawal of cerivastatin in 2001 reignited the issue of statin safety.Second, the efficacy and safety of statins in both the primary and secondary prevention of cardiovascular disease in diverse patient populations have helped shape the most recent set of guidelines from the National Cholesterol Education Program (NCEP). 2 The NCEP's Third Adult Treatment Panel (ATP III) forms the basis for contemporary lipid management.However, very recent trials suggest that even lower LDL cholesterol (LDL-C) targets may be indicated in high-risk patients.Improved understanding of the metabolism, safety, and clinical effects of this class of drugs has placed the statins at the forefront of drug strategies to treat dyslipidemia.
Human Infection Acquired in the Laboratory
Authors: William McD. Hammon
Journal: JAMA (1968)

Occasionally the microbiologist becomes the unintentional subject of his own experiment. While these laboratory accidents are relatively infrequent and the dispersed population of laboratory workers tends to conceal the problem further, the number of infections that have been produced is not inconsiderable. A committee created in 1950 by the American Public Health Association (APHA) now has records<sup>1</sup>of over 2,700 cases of laboratory-acquired infections and 107 fatalities. <i>Science</i>recently carried a report<sup>2</sup>by a subcommittee of the American Committee on Arthropod-Borne Viruses (ACAV) concerning the particular hazard confronting individuals who handle this one group of viruses. A total of 428 cases of laboratory-acquired disease are reported to have occurred among these workers, and 16 of the individuals have died. This report holds particular significance not only for the large number of physicians and virologists normally engaged in infectious disease studies but also for many persons engaged in research
A Realistic Journal Reading Plan: Quality as Well as Quantity
Authors: Craig B. Kaplan
Journal: JAMA (1983)

<h3>To the Editor.—</h3> As medical educators constantly deluged with reading material, we frequently also act as "literature consultants" to our house staff and students. We therefore applaud the efforts of Dr Scheckler in his recent article inThe Journal(1982;248:1987). Our communication is not meant to take issue with any of his practical suggestions but is intended to add the following comments. 1. It has been amply demonstrated that even the "best" of journals all too often include serious methodological and statistical flaws.1,2 One therefore has to be wary of drawing conclusions based on such data. 2. The idea of reading critically and "in depth" those articles that potentially will modify the way in which one approaches or treats a problem must be stressed. 3. "In-depth" reading requires reading with a critical eye, not simply the assumption that the conclusions given are valid because they are in a respected journal.
HIV-specific T Cell Cytotoxicity Mediated by RANTES Via the Chemokine Receptor CCR3
Authors: Fabienne Hadida, Vincent Vieillard, Brigitte Autran, Ian Clark-Lewis, Marco Baggiolini, Patrice Debré
Journal: The Journal of Experimental Medicine (1998)

CC chemokines produced by CD8+ T cells are known to act as HIV-suppressive factors. We studied the possible role of these chemokines in HIV-1–specific killing of target cells. We found that the activity of cytotoxic T lymphocytes (CTLs) in CTL lines or freshly isolated peripheral blood mononuclear cells from HIV-1–infected individuals is markedly enhanced by RANTES (regulated on activation, normal T cell expressed and secreted) and virtually abolished by an antibody neutralizing RANTES or the RANTES receptor antagonist RANTES(9-68). Lysis was mediated by CD8+ major histocompatibility complex class I–restricted T cells and was obtained with target cells expressing epitopes of the HIV-1LAI proteins Gag, Pol, Env, and Nef. The cytolytic activity observed in the presence or absence of added RANTES could be abolished by pretreatment of the CTLs with pertussis toxin, indicating that the effect is mediated by a G protein–coupled receptor. The chemokines monocyte chemotactic protein (MCP)-3, MCP-4, and eotaxin acted like RANTES, whereas macrophage inflammatory protein (MIP)-1α, MIP-1β, MCP-1, and stromal cell–derived factor 1 were inactive, suggesting a role for the eotaxin receptor, CCR3, and ruling out the involvement of CCR1, CCR2, CCR5, and CXCR4. CTL activity was abrogated by an antibody that blocks CCR3, further indicating that specific lysis is triggered via this chemokine receptor. These observations reveal a novel mechanism for the induction of HIV-1–specific cytotoxicity that depends on RANTES acting via CCR3.
Differential Effect of Dietary Fat and Weight Reduction on Serum Levels of Beta-Lipoproteins
Authors: WELDON J. WALKER, NORMAN WEINER, LAWRENCE J. MILCH
Journal: Circulation (1957)

Twenty-five patients sustained an average weight loss of 21.7 pounds on a diet in which 73 per cent of total calories consisted of animal fat. Their "new" weight was maintained on this high-fat diet and subsequently on a low-fat diet. Standard S f 0-12 lipoproteins were highly influenced by dietary fat intake independent of weight change. In contrast the S f 20-400 fraction was lowered by negative caloric balance and weight reduction despite the ingestion of large amounts of animal fat. These changes were statistically highly significant. Divergent responses of different classes of beta-lipoproteins may be missed if only total beta-lipoprotein measurements are made.
AN EARLY SIGN OF FEMORAL THROMBOSIS
Authors: GERALD H. PRATT
Journal: JAMA (1949)

The early diagnosis of thrombosis of the deep veins of the legs is one of the most difficult, as well as most important diagnoses doctors have to make. The condition, frequently, is unsuspected until embolism occurs. This missed diagnosis may cause a serious or a fatal complication. While surgical or anticoagulant therapy, or a combination of the two, can reduce effectively these complications, the diagnosis must be made first.  In a previous report on the diagnosis and treatment of thrombosis of the deep veins of the leg, I briefly mentioned the presence of three dilated veins over the tibia as an early sign. 1 Since then, this phenomenon has been observed so consistently that the term sentinal veins has been coined for it. I believe that these veins are the earliest objective sign of deep vein thrombosis and that attention should be directed to their presence so that effective therapy
Isolation for Infectious Diseases
Authors: B. K. Howells
Journal: BMJ (1964)

MEDIC"OURNAL of synergistic gangrene is by a wide excision ,of the affected area.In contrast to the acutely ill patient with streptococcal gangrene, the victim of synergistic gangrene has no _pyrexia, nor a toxic state until a very late stage.The main features of synergistic gan- grene are severe pain, exquisite tenderness, and marked psychological depression.As the lesion develops the appearance is that of a necrotic area of skin and subcutaneous fat enclosed by a rim of blackened skin.In turn the black rim is encompassed by a zone of hyperaemia.Coloured films of the established lesion were taken in a patient who came under my -care.As the condition is rare, anyone inter- ested in the appearances is welcome to a loan of the slides.-Iam, etc.,
Antioxidant status and glutathione metabolism in peripheral blood mononuclear cells from patients with chronic hepatitis C
Authors: Patricia Boya, Andrés de la Peña, Oscar Beloqui, Esther Larrea, Marian Conchillo, Yurdana Castelruiz, María-Pilar Civeira, Jesús Prieto
Journal: Journal of Hepatology (1999)
Family stigma in congenital physical handicap.
Authors: T Sensky
Journal: BMJ (1982)

It seems ironic that, for all the discussion last year in the medical press about the disabled, so little was said about stigmatisation, part of the process permitting society to set the disabled apart as a group deserving of their own Year. Perhaps this should not be surprising since stigma is a concept less familiar to doctors than to anthropologists1 and sociologists.2 It has been applied to groups3 as well as to individuals. While similar to each of these, the stigmatisation of families, also important, has its own unique features. Nowhere can these be better seen than at the birth of a handicapped or otherwise abnormal child, which has profound effects on parents and professionals alike. While it would be naive to suggest that responses to such an event could be reduced to the level of stigma and its management, focusing particularly on this affords useful insight into some of the difficulties faced by families under such circumstances. Stigmatisation also offers an appropriate perspective within which to view certain aspects of the development of handicapped children, notably their perceptions of themselves. Such issues are important in the medical and psychological management of these children and their families.
People with diabetes have one third higher mortality risk than general population, audit shows
Authors: S. Mayor
Journal: BMJ (2015)

The risk of death is one third higher among people with diabetes in England and Wales than in those without diabetes, the National Diabetes Audit has said, adding that this is due to complications resulting from poor diabetes control.

The National Diabetes Audit1 is the largest yearly clinical audit in the world. It collects information provided voluntarily by primary and secondary care providers about patients with diabetes and measures the effectiveness of their care against national guidelines and standards.

Latest …
DISTRIBUTION OF BROAD TAPEWORM
Authors: Thomas B. Magath
Journal: JAMA (1928)

ABSTRACT To the Editor: —The recent article by Vergeer (The Journal, March 3, p. 673) prompts me to call attention to my experiments on Diphyllobothrium latum, the broad tapeworm (Minnesota Med.10:614 [Oct.] 1927). Since my report was the first demonstration of the fact that North American fishes act as hosts for this worm, Vergeer's report may be looked on as confirmation of my observations. In my report it was indicated that I had evidence of the fact that there was an endemic area in and about Winnipeg, Manit. Since then I have obtained wall-eyed pike from Lake Winnipeg and have found larvae in a great percentage of them, which when fed to dogs produced typical tapeworms of the species D. latum. The importance of this is apparent when one learns that a great proportion of the wall-eyed pike sold in the middle western markets come from Canadian lakes and
Tuberculoid cutaneous infection due to a niacin-positive Mycobacterium chelonei
Authors: S.Y. YIP, P.C. WU, W.C. CHAN, C.H. TEOH-CHAN
Journal: British Journal of Dermatology (1979)

A case of cutaneous infection due to a niacin-positive Mycobacterium chelonei (previously called M. abscessus) on the dorsum of the hand of a professional cotton-classifier is reported from Hong Kong. The infection was probably directly acquired from handling contaminated raw cotton. The patient was successfully treated with combined anti-tuberculous drugs over a period of 1 year. Histologically, the skin lesion showed tuberculoid granulomas, in addition to abscesses.
CORRELATION BETWEEN MICROWAVE RADIOMETRY TEMPERATURES AND INTRAPLAQUE NEOANGIOGENESIS VISUALIZED BY CONTRAST-ENHANCED CAROTID ULTRASOUND: A POPULATION STUDY
Authors: Charalampia Georgios Nikolaou, Konstantinos Toutouzas, Archontoula Michelongona, Konstantinos Stathogiannis, Konstantina Aggeli, Ioannis Felekos, Andreas Synetos, Eleutherios Tsiamis, Dimitrios Tousoulis, Christodoulos Stefanadis
Journal: Journal of the American College of Cardiology (2012)
A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans
Authors: Akiko Kitamura, Yoichi Maekawa, Hisanori Uehara, Keisuke Izumi, Izumi Kawachi, Masatoyo Nishizawa, Yasuko Toyoshima, Hitoshi Takahashi, Daron M. Standley, Keiji Tanaka, Jun Hamazaki, Shigeo Murata, Koji Obara, Itaru Toyoshima, Koji Yasutomo
Journal: Journal of Clinical Investigation (2011)

Proteasomes are multisubunit proteases that play a critical role in maintaining cellular function through the selective degradation of ubiquitinated proteins. When 3 additional β subunits, expression of which is induced by IFN-γ, are substituted for their constitutively expressed counterparts, the structure is converted to an immunoproteasome. However, the underlying roles of immunoproteasomes in human diseases are poorly understood. Using exome analysis, we found a homozygous missense mutation (G197V) in immunoproteasome subunit, β type 8 (PSMB8), which encodes one of the β subunits induced by IFN-γ in patients from 2 consanguineous families. Patients bearing this mutation suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was highly expressed, and there was reduced expression of PSMB8. Downregulation of PSMB8 inhibited the differentiation of murine and human adipocytes in vitro, and injection of siRNA against Psmb8 in mouse skin reduced adipocyte tissue volume. These findings identify PSMB8 as an essential component and regulator not only of inflammation, but also of adipocyte differentiation, and indicate that immunoproteasomes have pleiotropic functions in maintaining the homeostasis of a variety of cell types.
Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized AAV2-mediated Gene Transfer
Authors: Jeannette Bennicelli, John Fraser Wright, Andras Komaromy, Jonathan B Jacobs, Bernd Hauck, Olga Zelenaia, Federico Mingozzi, Daniel Hui, Daniel Chung, Tonia S Rex, Zhangyong Wei, Guang Qu, Shangzhen Zhou, Caroline Zeiss, Valder R Arruda, Gregory M Acland, Lou F Dell'Osso, Katherine A High, Albert M Maguire, Jean Bennett
Journal: Molecular Therapy (2008)

We evaluated the safety and efficacy of an optimized adeno-associated virus (AAV; AAV2.RPE65) in animal models of the RPE65 form of Leber congenital amaurosis (LCA). Protein expression was optimized by addition of a modified Kozak sequence at the translational start site of hRPE65. Modifications in AAV production and delivery included use of a long stuffer sequence to prevent reverse packaging from the AAV inverted-terminal repeats, and co-injection with a surfactant. The latter allows consistent and predictable delivery of a given dose of vector. We observed improved electroretinograms (ERGs) and visual acuity in Rpe65 mutant mice. This has not been reported previously using AAV2 vectors. Subretinal delivery of 8.25 x 10(10) vector genomes in affected dogs was well tolerated both locally and systemically, and treated animals showed improved visual behavior and pupillary responses, and reduced nystagmus within 2 weeks of injection. ERG responses confirmed the reversal of visual deficit. Immunohistochemistry confirmed transduction of retinal pigment epithelium cells and there was minimal toxicity to the retina as judged by histopathologic analysis. The data demonstrate that AAV2.RPE65 delivers the RPE65 transgene efficiently and quickly to the appropriate target cells in vivo in animal models. This vector holds great promise for treatment of LCA due to RPE65 mutations.
Diagnosis and management after life threatening events in infants and young children who received cardiopulmonary resuscitation.
Authors: M P Samuels, C F Poets, J P Noyes, H Hartmann, J Hewertson, D P Southall
Journal: BMJ (1993)

OBJECTIVE--To determine the mechanisms and thereby appropriate management for apparent life threatening events treated with cardiopulmonary resuscitation in infants and young children. DESIGN--Prospective clinical and physiological study. SETTING--Royal Brompton Hospital or in patients9 homes, or both. SUBJECTS--157 Patients referred at median age 2.8 months (range 1 week to 96 months), 111 (71%) had recurrent events, 44 were born preterm, 19 were siblings of infants who had died suddenly and unexpectedly, and 18 were over 12 months old. INTERVENTIONS--Multichannel physiological recordings, including oxygenation, in hospital (n = 150) and at home (n = 61). Additional recordings with electroencephalogram, video, or other respiratory measures were used to confirm diagnoses. Management involved monitoring of oxygen at home, additional inspired oxygen, anticonvulsant treatment, or child protection procedures. MAIN OUTCOME MEASURES--Abnormalities on recordings compared to published normal data and their correlation with clinical events; sudden death. RESULTS--53 of 150 patients had abnormalities of oxygenation on hospital recordings, 28 of whom had an accompanying clinical event. Home recordings produced physiological data from 34 of 61 patients during subsequent clinical events. Final diagnoses were reached in 77 patients: deliberate suffocation by a parent (18), hypoxaemia induced by epileptic seizure (10), fabricated history and data (Munchausen syndrome by proxy; seven), acute hypoxaemia of probable respiratory origin (40), and changes in peripheral perfusion and skin colour without hypoxaemia (two). Four patients died: three suddenly and unexpectedly (none on home oxygen monitors) and one from pneumonia. CONCLUSIONS: Identification of mechanisms is essential to the appropriate management of infants with apparent life threatening events.