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Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial.

Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson’s disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.

BACKGROUND The consistency of endoscopic and histologic findings in patients with ulcerative colitis (UC) has not been elucidated. Choice of assessment may affect study outcomes. METHODS Post hoc analyses were performed using data from 2 randomized, controlled multicenter trials: (1) SAG-26, mesalazine granules for induction of remission in UC (n = 380), and (2) SAG-27, mesalazine granules for maintenance of UC remission (n = 647). Assessments included Clinical Activity Index, Endoscopic Index, modified Disease Activity Index, and Histology Index. RESULTS In SAG-26, 52 of 380 patients (13.7%) with clinically (Clinical Activity Index >4) and endoscopically (Endoscopic Index ≥4) active UC showed no histological signs of active inflammation (Histology Index ≤1) at baseline. Among endoscopically and histologically active patients, 246 of 327 (75.2%) reached clinical remission versus 48 of 52 patients (92.3%) with active endoscopy but no inflammation on histology (difference, 17.1%; P = 0.006). The difference in the proportion of patients achieving clinical remission according to endoscopy and histology in clinically inactive (Clinical Activity Index ≤4) patients was 30.8% in SAG-26 (at the study end) and 28.1% in SAG-27 (at baseline). In SAG-27, clinical relapse occurred in 21.2% of patients with endoscopic and histologic remission at baseline and 27.1% of patients with some histological inflammation at baseline (P = 0.111). Using the modified Disease Activity Index ≤1 (mucosal healing) instead of the Endoscopic Index score, the difference was similar (21.2% versus 28.0%, P = 0.073). CONCLUSIONS Endoscopic and histologic assessments differ in both active and inactive UC. Overdiagnosis of inflammation using endoscopy versus histology can significantly affect outcomes, at least in studies using induction of clinical remission as an endpoint. The assessment criteria for trials in UC should be reconsidered.

Glioblastomas (GBMs) containing foci that resemble oligodendroglioma are defined as GBM with oligodendroglioma component (GBMO). However, whether GBMO is a distinct clinicopathological variant of GBM or merely represents a divergent pattern of differentiation remains controversial. We investigated 219 consecutive primary GBMs, of which 40 (18.3%) were confirmed as GBMOs. The clinical features and genetic profiles of the GBMOs were analyzed and compared with the conventional GBMs. The GBMO group showed more frequent tumor-related seizures (P= .027), higher frequency of IDH1 mutation (31% vs.

We thank Mr. Saleh for his comments and are pleased he agrees that acceptance into melanoma therapeutic trials should not be contingent on undergoing sentinel node biopsy (SNB). We disagree with his assertion that SNB still has a viable role in melanoma management. Suppose SNB followed by completion lymphadenectomy (CL) was a drug therapy for melanoma, subjected to a ten-year randomized controlled trial involving 2000 patients where a survival benefit was not found. This article is protected by copyright. All rights reserved.

Scurvy is a thousand-year-old stereotypical disease characterized by apathy, weakness, easy bruising with tiny or large skin hemorrhages, friable bleeding gums, and swollen legs. Untreated patients may die. In the last five centuries sailors and some ships' doctors used oranges and lemons to cure and prevent scurvy, yet university-trained European physicians with no experience of either the disease or its cure by citrus fruits persisted in reviews of the extensive but conflicting literature. In the 20(th) century scurvy was shown to be due to a deficiency of the essential food factor ascorbic acid. This vitamin C was synthesized, and in adequate quantities it completely prevents and completely cures the disease, which is now rare. The protagonist of this medical history was James Lind. His report of a prospective controlled therapeutic trial in 1747 preceded by a half-century the British Navy's prevention and cure of scurvy by citrus fruits. After lime-juice was unwittingly substituted for lemon juice in about 1860, the disease returned, especially among sailors on polar explorations. In recent decades revisionist historians have challenged normative accounts, including that of scurvy, and the historicity of Lind's trial. It is therefore timely to reassess systematically the strengths and weaknesses of the canonical saga.

Objectives. The optimal therapeutic trial duration of anti-TNF-� therapy is currently unknown. The British Society for Rheumatology (BSR) guidance states that non-response at 3 months warrants re-evaluation of treatment and recommends not to persist beyond 6 months. The National Institute for Health and Clinical Excellence (NICE) specifies treatment continuation if response is achieved by 6 months, yet the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) maintain a 3 month cut-off. No evidence exists to support a 6 month therapeutic trial over 3 months. Thus, we undertook a study to evaluate the proportion of patients who failed to meet NICE response criteria at 3 months but obtained this by 6 months, and to identify predictive factors for this. Methods. Patients who commenced anti-TNF-� therapy for RA were studied, counting those who switched to a second or third agent separately for each instigation of therapy (n ¼ 244). Response at 3 and 6 months was defined according to NICE criteria as a � 1.2 reduction in Disease Activity Score (DAS28). Results. Of the 189 patients with available 3 month DAS28 responses, 149 fulfilled response criteria. Of the 40 who failed, 27 continued treatment, of whom 21 were available for follow-up at 6 months. Out of the 21 patients, 12 (57%; 95% CI 36, 78) achieved a response at this time. This data set was too small to investigate predictors of response at 6 months. Conclusions. A substantial proportion of patients who fail NICE response criteria at 3 months and continue on treatment to 6 months achieve a response. These results support a 6 month therapeutic trial over 3 months.

Endemic zinc deficiency is recognised to be a common and serious problem in developing countries. However, it may be seen in routine practice in the UK, and can be easily overlooked. Malnutrition from any cause in conjunction with an undiagnosed cutaneous problem should alert the clinician to the diagnosis. Investigations may be unreliable, and if in doubt, a therapeutic trial of zinc supplementation is indicated. We present three cases of malnourished patients, in whom zinc deficiency was diagnosed after the development of cutaneous features. The malnutrition resulted from alcoholism in two cases and anorexia nervosa in the third. The heterogeneity of underlying causes of zinc deficiency is discussed, along with its effects, treatment and zinc homeostasis.

Pediatric transplant infectious disease (PTID) is a growing area of clinical practice in pediatric infectious disease practice that faces challenges in education and training of practitioners: • Variable numbers and types of cases at different clinical centers, resulting in overall lack of experience • Relative paucity of diagnostic and randomized therapeutic trials, resulting in weak evidence base on which to base management guidelines

The technique of sentinel lymph node (SLN) biopsy has been in use for almost a decade, but its effect on survival has not yet been established. It is however the most accurate method for staging patients with primary cutaneous melanoma who lack clinical evidence of metastatic disease. This article discusses the rationale and logistics of SLN biopsy, and the management strategies that can be employed in those patients who are SLN positive. Future therapeutic trial in patients with primary cutaneous melanoma will only be meaningful if the SLN status of the subjects is established.

SUMMARY : We describe the use of activity indices during a prospective trial of 91 patients with active Crohn's disease. Data were recorded by experienced physician investigators in four centres, and several activity indices were compared. The indices studied included modifications of the Crohn's Disease Activity Index (CDAI), the Dutch Activity Index, and the European Severity/Activity Index. Correlation was made between each index, between the indices and physician's opinion, and between each index and patient progress. The correlation between indices was generally somewhat higher than that observed during a similar study in the early 1980s. Our results suggest close correlation between the variants of the CDAI, but less good correlation with the Dutch or European indices. There was also good correlation between CDAI variants and physicians' opinion, both as measured on linear analogue scale and as measured by physician action. All assessed indices correlated poorly, however, with short-term patient prognosis. New indices, or combinations of existing datasets, will be necessary to solve this problem.

Background Interest in incorporating quality of life as an end point in clinical studies of cancer treatment has intensified in recent years. Purpose We provide practical suggestions that will assist investigators considering including quality-of-life assessment in phase III therapeutic trials. Methods We discuss issues important in study planning, including quality-of-life definition, priority studies for quality-of-life assessment, eligibility requirements, and design. Conclusions Many of the problems that quality-of-life studies have encountered, from protocol approval to data analysis, could be addressed and alleviated during protocol development. This discussion is intended to assist and stimulate investigators conducting research in this area.

To the Editor, As a technique that relies on anatomical landmarks, percutaneous placement of a spinal cord stimulator (SCS) can be very difficult in patients with scoliosis. This is due not only to the abnormal anatomy of patients with scoliosis, but also to the postoperative changes that occur as a result of corrective procedures. Because of this, surgical placement is often opted for over percutaneous placement. As current literature supports only about a 50–60% success rate in treatment of patients with failed back surgery syndrome (FBBS) [1], we feel that a percutaneous trial placement is a more conservative and subsequently superior modality compared with undergoing surgical placement without trial. A literature search revealed only one case report of percutaneous placement with a case of advanced scoliosis [2]. We present another successful placement and hope to encourage other practitioners to consider a minimally invasive trial prior to scheduling a patient for operative placement. Percutaneous SCS placement has been shown to be a cost-effective technique and is minimally invasive [1,3]. Procedure-related discomfort that may compromise a therapeutic trial is also minimized. Percutaneous electrodes allow longitudinal access to multiple levels via a single interlaminar needle puncture. This facilitates mapping of multiple targets. The use of …

Appropriate Pain Treatments, Palliative Sedation, and Double Effect In caring for patients near the end of life, distressing symptoms may arise that fail to respond to comprehensive evaluations and aggressive therapeutic trials. Faced with unremitting suffering, patients, families, and the clinicians who serve them, may choose to accept sedation of the patient to provide symptomatic relief. The terms “terminal sedation,” “palliative sedation,” “sedation therapy,” and “sedation in the imminently dying” have all been used to describe this practice. Because of the critical need to convey to patients and colleagues the clinical intent to relieve distressing symptoms and not to hasten death, for its precision, I prefer the term “sedation for refractory symptoms in the imminently dying” (SRSID). The ethical basis for SRSID derives from the following principles: The principle of double effect, which has wide acceptance among both bioethicists …

Argues that a frequently cited statistic misrepresents the number of cancer patients treated in experimental therapeutic trials.

Sir, One of the most prominent features of the procoagulant antiphospholipid (Hughes) syndrome (APS) is headache.1 These vary from classical intermittent migraine to almost continuous incapacitating headache. Over and above the considerable fear of stroke in these patients, the headaches are, themselves, often incapacitating. We have anecdotally noted that in patients with, for example, DVT commencing anticoagulation with warfarin (coumadin), there has been a dramatic improvement—sometimes a total disappearance—of this symptom.2 Furthermore, we have observed the same phenomenon in some of our APS patients starting heparin …

Edited by Salvatore T. Butera. Caister Academic Press, Norwich, UK. Printed by Cromwell Press. British Library Cataloguing-in-Publication Data. ISBN 0-9542464-9-7. HIV Chemotherapy: A Critical Review is a multi-authored book covering a variety of subjects that are essential for clinical management of HIV-positive patients. In such a book one would expect, in addition to an adequate historic review, a complete overview of the current treatment strategies with definitions of timely gold-standard chemotherapeutic regimens. The historic aspects are excellently covered by well-known authors: detailed descriptions of historic patient management protocols, assessment of the relevance of drug resistance, implementation of treatment in developing countries. In the remaining chapters, novel antiviral procedures and compounds and their implications for future treatment are, again, well explained. The only historic features that are not fully described are those concerning therapeutic trials in the various animal …

Summary Results of therapeutic trial of diazepam in tetanus are presented. The trial included 200 cases of tetanus—167 non-neonates and thirty-three neonates. The patients were divided into two groups and were matched as regards age, sex and severity of the disease. The cases of group I received standard treatment while the cases of group II received diazepam in addition. Over-all mortality in group I was 54% and in group II, 26%. The results were statistically significant in non-neonates and in severe degree of tetanus. The drug was well tolerated and side effects were not observed.

Herpes simplex encephalitis and neonatal herpes simplex virus infections are important consequences of herpes simplex virus infections of humans. The association of both diseases with significant mortality and morbidity has prompted intensive therapeutic trials designed to improve outcome. The NIAID Collaborative Antiviral Study Group has been able to demonstrate that vidarabine therapy decreases the mortality and improves morbidity for both herpes simplex encephalitis and neonatal herpes simplex virus infections. Nevertheless, mortality for both diseases is about 40% and many survivors are left with significant neurological impairment. With the hope of improving outcome, we initiated comparative trials of vidarabine and acyclovir for these two diseases. This report summarizes the status of these trials, which are still underway, with particular reference to the complexities of studies such as these. Because adequate numbers of patients for definitive statistical analyses have not been entered into the trial, data were assessed according to outcome for the entire group, irrespective of drug administered. The mortality of herpes simplex encephalitis and neonatal herpes simplex virus infections has been reduced to 34 and 30%, respectively, a decrease of approximately 10% for each disease. Further analyses await completion of the trials.

Chronopharmacology, the study of time-dependent physiological response to drugs, and its relationship to current drug therapy are discussed. The objective of chronotherapy is to apply chronobiologic principles to the treatment of human disease. The appropriate patients for chronotherapy are those who are receiving high-risk drugs, who have a high-risk disease (e.g., cancer) or who are receiving a high-cost drug. Although little is known of the chronobiologic characteristics of many drugs or diseases, researchers should take into account the possible relationship of chronobiology to drug effects when designing therapeutic trials. Drug therapy can be optimized by tailoring dosing schedules and distribution systems to chronobiologic patterns.

Serial gadolinium-DTPA (Gd-DTPA) enhanced magnetic resonance imaging (MRI) was performed in 9 patients with multiple sclerosis (MS). On the first scan enhancing lesions were seen in 7 patients, all of whom were in acute relapse. Most enhancing lesions were asymptomatic. On the second scan (3 to 5 weeks later), persisting enhancement was seen in only 12/54 lesions which enhanced on the first scan. No lesion showed persisting enhancement on the third scan (after 6 months). Enhancement occurred in all 12 new lesion areas seen on the unenhanced second scan and in 8 of 15 new lesions seen on the third scan. Enhancement was also seen in 4 older lesions which had been nonenhancing on earlier scans. Relaxation time measurements demonstrated a high water content in some nonenhancing lesions, which could be due to a subtle blood-brain barrier disturbance not detected with Gd-DTPA. The results show that blood-brain barrier impairment is a consistent finding in new MS lesions detected with MRI. Gd-DTPA is a useful marker of new and biologically active lesions and should prove of value in monitoring therapeutic trials in MS.

The characteristic clinical, gross, and microscopic findings of two cases of gangrene of the breast following Dicumarol therapy are presented. A comparison is drawn between this lesion and purpura fulminans, based on gross and microscopic appearance and on the theoretic relationship of each to the Sanarelli-Shwartzman phenomenon. It is suggested that a therapeutic trial with heparin, corticosteroids, dextran, and antibiotics is warranted prior to resorting to surgery.

The authors present the results of a therapeutic trial of the conservative or surgical management of penetrating abdominal stab wounds (PASW) based on clinical criteria. In a prospective series of 100 patients, 70 were treated non-operatively. Thirty patients were operated upon, twenty-one immediately and nine during the 48 h observation period. In five laparotomies no significant injuries were found. Morbidity was similar in both immediate and delayed laparotomy groups (3/21 versus 1/9). Acute alcoholic intoxication identifies a subgroup of patients that are difficult to evaluate and hence are more likely to be managed by laparotomy (χ2 = 4·056, P

SUMMARY. A method is reported for the qualitative and quantitative analysis of less than milligram quantities of sebum into its lipid components using thin-layer absorption chromatography. The procedure has been developed to study relatively large numbers of samples, such as are collected from subjects taking part in a clinical therapeutic trial.

A glioblastoma multiforme from a 64-year-old man was heterotransplanted sc into nude mice (nu/nu BALB/c out-bred). The subsequent growth of the transplanted tumor featured the appearance and eventual domination by cells with ependymal characteristics. This finding supports the view that the host's influence on heterotransplants may be substantial and should be considered when extrapolating the results of therapeutic trials on such animal models to the clinical situation. The view that ependymal cells and astrocytes share a common precursor is also partly supported by the observations.