Phase 1 in the development of a patient-reported measure to quantify perceived inconvenience of radiotherapy: generation of issues.

AIMS: Current patient-reported measures (PROMs) do not specifically address radiotherapy (RT) related inconvenience. We conducted, as per guidelines of the European Organization for Research and Treatment of Cancer (EORTC), the initial (issue generation) phase of development of a RT inconvenience PROM. Specifically, we aimed to develop a conceptual framework for RT inconvenience and generate a comprehensive list of issues pertaining to it. METHODS: We reviewed existing PROMs and literature and gathered qualitative and quantitative data from consumers and health professionals, in order to generate a comprehensive list of issues pertaining to RT inconvenience. A framework for the consideration of RT inconvenience was defined and used to ensure all possible issues were explored and to list the issues into conceptual domains. RESULTS: Qualitative data from 26 consumers and 30 health professionals, and quantitative data from 1191 consumers and 253 health professionals resulted in the identification of 38 issues grouped into five conceptual domains: (1) inconvenience of RT opportunity, (2) inconvenience of decision-making, (3) inconvenience of treatment, (4) inconvenience of side effects, and (5) inconvenience of follow-up. CONCLUSIONS: This list of RT inconvenience issues will, in future work, be operationalized into a set of items for pretesting and then large-scale field testing as per the EORTC guidelines.

Polymorphisms in an intronic region of the myocilin gene associated with primary open-angle glaucoma--a possible role for alternate splicing.

PURPOSE: To examine the possible role of alternate splicing leading to aggregation of myocilin in primary open-angle glaucoma. METHODS: Several single nucleotide variations found in the myocilin (MYOC) genomic region were collected and examined for their possible role in causing splice-site alterations. A model for myocilin built using a knowledge-based consensus method was used to map the altered protein products. A total of 150 open-angle glaucoma patients and 50 normal age-matched control subjects were screened for the predicted polymorphisms, and clustering was performed. RESULTS: A total of 124 genomic variations were screened, and six polymorphisms that lead to altered protein products were detected as possible candidates for the alternative splicing mechanism. Five of these lay in the intronic regions, and the one that lay in the exon region corresponded to the previously identified polymorphism (Tyr347Tyr) implicated in primary open-angle glaucoma. Experimentally screening the intronic region of the MYOC gene showed the presence of the predicted g.14072G>A polymorphism, g.1293C/T heterozygous polymorphism, instead of our predicted g.1293C/- polymorphism. Other than the prediction, two novel SNPs (g.1295G>T and g.1299T>G) and two reported SNPs (g.1284G>T and g.1286G>T) were also identified. Cluster analysis showed the g.14072G>A homozygous condition was more common in this cohort than the heterozygous condition. CONCLUSIONS: We previously proposed that the disruption of dimer or oligomer formation by the C-term region allows greater chances of nucleation for aggregation. Here we suggest that polymorphisms in the myocilin genomic region that cause synonymous codon changes or those that occur in the intron regions can possibly lead to altered myocilin protein products through altered intron-exon splicing.

The mutations and potential targets of the forkhead transcription factor FOXL2.

Mutations of FOXL2, a gene encoding a forkhead transcription factor, have been shown to cause the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). This genetic disorder is characterized by eyelid and mild craniofacial abnormalities that can appear associated with premature ovarian failure. FOXL2 is one of the earliest ovarian markers and it offers, along with its targets, an excellent model to study ovarian development and function in normal and pathological conditions. In this review we summarize recent data concerning FOXL2, its mutations and its potential targets. Indeed, many mutations have been described in the coding sequence of FOXL2. Among them, polyalanine expansions and premature nonsense mutations have been shown to induce protein aggregation. In the context of the ovary, FOXL2 has been suggested to be involved in the regulation of cholesterol and steroid metabolism, apoptosis, reactive oxygen species detoxification and inflammation processes. The elucidation of the impact of FOXL2 mutations on its function will allow a better understanding of the pathogenic mechanisms underlying the BPES phenotype.

Simple sonochemical synthesis of novel grass-like vanadium disulfide: A viable non-enzymatic electrochemical sensor for the detection of hydrogen peroxide.

Design and fabrication of novel inorganic nanomaterials for the low-level detection of food preservative chemicals significant is of interest to the researchers. In the present work, we have developed a novel grass-like vanadium disulfide (GL-VS2) through a simple sonochemical method without surfactants or templates. As-prepared VS2 was used as an electrocatalyst for reduction of hydrogen peroxide (H2O2). The crystalline nature, surface morphology, elemental compositions and binding energy of the as-prepared VS2 were analyzed by X-ray diffraction, Raman spectroscopy, field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy. The electrochemical studies show that the GL-VS2 modified glassy carbon electrode (GL-VS2/GCE) has a superior electrocatalytic activity and lower-reduction potential than the response observed for unmodified GCE. Furthermore, the GL-VS2/GCE displayed a wide linear response range (0.1-260 µM), high sensitivity (0.23 µA µM-1 cm-2), lower detection limit (26 nM) and excellent selectivity for detection of H2O2. The fabricated GL-VS2/GCE showed excellent practical ability for detection of H2O2 in milk and urine samples, revealing the real-time practical applicability of the sensor in food contaminants.

Vitamin A contents of rat intestinal epithelium and jejunal mucinous adenocarcinoma.

Concentrations of retinol and tetinyl esters were assayed in rat intestinal mucosa and in chemically induced transplanted mucinous adenocarcinoma of the jejunum. Lipid extract from the tissues was chromatographed on deactivated alumina to isolate retinol and retinyl esters, which were determined by specific spectrofluorometry. Normal intestinal mucosa tissue contains 556 ng of retinol equivalents as retinyl esters and 303 ng of free retinol/g of wet tissue. The concentration of retinyl esters in the intestinal mucosa from rats carrying the transplanted tumor was 341 ng/g wet tissue; no free retinol was detected in the small intestinal epithelium of these rats. Liver tissue from the tumor-bearing rats contained 157 microng of retinol equivalents as retinyl esters and 136 microng of free retinol/g of wet tissue. The concentration of vitamin A per cell in the adenocarcinoma tissue was about 20 times less than that in intestinal epithelium.

Engaging Future Clinical Oncology Researchers: An Initiative to Integrate Teaching of Biostatistics and Research Methodology into Specialty Training.

AIMS: To evaluate the learner's perspectives on a novel workshop programme designed to improve skills in biostatistics, research methodology and critical appraisal in oncology. MATERIALS AND METHODS: Trainees were surveyed anonymously at the completion of each annual workshop from 2012 to 2015. In total, 103 trainees in years 2-4 of training in radiation oncology responded, giving a 94% survey response rate. A 1 day workshop, designed by biostatisticians and radiation oncologist facilitators, is the central component of a programme teaching skills in biostatistics, research methods and critical appraisal. This links short didactic lectures about statistical concepts to interactive trainee discussions around discipline-related publications. RESULTS: The workshop was run in conjunction with the major radiation oncology clinical trials group meeting with alternating programmes (A and B). Most of the participants (44-47/47 for A and 48-55/56 for B), reported that their understanding of one or more individual topics improved as a result of teaching. Refinement of the workshop over time led to a more favourable perception of the 'optimal' balance between didactic/interactive teaching: nine of 27 (33%) 'optimal' responses seen in 2013 compared with 23 of 29 (79%) in 2015 (P < 0.001). Commonly reported themes were: clinician facilitators and access to biostatisticians helped contextualise learning and small group, structured discussions provided an environment conducive to learning. CONCLUSIONS: Overall, radiation oncology trainees reported positive perceptions of the educational value of this programme, with feedback identifying areas where this resource might be improved. This model could readily be adapted to suit other medical disciplines and/or other training environments, using specialty-specific research to illuminate key statistical concepts.

Synchronous or metachronous lymphoma and metastatic cutaneous squamous cell carcinoma in the head and neck region: a diagnostic and management dilemma.

OBJECTIVE: To review our experience of managing patients with a dual diagnosis of metastatic cutaneous squamous cell carcinoma in the head and neck region and low-grade non-Hodgkin lymphoma. The secondary aim was to evaluate the utility of 18F-fluorodeoxyglucose positron emission tomography during diagnosis. METHODS: Patients diagnosed with metastatic cutaneous squamous cell carcinoma of the head and neck and low-grade non-Hodgkin lymphoma, in a five-year period, were identified. Patient, tumour and treatment characteristics were identified. 18F-fluorodeoxyglucose positron emission tomography imaging was reviewed and correlated with histopathology findings. RESULTS: Eight patients were identified. There was a delay in diagnosis of metastatic squamous cell carcinoma in two patients. 18F-fluorodeoxyglucose positron emission tomography differentiated metastatic squamous cell carcinoma from low-grade non-Hodgkin lymphoma with a sensitivity of 88.2 per cent and a specificity of 94.7 per cent. In 38 per cent of patients, compromises in management had to be made. CONCLUSION: The management of metastatic squamous cell carcinoma can be challenging in patients with low-grade non-Hodgkin lymphoma. 18F-fluorodeoxyglucose positron emission tomography can be useful in the diagnosis of metastatic squamous cell carcinoma in patients with low-grade non-Hodgkin lymphoma.

Effects of dietary taurocholate, fat and protein on the storage and metabolism of dietary beta-carotene and alpha-tocopherol in ferrets.

Dietary factors affecting tissue storage of beta-carotene (BC), alpha-tocopherol (alpha-T), and retinol (ROL) in mammals include taurocholate, protein, and fat. Few studies have examined the effects of these factors on the storage of BC, retinyl esters, and alpha-T in a mammalian system that is similar to humans. The main objective of the study was to investigate the effects of taurocholate (TC), fat, and protein on the absorption and metabolism of BC and alpha-T in ferret tissues. Three 4-week experiments were conducted using groups of 5-6 ferrets per treatment. All diets contained 0.2% BC. In Experiment 1, taurocholate was fed at concentrations of 0, 0.5, or 1%. Effects of two concentrations of dietary fat (6 and 23%) and three concentrations of protein (10, 20, and 40%) were also studied in Experiments 2 and 3, respectively. Tissues were analyzed for BC, retinoids, and alpha-T by high-pressure liquid chromatography (HPLC). Taurocholate enhanced hepatic and plasma concentrations of BC (2.3- to 3-fold), retinyl palmitate [(RP) 3.2- to 9.5-fold], retinyl stearate [(RS) 2.9- to 6- fold], and hepatic alpha-T (6- to 13- fold) at p < 0.05. High-fat diets elevated hepatic BC, RP, RS, and retinyl linoleate (RL) concentrations (2- to 3.6-fold, p < 0.05). In contrast, high-protein diets lowered hepatic RL 1.8-fold and alpha-T 8-fold (p < 0.05). Our results indicate the importance of taurocholate, fat, and protein in achieving adequate levels of vitamins A and E in mammals.

Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM.

OBJECTIVE: To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS: Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS: Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 +/- 6 bpm vs. 80 +/- 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 +/- 1.77 vs. 4.26 +/- 1.54 mmol/l, P < 0.01), and systolic BP responses to intravenous norepinephrine and angiotensin II were significantly higher on glibenclamide than on metformin (P < 0.02 and P < 0.05, respectively). Systolic BP responses to cold pressor testing appeared higher on glibenclamide than on metformin, but the difference did not quite achieve statistical significance (P = 0.052). Baseline forearm vascular resistance did not differ between the two drugs, nor did forearm vascular resistance responses to diazoxide, acetylcholine, sodium nitroprusside, and norepinephrine differ. CONCLUSIONS: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects.

Examining Determinants of Radiotherapy Access: Do Cost and Radiotherapy Inconvenience Affect Uptake of Breast-conserving Treatment for Early Breast Cancer?

AIMS: Radiotherapy utilisation is likely affected by multiple factors pertaining to radiotherapy access. Radiotherapy is an integral component of breast-conserving treatment (BCT) for early breast cancer. We aimed to determine if stepwise improvements in radiotherapy access in regional Australia affected the uptake of BCT and thus radiotherapy. MATERIALS AND METHODS: Breast cancer operations in the Central Coast of New South Wales between January 2010 and March 2014 for T1-2N0-1M0 invasive or in situ (≤5 cm) disease in female patients eligible for BCT were examined. BCT uptake was calculated for three 1 year periods: period 1 (local radiotherapy available at cost to user or out of area radiotherapy with travel cost and inconvenience); period 2 (as per period 1 + publicly funded transport and radiotherapy at out of area facilities at no cost to user); period 3 (as per period 1 + publicly funded local radiotherapy at no cost to user). RESULTS: In total, 574 cases met eligibility criteria. BCT declined with increasing distance to publicly funded radiotherapy (P = 0.035). BCT rates for periods 1, 2 and 3 were 63% (113/180), 61% (105/173) and 71% (156/221). There were no statistically significant differences in BCT between periods 1 and 2 in the whole cohort or within age, histology or tumour size subgroups. Overall, there was a 9% increase in BCT in the whole cohort in period 3 compared with periods 1 and 2 (P = 0.031). This increase was statistically significant for women over 70 years (19% increase, P = 0.034), for women with ductal carcinoma in situ (25% increase, P = 0.013) and for women with primary tumours that were ≤10 mm (21% increase, P = 0.016). CONCLUSIONS: Improving the affordability of radiotherapy through publicly funded transport and radiotherapy at out of area facilities did not improve BCT uptake in a region where radiotherapy was locally available, albeit at cost to the user. Improving both affordability and convenience through the provision of local publicly funded radiotherapy increased BCT uptake. Service availability and affordability have long been recognised as important determinants of radiotherapy access. Our findings suggest that inconvenience may also influence radiotherapy utilisation.

Patients' perceptions of health-related quality of life during and after adjuvant radiotherapy for T1N0M0 breast cancer.

AIMS: The effects of radiotherapy on health-related quality of life (HRQOL) may influence decisions about adjuvant radiotherapy after breast-conserving surgery. We sought women's ratings of HRQOL during and after radiotherapy. MATERIALS AND METHODS: Women completed HRQOL measures before, during and after adjuvant radiotherapy for node-negative, hormone receptor-positive breast cancers that were less than 2 cm in size. Acute and late toxicities were rated by clinicians. RESULTS: There were 161 participants with a median age of 58 years (range 34-82). Mean scores for most aspects of HRQOL worsened only slightly during radiotherapy and improved to baseline levels or better within a few months. The symptoms rated as most distressing were: difficulty sleeping (29%), fatigue (23%), breast discolouration (21%), uncertainty about the future (18%), feeling sad or depressed (18%), feeling anxious or worried (19%). Most rated their experience as better (39%) or much better (28%) than expected. Grade 3 toxicities were rare (5% acute, 1% late) with no grade 4 toxicities. CONCLUSIONS: Radiotherapy was associated with transient and generally mild impairments in a few aspects of HRQOL. Concerns about adverse effects on HRQOL should not weigh heavily on decisions about adjuvant breast radiotherapy.

Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207.

Prostate adenocarcinoma is the most common nonskin malignancy in males and the second most common cause of cancer death in the United States (Landis et al., 1998). Initial treatments of surgery or radiotherapy may cause impotence and/or incontinence from neural damage (Eastham and Scardino, 1998; Porter et al., 1998). When extraprostatic or metastatic disease develops, castration or pharmaceutical androgen ablation is utilized (Catalona, 1994). Androgen-resistant recurrence indicates a poor prognosis and justifies experimental chemotherapy (Oh and Kantoff, 1998). G207 (Mineta et al., 1995; Yazaki et al., 1995) is a multimutated herpes simplex virus 1 (HSV) vector that replicates within cancer cells, causing cellular death; however, replication is limited in normal cells, including those of the nervous system. In vitro, G207 at a low multiplicity of infection (MOI of 0.01) is oncolytic for multiple human prostate cancer cells. In athymic mice, a single intraneoplastic inoculation of G207 completely eradicates >22% of established subcutaneous human prostate cancer tumors irrespective of hormonal responsiveness. Two intraneoplastic inoculations of G207 completely eradicated two of three recurrent previously irradiated tumors and two intravenous administration of G207 induced tumor regression in distant subcutaneous tumors and completely eradicated one-fourth of the tumors.

Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus.

Replication-competent, attenuated herpes simplex virus (HSV) vectors have been developed for viral oncolytic therapy of primary and metastatic malignant brain tumors. However, the role of the host immune responses in the brain has not been elucidated. N18 neuroblastoma cells were used as a tumor model in syngeneic A/J mice to test the therapeutic efficacy of G207, a conditionally replicating HSV vector, in an immunocompetent condition. G207 inoculated intraneoplastically exhibited a prominent oncolytic antitumor effect in mice harboring N18 tumors in the brain or subcutaneously, and, in addition, elicited a systemic antitumor immune response. Subcutaneous tumor therapy with G207 caused regression of a remote, established tumor in the brain or in the periphery, which was potentially mediated by the systemic antitumor immune response, and provided persistent tumor-specific protection against N18 tumor rechallenge in the brain as well as in the periphery. Antitumor immunity was associated with an elevation of specific CTL activity against N18 tumor cells that persisted for at least 13 months. The results suggest that the oncolytic antitumor action of replication-competent HSV may be augmented by induction of specific and systemic antitumor immunity effective both in the periphery and in the brain.

Decreased beta-adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones.

The effect of streptozotocin-induced diabetes on the beta-adrenergic receptor-coupled adenylate cyclase was studied in rat heart particulate fractions. Streptozotocin treatment decreased the number of myocardial beta-adrenergic receptors by 34% with no change in the apparent affinity of these receptors for [3H]dihydroalprenolol. The maximal isoproterenol-activated accumulation of cAMP in streptozotocin-treated rat hearts was decreased by only 10%. Insulin administration to streptozotocin-treated rats increased the number of myocardial beta-adrenergic receptors to near or above control levels. Administration of L-T4 to streptozotocin-treated rats had the same effect. Total T4, free T4, and total T3 levels were all significantly decreased in the diabetic animals. Administration of insulin to streptozotocin-treated rats increased the serum thyroid hormone levels toward or above the levels found in control animals. Streptozotocin-induced diabetes had no significant effect on cardiac beta-adrenergic receptor number in thyroidectomized rats. Insulin did not elevate cardiac beta-adrenergic receptor number in thyroidectomized diabetic rats. The decrease in the number of myocardial beta-adrenergic receptors occurring in diabetes mellitus is probably mediated through thyroid hormones.

Long-term weight control study. VI. Individual participant response patterns.

We analyzed the individual response patterns of all 121 participants who entered the study. Fifty-one participants completed up to week 190. In 26 completers, the response pattern consisted of an initial beneficial effect (greater than or equal to 6 months of weight loss greater than or equal to 10% from baseline) and later success (weight loss of greater than or equal to 10% from baseline at week 160). These successful participants had lost 14.1 +/- 1.0 kg (mean +/- SEM); 15.9% +/- 0.9% of initial weight) at week 160 and 8.1 +/- 1.2 kg (9.1% +/- 1.3% of initial weight) at week 190. A second pattern observed in 16 completers consisted of initial benefit and later partial success (loss of 0.1% to 9.9% at week 160). Other response patterns observed in completers included showing initial benefit only (n = 3) and no success (n = 6). Seventy of the 121 participants left the study before week 190. There were 22 "dropout successes" who had consistent weight loss for 1 year or more and were greater than or equal to 10% below their initial weights at time of dropout. Fifteen "dropouts with initial benefit" stayed in the study for greater than or equal to 1 year with initial benefit (weight loss greater than or equal to 10% from baseline maintained for greater than or equal to 6 months). Medication-related reasons accounted for only 10 of the 37 dropouts in the group with initial or later benefit. Minimal benefit was seen in 17 dropouts. Another 16 were in the study less than 1 year. Analysis of individual participant responses made some other generalizations possible. Participants receiving continuous medication lost more weight and had fewer adverse effects than those receiving targeted intermittent medication. Upward dose adjustment appeared to help 24 participants achieve the criteria for late or partial success. Analyses of individual participant responses can suggest ways to optimize anorectic medication use for individual patients.

Long-term weight control study. VII (weeks 0 to 210). Serum lipid changes.

We analyzed serum total cholesterol, triglycerides, and lipoprotein profile changes occurring in the participants (N = 121) through 210 weeks of the study. On average, baseline lipid levels were within normal limits. The most consistent changes occurred in the high-density lipoprotein cholesterol (HDL-C), serum total cholesterol/HDL-C ratios, and triglyceride levels. HDL-C increased significantly (p less than 0.01), compared with baseline, by 10% at week 34, 15% at week 54, 19% at week 104, and 27% at week 139. At week 210, 20 weeks after treatment had ended, HDL-C was 15% higher than baseline. At weeks 34, 54, 104, and 139, the serum total cholesterol/HDL-C ratio was significantly decreased, compared with baseline, by 9%, 19%, 17%, and 25%, respectively. At week 210, serum total cholesterol/HDL-C ratio was 8% less than week 0. Compared with baseline, triglyceride levels decreased significantly by 21%, 31%, 29%, and 29% at weeks 34, 54, 104, and 139, respectively. At week 210, triglyceride levels were 16% below baseline. Total cholesterol levels and low-density lipoprotein cholesterol (LDL-C) showed less dramatic changes. Patterns of lipid and lipoprotein changes were qualitatively similar between men and women. However, greater decreases in serum total cholesterol, LDL-C, and triglyceride levels were observed in participants with high (n = 10) compared with low (n = 10) baseline lipid levels. Cholesterol changes were not affected by anorexiant medications. However, triglyceride levels at week 34 were significantly (p less than 0.025) less in the participants treated with anorexiants.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet alpha-2 adrenoceptors and the menstrual cycle.

To clarify further the suggested influence of menstrual cycle phase on platelet alpha 2-adrenoceptors, we carried out cross-sectional studies in 77 subjects in a clinical trial of weight control strategies. Blood samples were drawn at baseline and after 6 weeks of diet, behavior modification, and exercise, a program that resulted in a mean weight loss of 4.5 kg. For the analyses, 42 premenopausal women were divided into four groups according to the week of menstrual cycle at the time of blood sampling. At baseline, there was no significant difference in mean platelet alpha 2-adrenoceptor numbers among the four groups. At week 6 accompanying the weight loss, there was a significant increase in the platelet alpha 2-adrenoceptor number for all groups. Despite the fact that the women were at a different phase of the menstrual cycle than at baseline, there was again no significant difference in mean platelet alpha 2-adrenoceptor number. Mean baseline platelet alpha 2-adrenoceptor number in the premenopausal women (113.7 +/- 5.5 fmol/mg protein) did not differ from values in 12 postmenopausal women (113.7 +/- 12.0 fmol/mg protein), four women with hysterectomies (105.9 +/- 8.9 fmol/mg protein), or 19 men (101.8 +/- 6.2 fmol/mg protein). Numbers at 6 weeks also did not differ. We conclude that the menstrual cycle has minimal effects on platelet alpha 2-adrenoceptor number and should not confound clinical studies of platelet alpha 2-adrenoceptors.

Methodology for demonstrating sustained efficacy of hypnotics: a comparative study of triazolam and flurazepam.

To test for sustained hypnotic efficacy, triazolam (0.6 mg) or flurazepam (30 mg) was given to chronic insomniac patients for 7 consecutive nights in parallel, double-blind design. Triazolam at this dose was an effective hypnotic by all usual subjective measures and did not produce appreciable hangover. Flurazepam performed similarly. For either drug, comparison of the mean scores for the first 2 nights with that for the last 2 nights for any of the parameters did not reveal any significant difference. Thus, both triazolam and flurazepam showed sustained efficacy for 1 week at these doses. Some interesting theoretical and practical questions about the measurement of sustained efficacy of hypnotics in situations of repetitive dosing were addressed by the study. While a placebo control is desirable, the results obtained may be uninterpretable. An acute-care hospital setting may not be the ideal setting for doing such studies. There were indications from the study that the first-night results in a hypnotic clinical trial may be atypical.