Signatures of a jet cocoon in early spectra of a supernova associated with a γ-ray burst.

Long γ-ray bursts are associated with energetic, broad-lined, stripped-envelope supernovae1,2 and as such mark the death of massive stars. The scarcity of such events nearby and the brightness of the γ-ray burst afterglow, which dominates the emission in the first few days after the burst, have so far prevented the study of the very early evolution of supernovae associated with γ-ray bursts3. In hydrogen-stripped supernovae that are not associated with γ-ray bursts, an excess of high-velocity (roughly 30,000 kilometres per second) material has been interpreted as a signature of a choked jet, which did not emerge from the progenitor star and instead deposited all of its energy in a thermal cocoon4. Here we report multi-epoch spectroscopic observations of the supernova SN 2017iuk, which is associated with the γ-ray burst GRB 171205A. Our spectra display features at extremely high expansion velocities (around 115,000 kilometres per second) within the first day after the burst5,6. Using spectral synthesis models developed for SN 2017iuk, we show that these features are characterized by chemical abundances that differ from those observed in the ejecta of SN 2017iuk at later times. We further show that the high-velocity features originate from the mildly relativistic hot cocoon that is generated by an ultra-relativistic jet within the γ-ray burst expanding and decelerating into the medium that surrounds the progenitor star7,8. This cocoon rapidly becomes transparent9 and is outshone by the supernova emission, which starts to dominate the emission three days after the burst.

Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort.

OBJECTIVE: Mutations in the FUS gene on chromosome 16 have been recently discovered as a cause of familial amyotrophic lateral sclerosis (FALS). This study determined the frequency and identities of FUS gene mutations in a cohort of Italian patients with FALS. METHODS: We screened all 15 coding exons of FUS for mutations in 94 Italian patients with FALS. RESULTS: We identified 4 distinct missense mutations in 5 patients; 2 were novel. The mutations were not present in 376 healthy Italian controls and thus are likely to be pathogenic. CONCLUSIONS: Our results demonstrate that FUS mutations cause approximately 4% of familial amyotrophic lateral sclerosis cases in the Italian population.

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

New VAPB deletion variant and exclusion of VAPB mutations in familial ALS.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder involving upper and lower motor neurons. The vesicle-associated membrane protein B (VAPB) gene has been genetically linked to ALS in several large Brazilian families in which the disorder is caused by a proline to serine mutation at codon 56 (P56S). No additional mutations have been identified. METHODS: To establish the prevalence of VAPB mutations, we screened 80 familial ALS samples by DNA sequencing. RESULTS: Our study failed to identify any novel VAPB gene mutations but identified a single Brazilian family harboring the P56S mutation. In a second familial ALS case, we identified a three-base pair deletion within exon 5 of the VAPB gene that deleted the serine residue at position 160 (Delta S160). This variant is detected in a normal population at low frequency (0.45%). Analyses of homology alignment and secondary structure predict that this deletion significantly alters the structure of VAPB, although a GFP-Delta S160 VAPB fusion protein demonstrates a wild-type subcellular localization. This contrasts the aberrant localization observed in a GFP-P56S VAPB fusion protein. The allele frequency of Delta S160 in patients with sporadic ALS does not differ significantly from that in the normal population. CONCLUSIONS: Mutations in the VAPB gene are rare and the Delta S160 variant does not contribute to the development of amyotrophic lateral sclerosis.

Quality improvement in acute stroke: the New York State Stroke Center Designation Project.

BACKGROUND: Many hospitals lack the infrastructure required to treat patients with acute stroke. The Brain Attack Coalition (BAC) published guidelines for the establishment of primary stroke centers. OBJECTIVE: To determine if stroke center designation and selective triage of acute stroke patients improve quality of care. METHODS: Baseline chart abstraction was performed on all stroke patients admitted to 32 hospitals serving Brooklyn and Queens, NY, from March to May 2002. Hospitals were invited to meet BAC guideline-based criteria. Adherence was verified by on-site visits. After designation, acute stroke patients were selectively triaged. Remeasurement data were collected from August to October 2003. RESULTS: The authors abstracted 1,598 charts at baseline and 1,442 charts at remeasurement. From baseline to remeasurement, median times decreased for door to physician contact (25 vs 15 minutes, p = 0.001), CT performance for potential tissue plasminogen activator (t-PA) candidates (68 vs 32 minutes, p < 0.001), and t-PA administration (109 vs 98 minutes (p = NS). IV t-PA utilization increased from 2.4 to 5.2% (p < 0.005), select t-PA protocol violations decreased from 11.1 to 7.9% (p = NS), and the stroke unit admission rate increased from 16 to 39% (p < 0.001). In stroke centers (n = 14) vs nondesignated hospitals (n = 18), there were shorter median times from door to physician contact (10 vs 25 minutes, p < 0.001), CT performance for potential t-PA candidates (31 vs 40 minutes, p = NS), and t-PA administration (95 vs 115 minutes, p < 0.05). Stroke centers, compared with nondesignated centers, admitted acute stroke patients to stroke units more often (55.9 vs 10.9%, p < 0.001). CONCLUSIONS: Stroke center designation and selective triage of acute stroke patients improved the quality of care, including access to timely thrombolytic therapy and stroke units.

Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial.

BACKGROUND: Hyperglycemia during acute ischemic stroke may augment brain injury, predispose to intracerebral hemorrhage (ICH), or both. METHOD: To analyze the relationship between admission glucose level and clinical outcomes from acute ischemic stroke, the authors performed multivariate regression analysis with the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial data. Neurologic improvement was defined as improvement on the NIH Stroke Scale by 4 or more points from baseline to 3 months, or a final score of zero. Favorable outcome was defined as both Glasgow Outcome score of 1 and Barthel Index 95 to 100 at 3 months. Symptomatic ICH was defined as CT-documented hemorrhage temporally related to clinical deterioration within 36 hours of treatment. Potential confounding factors were controlled, including acute treatment (rt-PA or placebo), age, baseline NIH Stroke Scale score, history of diabetes mellitus, stroke subtype, and admission blood pressure. RESULTS: There were 624 patients enrolled within 3 hours after stroke onset. As admission glucose increased, the odds for neurologic improvement decreased (odds ratio [OR] = 0.76 per 100 mg/dL increase in admission glucose, 95% CI 0.61 to 0.95, p = 0.01). The relation between admission glucose and favorable outcome depended on admission mean blood pressure (MBP): as admission MBP increased, the odds for favorable outcome related to increasing admission glucose levels progressively decreased (p = 0.02). As admission glucose increased, the odds for symptomatic ICH also increased (OR = 1.75 per 100 mg/dL increase in admission glucose, 95% CI 1.11 to 2.78, p = 0.02). Admission glucose level was not associated with altered effectiveness of rt-PA. CONCLUSIONS: In patients with acute ischemic stroke, higher admission glucose levels are associated with significantly lower odds for desirable clinical outcomes and significantly higher odds for symptomatic ICH, regardless of rt-PA treatment. Whether this represents a cause and effect relationship remains to be determined.

Thrombolysis in patients with transient neurologic deficits.

What is the risk of thrombolysis in patients with acute stroke who might recover without treatment? In the National Institute of Neurological Disorders and Stroke rt-PA for Acute Stroke Trial, 2.6% of patients taking placebo showed spontaneous 24-hour recovery, compared to 11.5% of recombinant tissue-type plasminogen activator (rt-PA)-treated patients (p < 0.001). There were no symptomatic ICH in the patients taking placebo; one hypertensive, rt-PA-treated patient hemorrhaged. Assuming the National Institute of Neurological Disorders and Stroke protocol is followed rigorously, patients with acute stroke rarely recover spontaneously and the thrombolytic risk is low.

A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2.

Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Differences between anterior and posterior circulation stroke in TOAST.

BACKGROUND AND PURPOSE: Clinicians have tended to view anterior circulation (AC) and posterior circulation (PC) strokes as separate entities, with different underlying pathogenesis, natural histories, and potential responsiveness to interventions such as anticoagulation. We sought to explore differences between AC and PC stroke in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). METHODS: For patients enrolled in TOAST, prospective clinical information was collected including outcome at 3 months. Data on vascular distribution were obtained from the clinical impression of the investigators. Group comparisons for categorical data were performed using Fisher's exact test. Independent sample t tests and analysis of covariance were used for all continuous data. RESULTS: The analysis included 1,039 patients with AC stroke and 180 patients with PC stroke. There were fewer women in the PC than in the AC groups, but otherwise there were no differences in demographics, risk factors or stroke subtypes between the two groups. Headache (AC 8.7%, PC 15%, p = 0.013) and vomiting (AC 3.5%, PC 17.8%, p < 0.001) were more common among PC patients. Mean baseline National Institutes of Health Stroke Scale (NIHSS) score was lower (less severe) among PC (6.1) than AC patients (9.5; p < 0.001). On univariate analysis, favorable outcome at 3 months was more common for PC patients in both the placebo group (PC 82%, AC 71%, p = 0.04) and heparinoid group (PC 87%, AC 73%, p = 0.005). However, multivariate analysis, controlling for gender, history of previous stroke and baseline NIHSS score, showed no difference in outcome between PC and AC stroke. For favorable outcome, there was no interaction between vascular distribution and treatment category, suggesting that the effect of heparinoid did not differ between PC and AC strokes. CONCLUSION: Patients with PC stroke seem to have a better long-term outcome than do AC patients, but this difference is no longer apparent when controlling for important prognostic variables. PC patients did not show any particular benefit from anticoagulation, and the efficacy of heparinoid did not vary between AC and PC stroke. While AC and PC patients do differ in some respects, it may be inappropriate to single out PC patients for anticoagulant treatment.

Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. METHODS: Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT-treatment interaction. Tests for OTT-treatment interactions adjusting for potential masking confounders were performed. An OTT-treatment interaction was considered significant if p < or = 0.10, implying that treatment effectiveness was related to OTT. RESULTS: For 24-hour improvement, there were no masking confounders identified and there was an OTT-treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT-treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. CONCLUSIONS: If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.

Predicting prognosis after stroke: a placebo group analysis from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial.

BACKGROUND: Physicians are often asked to predict outcome after acute stroke. Very little information is available that can reliably predict the likelihood of severe disability or death. OBJECTIVE: To develop a practical method for predicting a poor outcome after acute ischemic stroke. METHODS: Data from the placebo arms of Parts 1 and 2 of the National Institute of Neurological Disorders and Stroke rt-PA [recombinant tissue plasminogen activator] Stroke Trial were used to identify variables that could predict a poor outcome, defined as moderately severe disability, severe disability, or death (Modified Rankin Scale score >3) 3 months after stroke. RESULTS: Baseline variables that predicted poor outcome were the NIH Stroke Scale (NIHSS) >17 plus atrial fibrillation, yielding a positive predictive value (PPV) of 96% (95% CI, 88 to 100%). The best predictor at 24 hours was NIHSS >22, yielding a PPV of 98% (95% CI, 93 to 100%). The best predictor at 7 to 10 days was NIHSS >16, yielding a PPV of 92% (95% CI, 85 to 99%). CONCLUSIONS: Patients with a severe neurologic deficit after acute ischemic stroke, as measured by the NIHSS, have a poor prognosis. During the first week after acute ischemic stroke, it is possible to identify a subset of patients who are highly likely to have a poor outcome. These findings require confirmation in a separate study.

Effects of external beam radiation on the allograft dermal implant.

OBJECTIVE: The purpose of this study was to define the effects of external beam radiation (EBR) on AlloDerm (LifeCell Corp) through the analysis of graft thickness, fibroblast recellularization, and neovascularization as a function of time. METHODS AND MATERIAL: Thirty-six male Sprague-Dawley rats (n = 36) were randomly assigned to 1 of 4 groups (A, B, C, and D). AlloDerm was implanted subcutaneously into the hind legs of each rat, and 20 Gy of EBR was administered to one side. Grafts harvested 1, 2, 4, and 12 weeks after radiation were subjected to blinded histologic analysis. RESULTS: In groups A, B, and C, the irradiated grafts showed a significant decrease in recellularization versus nonirradiated (P < 0.001). At 12 weeks (group D), recellularization equalized, but neovascularization was significantly less (P = 0.048) in the irradiated group. Graft thickness was unaffected. CONCLUSIONS: In the rat model, EBR of the implanted AlloDerm graft hinders recellularization in the early posttreatment period. However, EBR did not adversely affect graft thickness, recellularization or ultimate graft survival.

Placebo treatment in acute stroke trials : benefit or harm to patients?

BACKGROUND AND PURPOSE: Some stroke patients and their families express reservations about participating in trials of experimental therapies for acute stroke. Among many reasons given for this is the concern that by participating, patients may be deprived of some component of routine care. We sought to determine the effect on outcome of participating in a clinical stroke trial while being treated with placebo. METHODS: Prospective clinical information was collected for all patients admitted with acute ischemic stroke between July 1995 and July 1996. A subgroup of these patients was enrolled in a clinical trial of acute stroke therapy and had been randomly assigned to the placebo group. The control group was selected from concurrent stroke patients who were not enrolled in any clinical trial. The National Institutes of Health Stroke Scale (NIHSS) was performed on admission and on day 7 after admission. The Glasgow Outcome Scale (GOS) was also performed at discharge. Stroke severity was classified as "severe" if NIHSS was >/=9 or GOS >/=3. Group comparisons were performed with chi(2) tests. RESULTS: One hundred twenty-six patients were evaluated. Forty-seven were placebo patients, and 79 were selected as control subjects. There were no significant differences between the groups with respect to age, sex, hematocrit, blood glucose level, history of hypertension, diabetes, smoking, or initial NIHSS. In addition, there was no difference between groups in terms of the frequency of baseline stroke subtype. Among our controls, 55 patients (70%) were on antithrombotic treatment during hospitalization, whereas none of our placebo patients were on any antithrombotic treatment. For the GOS at follow-up, a good outcome was attained by 76% of the control subjects and 72% of placebo patients (not significant). A severe NIHSS (>9) at follow-up, however, was documented in 15% of controls and 59% of placebo patients (P<0.001). There was a trend toward a higher ("worse") mean follow-up NIHSS among placebo patients (mean NIHSS, 11) versus controls (mean NIHSS, 6) (P=0.09). CONCLUSIONS: Patients enrolled in the placebo arms of some acute clinical stroke trials have similar functional outcomes but more severe neurological deficits at 1 week than did a control group. These findings might be partially explained by the withholding of antithrombotic medication and the exclusion criteria inherent in most trials. Vigilance is required to ensure that all patients participating in stroke studies be guaranteed optimal known medical therapy.

Agreement and variability in the interpretation of early CT changes in stroke patients qualifying for intravenous rtPA therapy.

BACKGROUND AND PURPOSE: Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment. However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes. METHODS: Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, kappa-statistics were used to assess the proportion of agreement beyond chance. RESULTS: kappa-Values (95% confidence interval [CI]) ranged from 0.20 (-0.20, 0.61) (fair agreement) to 0.41 (0.37, 0.45) (moderate agreement) among the 16 viewers, and the kappa-value was only 0.39 (0.29, 0.49) (fair) in answer to the question "do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?" There was substantial variability within each specialty group and between groups. kappa-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA. Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the kappa-value of 0.39 suggested only moderate agreement beyond chance. CONCLUSIONS: There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed.

Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group.

BACKGROUND: In 1995, the two-part National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator Stroke Trial found that patients who were treated with tissue plasminogen activator (t-PA) within three hours after the onset of symptoms of acute ischemic stroke were at least 30 percent more likely than patients given placebo to have minimal or no disability three months after the stroke. It was unknown, however, whether the benefit would be sustained for longer periods. METHODS: In the NINDS Trial, a total of 624 patients with stroke were randomly assigned to receive either t-PA or placebo. We collected outcome data over a period of 12 months after the occurrence of stroke. The primary outcome measure was a "favorable outcome," defined as minimal or no disability as measured by the Barthel index, the modified Rankin Scale, and the Glasgow Outcome Scale. We assessed the treatment effect using a global statistic. RESULTS: Using an intention-to-treat analysis for the combined results of the two parts of the trial at 6 months and 12 months, we found that the global statistic favored the t-PA group (odds ratio for a favorable outcome at 6 months, 1.7; 95 percent confidence interval, 1.3 to 2.3; odds ratio at 12 months, 95 percent confidence interval, 1.7; 1.2 to 2.3). The patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at 12 months than were the placebo-treated patients (absolute increase in the proportion with a favorable outcome, 11 to 13 percentage points). There was no significant difference in mortality at 12 months between the t-PA group and the placebo group (24 percent vs. 28 percent, P=0.29). There was no interaction between the type of stroke identified at base line and treatment with respect to the long-term response. The rate of recurrent stroke at 12 months was similar in the two groups. CONCLUSIONS: During 12 months of follow-up, the patients with acute ischemic stroke who were treated with t-PA within three hours after the onset of symptoms were more likely to have minimal or no disability, than the patients given placebo. These results indicate a sustained benefit of t-PA for such patients.

Safety of recombinant human bone morphogenetic protein-2 after spinal laminectomy in the dog.

STUDY DESIGN: This was a randomized, blinded trial of the safety of the application of recombinant human bone morphogenetic protein (rhBMP)-2 or autologous bone graft onto a laminectomy defect of the dog in the presence or absence of a dural membrane puncture. OBJECTIVE: To test the safety of rhBMP-2 in an application in which direct contact of the material with neural tissue occurs. SUMMARY OF BACKGROUND DATA: Application of rhBMP-2 in laboratory animals stimulates local bone formation to effect spinal fusion and healing of segmental bone defects. The use of rhBMP-2 as a bone graft substitute in spinal fusion would eliminate donor site morbidity and may augment the rate of successful fusion. Because rhBMP-2 may unintentionally come in contact with neural tissue, the consequences of such a safety issue must be addressed in an animal model before human trials. METHODS: Twenty skeletally mature beagles underwent spinal exposure followed by bilateral laminectomy at L5. In half of the dogs, a puncture wound was made to the dura with the expression of cerebrospinal fluid at the site of the puncture. In randomly selected animals, the exposed dural elements received either autologous bone graft with the bone removed from the laminectomy site or an implant of the rhBMP-2 device. The animals was observed for 12 weeks with periodic clinical examinations and monthly computed tomographic scans. RESULTS: There was no clinical, radiographic, or histologic evidence of neurologic abnormalities in these animals. The rhBMP-2 stimulated bone growth in the laminectomy defect and came into direct contact with the dural membrane. There was no evidence of abnormal mineralization within the thecal sac or in the spinal cord itself. CONCLUSIONS: The rhBMP-2 implant stimulated bone formation in the laminectomy site. Neither autologous bone, rhBMP-2, nor the dural puncture had deleterious consequences for the animals.

Outcomes after laser stapedotomy with and without preservation of the stapedius tendon.

Our goal was to investigate the postoperative differences in hearing between patients who had their stapedius tendon sacrificed and those whose stapedius tendon was preserved during laser stapes surgery for otosclerosis. To that end, we performed a retrospective review by mailing extensive questionnaires to patients who had been operated on between 1994 and 1997. We also performed routine and special audiometric testing to augment the subjective data. Seventy-nine of 124 questionnaires (64%) were returned. Of the respondents, 75 patients had undergone additional pre- and/or postoperative audiometric testing, including tests to evaluate "hearing in noise" and to determine the "uncomfortable loudness level" (dynamic range). We found no statistically significant differences between the two groups with respect to their subjective responses and their audiologic test results. The responses to the questionnaire indicated that in most cases, hearing was improved by stapes surgery. We conclude that the stapedius tendon should be preserved whenever possible during stapes surgery, provided that it does not jeopardize the exposure or outcome.

Research fundamentals: III. elements of a research protocol for clinical trials.

A clinical trial is a powerful technique for evaluating the effectiveness of an experimental intervention. The initial stages of planning a clinical trial involve choosing and refining a research question, selecting a study design, and deciding on appropriate statistical tests and sample sizes. The success of the study depends upon how well these issues are thought out in advance, and how they can be put into practice. The protocol is the written document that allows the investigator to communicate details of how the research question will be answered. In the following article, the basic components of the research protocol are described. Issues related to quality control, data entry, and pilot testing are discussed. This is the third in a series of research fundamental concept papers, written by members of the SAEM Research Committee.

Research fundamentals: II. Choosing and defining a research question.

This is the second in a series of articles developed by members of the SAEM Research Committee to describe a stepwise approach to the research process. This series is aimed at junior academic emergency physicians (EPs), as well as nonacademic EPs with an interest in the research process. This article describes the development of a testable research hypothesis. While a multitude of sources provide interesting questions for consideration, choosing and refining the research question, so that it can be tested adequately and answered completely, are difficult tasks.

Early development of emergency medicine in Chennai (Madras), India.

India is the second most populous country in the world, with a population approaching 1 billion people. The development of emergency medicine is still in its earliest stages because the Medical Council of India (MCI) does not yet recogonize the specialty. Recent developments may cause the MCI to reconsider specialty status for emergency medicine as an academic discipline.