Thrombectomy with Conscious Sedation Compared with General Anesthesia: A DEFUSE 3 Analysis.

BACKGROUND AND PURPOSE: The optimal patient sedation during mechanical thrombectomy for ischemic stroke in the extended time window is unknown. The purpose of this study was to assess the impact of patient sedation on outcome in patients undergoing thrombectomy 6-16 hours from stroke onset. MATERIALS AND METHODS: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE 3) was a multicenter, randomized, open-label trial of thrombectomy for ICA and M1 occlusions in patients 6-16 hours from stroke onset. Subjects underwent thrombectomy with either general anesthesia or conscious sedation at the discretion of the treating institution. RESULTS: Of the 92 patients who were randomized to intervention, 26 (28%) underwent thrombectomy with general anesthesia and 66 (72%) underwent thrombectomy with conscious sedation. Baseline clinical and imaging characteristics were similar among all groups. Functional independence at 90 days was 23% for general anesthesia, 53% for conscious sedation, and 17% for medical management (P = .009 for general anesthesia versus conscious sedation). Conscious sedation was associated with a shorter time from arrival in the angiosuite to femoral puncture (median, 14 versus 18 minutes; P = 0.05) and a shorter time from femoral puncture to reperfusion (median, 36 versus 48 minutes; P = .004). Sixty-six patients were treated at sites that exclusively used general anesthesia (n = 14) or conscious sedation (n = 52). For these patients, functional independence at 90 days was significantly higher in the conscious sedation subgroup (58%) compared with the general anesthesia subgroup (21%) (P = .03). CONCLUSIONS: Patients who underwent thrombectomy with conscious sedation in the extended time window experienced a higher likelihood of functional independence at 90 days, a lower NIHSS score at 24 hours, and a shorter time from femoral puncture to reperfusion compared with those who had general anesthesia. This effect remained robust in institutions that only treated patients with a single anesthesia technique.

What do Key Stakeholders Think About HIV Self-Testing in Canada? Results from a Cross-Sectional Survey.

Human immunodeficiency virus (HIV) self-testing presents an empowering alternative to facility-based testing for reaching undiagnosed HIV infected individuals, but is not currently available in Canada. We surveyed stakeholders (clinical providers, public health professionals, researchers) engaged in HIV testing initiatives nationwide to identify the concerns, opportunities and challenges to implementing HIV self-testing in Canada. An online cross-sectional survey was disseminated by the Canadian Institutes of Health Research Centre for REACH 2.0 National HIV & sexually transmitted and blood borne infections working group to stakeholders nationwide, with a target sample size of 200. Quantitative and qualitative data were analyzed using a mixed-methods, respondent-informed approach, to inform subsequent HIV self-testing in a country where self-testing is not yet accessible. A total of 183 responses were received. A majority (70.7%) (128/181) felt that self-testing was a necessary investment to reach the undiagnosed. 64.6% (117/181) felt that self-tests should be made available to their clients and 71.5% (128/179) of respondents agreed that self-test instructions required improvements. However, 50% (90/180) felt that self-testing will pose an economic challenge to current HIV testing models. Regardless, 21% urged for timely action and availability of HIV self-tests. Thematic analyses reflected the following concerns: (a) need for affordable self-tests, (b) need for expedited, customized, and accessible linkages to counselling, (c) concern for patients to cope with positive self-test results, (d) accuracy of self-tests to detect acute HIV and (e) liability in the context of non-disclosure. Stakeholders agreed to the provision of an option of HIV self-testing to reach the undiagnosed individuals. Concerns regarding costs and accuracy of self-tests, expedited linkages to counselling, and integration of self-test within prevailing HIV testing models, will need to be addressed before their widespread implementation.

Controversies in orthopaedic trauma--management of fractures of shaft of femur in children between 6 and 12 years of age.

The management of femoral shaft fractures in children is largely directed by the age and built of the child. There is wide consensus on the non operative treatment of children less than six years of age. Operative treatment is recommended for children more than 12 years of age, only the surgical options vary. The age group of 6-12 years remains a controversial area with multiple studies advocating different lines of treatment. We studied the literature on treatment of femoral shaft fractures in 6 to 12 year age group over the past 25 years through PubMed search and found 79 studies dealing with management of paediatric shaft femur fractures in this age group. Studies dealing with other age groups, animal studies and languages other than English were excluded. The treatment modalities included early or immediate hip spica, traction alone, external fixator, plating (open/minimally invasive), intramedullary nailing- rigid/flexible and intramedullary Kirschner wire. The short listed articles were studied for rate and time of union, complications such as non-union and malunion, leg length discrepancy, infection, implant impingement, refracture and cost analysis. Operative treatment is usually the preferred treatment option in this age group, as it decreases hospitalization time, decreases morbidity and allows early return of child to school. Flexible intramedullary nailing is recommended for length stable fractures. Submuscular bridge plating (minimally invasive) is reserved for comminuted fractures. External fixator is reserved for open fractures and initial stabilization of femoral shaft fractures in polytrauma pediatric patients. Intramedullary K wire is a viable option in resource contrained centres where specialized implants and instrumentation is not available.

Solitary myofibroma of the breast: a case report.

Solitary myofibromas are relatively rare neoplasms but one of the most common fibrous neoplasms occurring in infancy and childhood. Adult cases have also been reported in the literature. We describe here a case report of an eighteen-month-old child who presented with a gradually enlarging nodule in the right breast. The case is presented for an insight into contemporary knowledge about its histogenetic origin, behaviour and prognosis.

Angiosarcoma of pericardium: a report of two cases.

Angiosarcomas are uncommon malignant neoplasms characterized by rapidly proliferating extensively infiltrating anaplastic cells derived from blood vessels and lining irregular, blood-filled spaces. The cells manifest many of the functional and morphological properties of normal endothelium. They are collectively one of the rarest forms of soft tissue neoplasms. Here we present two cases of pericardial angiosarcoma, one of them showing widespread dissemination, which caused considerable diagnostic dilemma and the diagnosis could only be established very late in their course of disease.

Placental site trophoblastic tumour--a case report.

Placental site trophoblastic tumour is a rare form of gestational trophoblastic disease, which seldom metastasizes. It is chemoresistant though has an excellent prognosis after complete resection of the tumour. Its characterization is thus important for treatment and further management. We present an unusual case who presented with ascites of non-neoplastic origin and was found to have metastases to the lymph node.

Statistical validation of reproducibility of HPLC peptide mapping for the identity of an investigational drug compound based on principal component analysis.

Peptide mapping is a key analytical method for studying the primary structure of proteins. The sensitivity of the peptide map to even the smallest change in the covalent structure of the protein makes it a valuable "fingerprint" for identity testing and process monitoring. We recently conducted a full method validation study of an optimized reverse-phase high-performance liquid chromatography (RP-HPLC) tryptic map of a therapeutic anti-CD4 monoclonal antibody. We have used this method routinely for over a year to test production lots for clinical trials and to support bioprocess development. One of the difficulties in the validation of the peptide mapping method is the lack of proper quantitative measures of its reproducibility. A reproducibility study may include method and system precision study, ruggedness study, and robustness study. In this paper, we discuss the use of principal component analysis (PCA) to quantitate peptide maps properly using its projected scores on the reduced dimensions. This approach allowed us not only to summarize the reproducibility study properly, but also to use the method as a diagnostic tool to investigate any troubles in the reproducibility validation process.

Validation of a peptide mapping method for a therapeutic monoclonal antibody: what could we possibly learn about a method we have run 100 times?

Peptide mapping is a key analytical method for studying the primary structure of proteins. The sensitivity of the peptide map to even the smallest change in the covalent structure of the protein makes it a valuable 'finger-print' for identity testing and process monitoring. We recently conducted a full method validation study of an optimised reverse-phase high-performance liquid chromatography (RP-HPLC) tryptic map of a therapeutic anti-CD4 IgG1 monoclonal antibody. We have used this method routinely for over 1 year to support bioprocess development and test production lots for clinical trials. Herein we summarize the precision and ruggedness of the testing procedure and the main findings with respect to 'coverage of amino acid sequence' and limits-of-detection for various hypothetical structural variants. We also describe, in more detail, two unanticipated insights into the method gained from the validation study. The first of these is a potentially troublesome side-product arising during the reduction/alkylation step. Once the cause of this side-product was identified, it was easily prevented. We also report on subtle changes to the peptide map upon extended storage of the digest in the autosampler. These findings helped us to develop a 'robust' method for implementation in a quality control laboratory.

RP-HPLC tryptic mapping of IgG1 proteins with post-column fluorescence derivatization.

Peptide mapping is an important analytical technique widely used to study the primary structure of proteins. In quality control settings, it is employed as an identity test to probe for small changes in protein primary structure. A great challenge in peptide mapping is to minimize the detection limit for peptides due to the low detectability of smaller peptides based on their ultraviolet absorbance. The detection of peptide fragments can be enhanced by pre-or post-column derivatization with fluorescent tags. The use of post-column o-pthalaldehyde (OPA) and fluorescamine chemistries for on-line derivatization of peptide fragments from the RP-HPLC tryptic maps of several IgG1 monoclonal antibodies was explored. This paper describes the simple and sensitive peptide mapping technique for structural confirmation of proteins using picomoles of samples by post-column fluorescence derivatization. A comparison of UV and fluorescence detection of a peptide map is also presented. The method includes post column OPA derivatization of tryptic peptides from RP-HPLC tryptic maps with fluorescence detection. The conclusion reached that fluorescence detection gave relative detectability for tryptic peptides that range from 10- to 100-fold better than those observed with UV detection. The sensitivity of the peptide map increased by about 200-500 fold, i.e. peptide maps could be obtained using 2-5 pmol of digest instead of 1 nmol of digest. A roughly equal fluorescence response for all peptides (equal peak areas) was generally observed.

Multilaboratory comparison of in vitro tests for chromosome aberrations in CHO and CHL cells tested under the same protocols.

Different test results have been reported for the same chemicals in two in vitro chromosome aberration test systems, CHL cells tested by a Japanese protocol and CHO cells tested by the US National Toxicology Program [Sofuni et al., Mutat Res 241:173-213,1990]. Here, laboratories in Japan, the US and the UK tested 9 such chemicals in CHL and CHO cells using the same protocols and found all 9 positive in both cell types; differences in earlier conclusions with these chemicals were due mainly to test protocol, not to different sensitivities of the cells. The most important protocol difference is sampling time. Chemicals that were negative in the NTP series using a sampling time of 10 to 13 hours often produced positive results when retested here with a 20- to 24-hour sampling time. While positive results were obtained in both cell types, CHL cells sometimes had higher aberration levels and survived at higher doses than CHO cells would tolerate. This may reflect some intrinsic difference in sensitivity but may also be affected by factors such as cell cycle length and culture media (e.g., oxygen scavenging capacity). The collaboration reported here also contributed to a better understanding of scoring aberrations, especially "gaps"; there was good agreement on what types of aberrations should be included in the totals when scoring criteria were clearly defined, for example, many changes classified as "gaps" by the Japanese system were classified as "breaks" in the scoring systems used in the United States and the United Kingdom, and were appropriately included in total aberration counts.

Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats.

The phthalate ester di-n-butylphthalate (DBP) is used extensively in the manufacture of plastics; its reproductive toxicity was tested in rats by the National Toxicology Program's Reproductive Assessment by Continuous Breeding protocol. Levels of 0.1, 0.5, and 1.0% DBP in the diet were selected, and this dosing design yielded average daily DBP intakes of 52, 256, and 509 mg/kg for males and 80, 385, and 794 mg/kg for females, respectively. DBP consumption by F0 rats reduced the total number of live pups per litter in all treated groups by 8-17% and live pup weights in the 0.5% and 1.0% dose groups by < 13%. In tests to determine the affected sex, the number of offspring was unchanged, but the weights of pups from treated females were significantly decreased and offspring from treated males were unchanged. At necropsy, high-dose F0 females had a 14% reduction in body weight, and both sexes had approximately 10-15% increased kidney and liver to body weight ratios compared to controls. Sperm parameters and estrous cyclicity were not affected. In the F1 mating trial, indices of mating, pregnancy, and fertility in the 1.0% dose group were all sharply decreased (one live litter was delivered out of 20 cohabited pairs), concomitant with a 13% decrease in dam body weight. Live F2 pup weights were 6-8% lower in all dose groups. F1 necropsy results revealed that epididymal sperm counts and testicular spermatid head counts were significantly decreased in the 1.0% dose group. Histopathologic investigation showed that 8 of 10 F1 males consuming 1.0% DBP had degenerated seminiferous tubules and 5 of 10 had underdeveloped or otherwise defective epididymides. No ovarian or uterine lesions were observed. In conclusion, this study showed that DBP is a reproductive/developmental toxicant in Sprague-Dawley rats exposed both as adults and during development; it also indicates that the adverse reproductive/developmental effects of DBP on the second generation were greater than on the first generation.

Assessment of the reproductive toxicity of a complex mixture of 25 groundwater contaminants in mice and rats.

The potential reproductive toxicity of a mixture of 25 chemicals (MIX) formulated to simulate contaminated groundwater supplies near hazardous waste dumps was evaluated in CD-1 Swiss mice and Sprague-Dawley rats using the reproductive assessment by continuous breeding protocol. Male and female mice and rats were exposed to MIX in the drinking water at concentrations of 1, 5, and 10% of a technically achievable stock solution. For mice, body weight and feed consumption were not affected by MIX but water consumption was decreased for both the 5 and 10% MIX groups in both F0 and F1 animals. For F0 mice, the number of live pups/litter was decreased at 10% MIX and the number of females/litter was decreased 10 and 17% at the mid and high MIX dose, respectively. Vaginal cytology was normal, as were testis weight and testicular spermatid head count. For F1 mice, fertility was unaffected, but there was a decreased number of female pups/litter (19%) and a decreased adjusted live pup weight at 10% MIX. At necropsy, cauda epididymal sperm concentration and spermatid head count were reduced (20%) in the presence of normal testis, epididymis, prostate, seminal vesicle, liver, and kidney/adrenal weight. Female estrous cyclicity was altered at 5 and 10% MIX with normal kidney/adrenal, uterus, and ovary/oviduct weight. For rats, F0 body weight and feed consumption were not affected by MIX but water consumption was decreased 10, 30, and 40% in the low-, medium-, and high-dose MIX groups, respectively, and 39% in the high-dose MIX F1 animals. Rat fertility was normal but there was a decreased number of male pups/litter (11%) and a decreased live pup weight (6%) at 10% MIX. Male and female (F1) pup weights were decreased on Postnatal Days 0, 4, 7, 14, and 21 (10% MIX) and remained lower through necropsy on Day 120 +/- 10. F1 fertility was normal but F2 pup weights were decreased (10% MIX). At necropsy, F1 (10% MIX) male body weight was decreased 16% and relative kidney, testis, epididymis, and prostate weights were increased in the presence of normal sperm concentration percentage motile sperm and percentage abnormal sperm. Estrous cyclicity was normal as were kidney/adrenal and ovary weight while female liver weight was reduced 14%. In summary, a "cocktail" of 25 chemicals commonly found in contaminated groundwater at or near hazardous waste sites was administered in drinking water at doses which resulted in severely decreased water consumption in both mice and rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Phenolphthalein: induction of micronucleated erythrocytes in mice.

Phenolphthalein was tested for the induction of micronucleated erythrocytes in mice. Results of an initial investigation revealed significant, dose-related increases in micronucleated polychromatic erythrocytes (MN-PCE) and normochromatic erythrocytes (MN-NCE) in peripheral blood samples of male and female mice exposed to 0.6% to 5% phenolphthalein (approximately 1100 to 10,000 mg/kg/day) in feed for 90 days (Dietz et al., 1992). Results from a second long-term feed study with Swiss CD-1 mice confirmed this effect. However, administration of comparable doses of phenolphthalein by corn oil gavage on two consecutive days gave negative results in a mouse bone marrow micronucleus test. Subsequent tests were performed to clarify the conflicting results seen in the chronic exposure, dosed-feed, peripheral blood studies and the acute, corn oil gavage, bone marrow studies. Phenolphthalein was administered to male B6C3F1 mice in feed (3%) for 14 days. Peripheral blood samples taken at 4, 7, and 14 days all showed significant increases in micronucleated PCE; bone marrow samples taken on days 7 and 14 also were clearly positive for micronucleus induction. Therefore, comparable results were obtainable from both bone marrow and peripheral blood analyses. Because of the negative results in the two-exposure gavage test, additional tests were then designed to investigate the effects of bolus vs continuous dosing, feeding vs gavage administration, and corn oil vs feed as a carrier for phenolphthalein. Results of these tests indicated that the rate of exposure to phenolphthalein affects the frequency of induced MN-PCE and that micronucleated erythrocytes can be induced by phenolphthalein either by feeding or by corn oil gavage administration. In all the acute exposure studies, relatively high doses of phenolphthalein (2000-6000 mg/kg/day for at least 2 days) were required to induce micronuclei. The positive results obtained with phenolphthalein in vivo were consistent with the results of an in vitro chromosomal aberration test in Chinese hamster ovary cells, where dose-related increases in aberrations were noted only in cells treated in the presence of induced rat liver S9.

Cytogenetic studies of sodium fluoride in mice.

The cytogenetic effects of sodium fluoride (NaF) were measured in mice following administration in the drinking water for 6 weeks. Bone fluoride levels were determined and showed a dose-related incorporation of fluoride. Micronuclei were measured in peripheral blood erythrocytes following 1 and 6 weeks of NaF administration. Bone marrow cell preparations were examined for the presence of chromosome aberrations following 6 weeks of treatment; metaphase and anaphase cells were examined. Anaphase cells were scored in three independent laboratories, two of which also scored metaphase cells from the same slides. No increases in micronuclei were seen in peripheral erythrocytes at either time point, and no increases in chromosome aberrations were seen in bone marrow cells when metaphase or anaphase cells were examined. A concurrent positive control, cyclophosphamide, produced significant increases in peripheral blood cell micronuclei and in chromosome aberrations in bone marrow cells in metaphase. No increases in aberrations were seen in the same cyclophosphamide-treated mice when anaphase cells were examined.

Assessment of the reproductive and developmental toxicity of pesticide/fertilizer mixtures based on confirmed pesticide contamination in California and Iowa groundwater.

Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce reproductive or developmental toxicity at concentrations up to 100 x the median level found in groundwater, we prepared and studied two mixtures of pesticides and a fertilizer (ammonium nitrate). One mixture containing aldicarb, atrazine, dibromochloropropane, 1,2-dichloropropane, ethylene dibromide, and simazine plus ammonium nitrate was considered to be a representative of groundwater contamination in California (CAL). The other, containing alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate, simulated groundwater contamination in Iowa (IOWA). Each mixture was administered in the drinking water of either Swiss CD-1 mice during a Reproductive Assessment by Continuous Breeding study or pregnant Sprague-Dawley rats (gd 6-20) at three dose levels (1x, 10x, and 100x) where 1x was the median concentration of each pesticide component as determined in the groundwater surveys in California or Iowa. Unlike conventional toxicology studies, the purpose of this study was to evaluate the health effects of realistic human concentrations. Thus, the testing concentrations are probably well below the maximally tolerated dose. Propylene glycol was used as the solubilizer for the pesticides in drinking water formulations in both studies. In the reproductive study, neither mixture caused any clinical signs of toxicity, changes in food or water consumption, or body weight in either F0 or F1 mice at doses up to 100x the median groundwater concentrations. There were no treatment-related effects on fertility or any measures of reproductive performance of either the F0 or the F1 generation mice exposed to either CAL or IOWA at up to 100x. Similarly, measures of spermatogenesis, epididymal sperm concentration, percentage motile sperm, percentage abnormal sperm, and testicular and epididymal histology were normal. In the developmental study, CAL- or IOWA-exposed females did not exhibit any significant treatment-related clinical signs of toxicity. No adverse effects of CAL or IOWA were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, or fetal body weight. CAL or IOWA did not cause an increased incidence of fetal malformations or variations. In summary, administration of these pesticide/fertilizer mixtures at levels up to 100-fold greater than the median concentrations in groundwater supplies in California or Iowa did not cause any detectable reproductive (mice), general, or developmental toxicity (rats).

Are mouse strains differentially susceptible to the reproductive toxicity of ethylene glycol monomethyl ether? A study of three strains.

Most rodent reproductive toxicology studies utilize strains of high fecundity. These studies were conducted to examine the possibility that mouse strains of differing fecundity would respond differently to a known reproductive toxicant. Thirty pairs each of Swiss CD-1, C57B1, and C3H mice were cohabited for 14 weeks while consuming 0, 0.03, 0.10, or 0.30% EGME in the drinking water. Litter data were collected during cohabitation. Body and organ weights, and various sperm data, were collected at necropsy, and second-generation fertility was evaluated. The data show that the most fecund strain (Swiss) was affected the least by exposure to EGME, while the least fecund strain (C3H) suffered the greatest declines in fertility. These differences might alter interspecies extrapolation factors, or the permissible exposure levels for humans.