Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

Colorectal cancer detection: time to abandon barium enema?

OBJECTIVES: To assess the sensitivity of double contrast barium enema (DCBE) for diagnosing colorectal cancer (CRC). DESIGN: Retrospective evaluation of DCBE performed in the 2 years prior to diagnosis of CRC. SETTING: Teaching hospital in Cambridge, UK. PATIENTS: 1310 consecutive cases of CRC identified from cancer registry data. INTERVENTIONS: DCBE and colonoscopy. MAIN OUTCOME MEASURES: Sensitivity of DCBE for diagnosing CRC. RESULTS: 215 patients had undergone a DCBE within the 2 years prior to diagnosis with CRC. After excluding those reported as inadequate, 37 of these were reported as normal, giving a sensitivity of 83% (81-85%). CONCLUSIONS: The performance of DCBE is inadequate for the exclusion of CRC. Expansion of colonoscopy and CT colonography capacity is urgently required nationally so that DCBE can finally be abandoned as a firstline test in patients at risk of CRC.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.

Microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile neutropenic oncology patients: comparison between two consecutive time periods with use of different antibiotic treatment protocols.

This study was devised to look at trends in the microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile oncology patients. The retrospective study compared various microbiological aspects recorded for febrile oncology neutropenic patients treated with two different empirical antibiotic regimens (ceftazidime plus gentamicin during 1998-1999 and piperacillin/tazobactam plus amikacin during 2000-2002). Eighty-one bacteraemic episodes occurred in 41 patients. Overall, 132 (34 during 1998-1999 and 98 during 2000-2002) organisms were isolated: 84 (65%) Gram-negative bacteria, 39 (30%) Gram-positive bacteria and 7 (5%) fungi. Enterobacter spp. incidence decreased from 18 to 6% (P=0.07) while the recovery rates of Gram-positive organisms increased from 24 to 32% (P=0.4) during 2000-2002 compared with 1998-1999. MRSA were not isolated from any episode of bacteraemia. Five (18%) of the 28 Escherichia coli and Klebsiella spp. isolates were beta-lactamase producers (80% [4/5] isolated during 2000-2002). Twenty-seven of 28, 27/27, 23/28, 20/25 and 27/28 of these isolates were susceptible to imipenem, piperacillin/tazobactam, gentamicin, ceftazidime and ciprofloxacin, respectively. Thirty-two of 34 (94%) and 60/74 (81%) of the Gram-negative organisms isolated during 2000-2002 were susceptible to piperacillin/tazobactam and ceftazidime, respectively (P=0.076). No major differences in the microbial spectrum and antibiotic susceptibilities were recorded between the two consecutive study periods. An increase in the number of extended beta-lactamase producing E. coli and Klebsiella spp. occurred during 2000-2002. All beta-lactamase producing organisms were susceptible to piperacillin/tazobactam and initial empirical therapy with piperacillin/tazobactam was more appropriate than ceftazidime to cover most of the pathogens causing bacteraemia.

Adjuvant therapy of melanoma with interferon-alpha-2b is associated with mania and bipolar syndromes.

BACKGROUND: The use of a high dose regimen of interferon-alpha-2b (IFN) has recently been demonstrated to benefit patients with resected high risk melanoma. The incidence of melanoma is rising rapidly, and the use of this regimen is becoming increasingly common. IFN has been associated with numerous psychiatric side effects. METHODS: The authors describe four melanoma patients treated with adjuvant IFN who developed a manic-depressive syndrome or mood instability with therapy, and they review the literature on mania and the mixed affective syndromes associated with IFN. RESULTS: The authors suggest that IFN may induce a mixed affective instability, and that patients risk developing hypomania or mania as IFN doses fluctuate or as IFN-induced depression is treated with antidepressants alone. Mania is particularly associated with dose reductions or pauses in IFN treatment. The risk of mood fluctuation continues after treatment with IFN stops, and patients should be monitored for 6 months following completion of therapy. Gabapentin appeared effective as monotherapy for acute mania, as an antianxiety agent, as a hypnotic, and as a mood stabilizer in these individual cases. CONCLUSIONS: Mania and mood instability can occur in patients being treated with IFN therapy for melanoma. In this study, gabapentin was an effective mood-stabilizing agent for these patients.

Different preferences for oils with similar fatty acid profiles.

While preference for fat can be influenced by concentration and physical form, the influence of fatty acid composition on relative preference for oils has not been systematically investigated. Therefore, the purpose of the present investigation was to assess the relative preference for oils rich in oleic (Extra Light Olive Oil and Extra Virgin Olive Oil) and linoleic (Safflower Oil) acid. Male Fischer rats (n = 10) were used to determine preference in a two-choice testing procedure in which three pairs of oils were each tested twice. Preference testing occurred at dark onset at which time the rodent diet and water were removed and each rat was allowed 2-h access to his assigned pair of oils. There was a main effect of oil type (p<0.01), but no significant effect of oil pairing and no interaction between oil pairing and oil type. Rats preferred the Extra Light Olive Oil to the Extra Virgin Olive Oil (p<0.05). This is the first report of preference testing in which two oils with similar fatty acid profiles were included. The present data indicate that the fats with similar fatty acid profiles were not equally preferred, suggesting that a property other than the fatty acid composition of the oils accounts for the demonstrated preference.

Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures.

Marijuana and related drugs (cannabinoids) have been proposed as treatments for a widening spectrum of medical disorders. R(+)-[2, 3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate (R(+)-WIN 55212-2), a synthetic cannabinoid agonist, decreased hippocampal neuronal loss after transient global cerebral ischemia and reduced infarct volume after permanent focal cerebral ischemia induced by middle cerebral artery occlusion in rats. The less active enantiomer S(-)-WIN 55212-3 was ineffective, and the protective effect of R(+)-WIN 55212-2 was blocked by the specific central cannabinoid (CB1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride. R(+)-WIN 55212-2 also protected cultured cerebral cortical neurons from in vitro hypoxia and glucose deprivation, but in contrast to the receptor-mediated neuroprotection observed in vivo, this in vitro effect was not stereoselective and was insensitive to CB1 and CB2 receptor antagonists. Cannabinoids may have therapeutic potential in disorders resulting from cerebral ischemia, including stroke, and may protect neurons from injury through a variety of mechanisms.

Dynamics of pneumococcal nasopharyngeal colonization during the first days of antibiotic treatment in pediatric patients.

BACKGROUND: Nasopharyngeal (NP) carriage of antibiotic-resistant Streptococcus pneumoniae was shown to be associated with recent antibiotic treatment. To date no studies have evaluated early dynamics of pneumococcal NP carriage during antibiotic treatment. OBJECTIVES: To observe changes in NP pneumococcal carriage within 3 to 4 days after initiation of antibiotic treatment in acute otitis media (AOM). METHODS: Patients ages 3 to 36 months with AOM treated with various antibiotics were prospectively followed. Nasopharyngeal culture for S. pneumoniae was obtained before (Day 1) and 72 to 96 h after initiation of treatment (Days 4 to 5). Antibiogram and serotyping were performed in all isolates as was also the MIC of penicillin. The disappearance and persistence of the initial isolates as well as the appearance of isolates with new serotype or with new antibiotic susceptibility patterns were investigated. RESULTS: A total of 120 patients were studied: 106 received beta-lactam antibiotics and 14 received azithromycin. Among the initial 76 pneumococcal isolates 63, 37 and 13% were resistant to > or =1, > or =2 and > or =3 antibiotic drugs. After 3 to 4 days of treatment with various beta-lactam drugs, 45, 63 and 100% of isolates with MIC values of <0.1 microg/ml, 0.125 to 0.25 microg/ml and 0.38 to 1.0 microg/ml, respectively, persisted in the NP (P = 0.038). There was a difference between the various beta-lactam drugs in their effect on NP colonization: a drug with lower MIC values (cefuroxime-axetil) had a better eradication rate of penicillin-susceptible organisms than a less active one (cefaclor), but neither significantly reduced carriage of penicillin nonsusceptible isolates. Azithromycin eliminated carriage of macrolide-susceptible organisms but increased the carriage of macrolide-resistant ones. In 19 of 120 (16%) patients a new S. pneumoniae isolate was recovered 3 to 4 days after initiation of treatment. Of those 16 (84%) were resistant to the drug the patient was receiving. CONCLUSION: A rapid selection of nonsusceptible NP pneumococcal isolates during antibiotic treatment for AOM is common. This phenomenon may contribute to the spread of resistant pneumococci.

Active X based standards for healthcare integration.

With cost pressures brought to the forefront by the growth of managed care, the integration of healthcare information systems is more important than ever. Providers of healthcare information are under increasing pressure to provide timely information to end users in a cost effective manner. Organizations have had to decide between the strong functionality that a multi-vendor 'best of breed' architecture provides and the strong integration provided by a single-vendor solution. As connectivity between systems increased, these interfaces were migrated to work across serial and eventually, network, connections. In addition, the content of the information became standardized through efforts like HL7 and ANSI X12 and Edifact. Although content-based standards go a long way towards facilitating interoperability, there is also quite a bit of work required to connect two systems even when they both adhere to the standard. A key to accomplishing this goal is increasing the connectivity between disparate systems in the healthcare environment. Microsoft is working with healthcare organizations and independent software vendors to bring Microsoft's powerful enterprise object technology, ActiveX, to the healthcare industry. Whilst object orientation has been heralded as the 'next big thing' in computer applications development, Microsoft believe that, in fact, component software is the technology which will provide the greatest benefit to end users.

Bacteriologic response to oral cephalosporins: are established susceptibility breakpoints appropriate in the case of acute otitis media?

Bacteriologic response to cefuroxime axetil and cefaclor administered for 10 days was evaluated in acute otitis media (AOM) in patients aged 6-36 months. Middle ear fluid culture was obtained by tympanocentesis before treatment, on day 4 or 5 after initiation of treatment, and if clinical relapse occurred before day 17. Bacteriologic failure was observed in 32% of patients receiving cefaclor versus 15% of patients receiving cefuroxime axetil (P = .009). Failure rates increased with increasing MIC: For Streptococcus pneumoniae, 0.5 microg/mL (established as cutoff value for cefuroxime by the National Committee for Clinical Laboratory Standards [NCCLS]) discriminated between success and failure. For Haemophilus influenzae, high failure rates were observed for cefaclor, even with low MICs (< or = 1.0 microg/mL), and with both drugs they tended to increase with increasing MIC, even for values below the cutoff suggested by the NCCLS (8.0 and 4.0 microg/mL for cefaclor and cefuroxime, respectively). Thus, for AOM caused by H. influenzae, lower susceptibility cutoff levels for MICs should be established.

Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin.

BACKGROUND: Penicillin resistance of Streptococcus pneumoniae, one of the most common causes of acute otitis media, has recently increased and is now highly prevalent in many regions. However, its contribution to clinical failure still must be proved. Because the role of antibiotics in acute otitis media is to eradicate the pathogens present in the middle ear fluid, we conducted a randomized controlled study to determine bacterial eradication of pathogens in acute otitis media by two commonly used oral cephalosporins, cefuroxime axetil (30 mg/kg/day) and cefaclor (40 mg/kg/day). METHODS: Patients 6 to 36 months old with pneumococcal otitis media seen in the Pediatrics Emergency Room were studied. An initial middle ear fluid culture was obtained at enrollment, and a second culture was obtained on Day 4 or 5 during treatment. Follow-up was done also on Days 10, 17 and 42 after initiation of treatment. In cases of clinical relapse a third culture was obtained. RESULTS: In total 78 patients were enrolled, 41 in the cefuroxime axetil group and 37 in the cefaclor group. Of the 78 S. pneumoniae isolates 31 (40%) were intermediately penicillin-resistant (MIC 0.125 to 1.0 microgram/ml). Of the 47 patients with penicillin-susceptible organisms 3 (6%) had bacteriologic failure vs. 4 of 19 (21%) and 7 of 11 (64%) of those with MIC of 0.125 to 0.25 microgram/ml and 0.38 to 1.0 microgram/ml, respectively (P < 0.001). For intermediately resistant pneumococci, in 7 of 12 (58%) of those receiving cefaclor the isolate was not eradicated vs. only 4 of 19 (21%) of those receiving cefuroxime axetil (P = 0.084). MIC to the administered cephalosporin of > 0.5 microgram/ml was associated with bacteriologic failure. Clinical failure was observed in 9 of 14 (64%) patients with bacteriologic failure vs. 10 of 52 (19%) patients with bacteriologic eradication (P = 0.003). CONCLUSION: Intermediately penicillin-resistant S. pneumoniae is associated with an impaired bacteriologic and clinical response of acute otitis media to cefaclor and cefuroxime axetil. This effect was more pronounced with cefaclor than with cefuroxime axetil.

Physical and biological doses produced from neutron capture in a 235U foil.

As a follow-on study to the feasibility of neutron capture therapy (NCT) with 235U brachytherapy seeds, physical doses were calculated and measured for the radiation from a 235U foil in a lucite phantom which was irradiated at the epithermal neutron irradiation port of the Brookhaven Medical Research Reactor. In addition, cell survival experiments were performed to obtain the relative biological effectiveness (RBE) for the neutron part of the radiation. The calculated absorbed doses agree with the measured ones. From cell survival experiments, it is deduced that the fission neutrons from the 235U foil have a RBE of 3.0 while the fast neutrons in the beam have a RBE of 3.8. Also observed is that, with the cells 7 mm from the foil, a significant amount of absorbed dose comes from the beta rays of 235U fission events. This absorbed dose from beta rays is a significant addition to the therapeutic dose. Due to the limited ranges of beta rays in tissue, this absorbed dose is restricted to the vicinity of the foil. This is the first demonstration of beta rays as part of NCT.

Coronary thrombolysis. Comparative effects of intracoronary administration of recombinant tissue plasminogen activator and urokinase.

We employed a canine model of coronary thrombosis, induced by injection of radioactive blood clot, via a catheter placed in the left anterior descending coronary artery, to compare effects of intracoronary administration of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) on rate and extent of coronary thrombolysis. Two doses of UK, 15,000 U/kg (UK15) and 30,000 U/kg (UK30) and two doses of rtPA, 0.25 mg/kg (rtPA.25) and 0.75 mg/kg (rtPA.75) were given. Drugs were infused over 45 min. Compared with the other regimens, rate and extent of coronary thrombolysis were significantly increased with rtPA.75. Also, despite a much higher dose of UK, coronary thrombolysis was similar with UK30 and rtPA.25. Compared with UK15, rate and extent of coronary thrombolysis were increased with rtPA.25. These results indicate that intracoronary administration of rtPA is superior to intracoronary UK in inducing thrombolysis.

Failure to detect increases in brain dopamine metabolism in rats sham feeding sucrose and corn oil.

In a recent study we found that when rats sham fed 6% sucrose, 10% sucrose, and 100% corn oil, the rank order of inhibitory potency for D-1 and D-2 receptor antagonists was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a complementary study, sham-feeding rats preferred 100% corn oil greater than 10% sucrose greater than 6% sucrose as measured by two-bottle preference tests. The preferences are evidence for the rank order of reward value of these solutions. In the present study we tested the hypothesis that the relative antagonist potencies were due to differential release of DA, dependent on the reward value of the sham-fed solution. Dopamine metabolism, estimated by the ratio of dihydroxphenylacetic acid (DOPAC) to DA, was measured in forebrain-DA terminal fields during sham feeding of 100% corn oil, 6% sucrose, and 10% sucrose. The results did not support our hypothesis: no increase in DA metabolism was observed after the sham feeding of any solution.

Obese and lean Zucker rats differ in preferences for sham-fed corn oil or sucrose.

Obese Zucker rats show greater preference for fatty foods in dietary selection studies than do lean rats. We wished to evaluate the preference for dietary fats in Zucker rats in the absence of postingestive cues. Zucker rats (6 lean and 6 obese) were fitted with gastric cannulas for sham feeding. All sham-feeding tests lasted for 30 min. On training days, rats were sham fed 100% corn oil or, on alternate days, rats were sham fed various concentrations of sucrose in volumes yoked to intakes of corn oil. On preference test days, rats were offered 100% corn oil and one sucrose concentration simultaneously for sham feeding. During preference tests, obese rats preferred 100% corn oil to 10% sucrose, whereas lean rats preferred 10% sucrose to 100% corn oil. Obese rats equally preferred 17.5% sucrose and 100% corn oil, whereas lean Zucker rats equally preferred 2.5% sucrose and 100% corn oil. When sucrose concentration was increased to 20% both obese and lean Zucker rats preferred sucrose to 100% corn oil. These results combined with our previously reported results showing that intraduodenally administered fats do not differ in satiating potency for obese and lean Zucker rats (6) strongly suggest that the preference of obese rats for fatty foods is largely mediated by orosensory mechanisms.

The potency of D-1 and D-2 receptor antagonists is inversely related to the reward value of sham-fed corn oil and sucrose in rats.

Intraperitoneal injection of 50 micrograms.kg-1 of the selective dopamine D-1 receptor antagonist, SCH 23390, significantly decreased sham feeding of 6% and 10% sucrose solutions, but not sham feeding of 100% corn oil. Intraperitoneal injection of raclopride, a D-2 antagonist, elicited a significant dose-dependent (200-400 micrograms.kg-1) decrease in sham intake of both sucrose concentrations and corn oil at doses that did not increase the latency to sham feed or produce overt motor impairment. The rank order of inhibitory potency for both SCH 23390 and raclopride was 6% sucrose greater than 10% sucrose greater than 100% corn oil. In a second experiment, we found that in 2-bottle preference tests, the rank order of preference for these three liquids was 100% corn oil greater than 10% sucrose greater than 6% sucrose. Assuming that preference measured the relative reward value of the liquids, the potencies of the two antagonists were inversely related to the reward value of the liquid that was sham fed. This result supports but does not prove the dopamine hypothesis of the positive reinforcing effect of orosensory stimulation by nutrients. In addition, the differential selectivity of the two antagonists for different classes of nutrients suggests that normal sensory and/or hedonic processing of sham-fed sucrose depends on stimulation of both D-1 and D-2 receptors, but the normal sensory and/or hedonic processing of sham-fed corn oil depends primarily, perhaps exclusively, on stimulation of D-2 receptors.

Corn oil and mineral oil stimulate sham feeding in rats.

To determine the orosensory effects of oils on ingestion, we measured the 1-bottle intake of corn oil and of mineral oil during 30 minutes of sham feeding in rats that were food deprived overnight or nondeprived. Rats sham fed both oils. Food-deprived rats ingested significantly more of both oils than nondeprived rats. Rats discriminated corn oil from mineral oil and as little as 0.78% corn oil emulsion from water. When rats sham fed 8 dilutions of corn oil, intake was an inverted-U function of concentration with maximal intakes produced by 12.5%, 25% and 50% corn oil emulsions. Despite similar, sometimes equal, intakes of corn oil and mineral oil in 1-bottle tests, food-deprived and nondeprived rats showed a strong preference for corn oil in 2-bottle, sham-feeding, preference tests. The sensory mechanisms that mediate the oral effects of oil on intake and preference are not known, but the olfactory and trigeminal sensory systems are the most likely candidates. Further work is required to characterize the potency, sensitivity, and discriminability of the orosensory effects of oils, the mechanisms that mediate them, and their role in the control of fat intake.

Thrombolytic therapy in canine pulmonary embolism. Comparative effects of urokinase and recombinant tissue plasminogen activator.

We compared thrombolytic and pulmonary hemodynamic effects of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) in canine micropulmonary thromboembolism. Dogs were embolized with radioactive autologous blood clot to increase mean pulmonary artery pressure (from 13 to 34 mm Hg, p less than 0.005) and decrease cardiac output (2.5 to 1.6 L min, p less than 0.005). Four groups of six dogs were treated. We employed two doses of UK, 30,000 U/kg (UK30) and 60,000 U/kg (UK60), and two doses of rtPA, 1 mg/kg (rtPA1) and 2 mg/kg (rtPA2). Drugs were infused over 15 min. Rate and extent of pulmonary thrombolysis were assessed by continuously counting over both lung fields with a gamma camera. Compared with treatment with UK, both rtPA regimes significantly increased thrombolysis. Mean total pulmonary thrombolysis was 14 and 23% with UK30 and UK60, respectively, and 35 and 43% with rtPA1 and rtPA2. Corresponding to the increased thrombolysis, pulmonary hemodynamics improved most with rtPA. From 90 min to 3 h, pulmonary artery pressure was significantly lower with both rtPA regimes than with either UK regime. These results indicate, at least in the model employed, that compared with treatment with UK, pulmonary thrombolysis and corresponding hemodynamic improvement are greatest with rtPA.