Results of carotid endarterectomy in patients with contralateral internal carotid artery occlusion from the Mid-America Vascular Study Group and the Society for Vascular Surgery Vascular Quality Initiative.

OBJECTIVE: Carotid endarterectomy (CEA) is among the most commonly performed vascular procedures. Some have suggested worse outcomes with contralateral internal carotid artery (ICA) occlusion. We compared patients with and patients without contralateral ICA occlusion using the Society for Vascular Surgery Vascular Quality Initiative database. METHODS: Deidentified data were obtained from the Vascular Quality Initiative. Patients with prior ipsilateral or contralateral CEA, carotid stenting, combined CEA and coronary artery bypass graft, or <1-year follow-up were excluded, yielding 1737 patients with and 45,179 patients without contralateral ICA occlusion. Groups were compared with univariate tests, and differences identified in univariate testing were entered into multivariate models to identify independent predictors of outcomes and in particular whether contralateral ICA occlusion is an independent predictor of outcomes. RESULTS: Patients with contralateral ICA occlusion were younger and more likely to be smokers; they were more likely to have chronic obstructive pulmonary disease, preoperative neurologic symptoms (56% vs 47%), nonelective CEA (16% vs 13%), and shunt placement (75% vs 53%; all P < .001). The 30-day ipsilateral stroke risk was 1.3% with vs 0.7% without contralateral ICA occlusion (P = .004). The 30-day and 1-year survival estimates were 99.0% ± 0.5% and 94.1% ± 1.1% with vs 99.6% ± 0.1% and 96.0% ± 0.2% without contralateral ICA occlusion (log-rank, P < .001). Logistic regression analysis identified prior neurologic event (P = .046), nonelective surgery (P = .047), absence of coronary artery disease (P = .035), and preoperative angiotensin-converting enzyme inhibitor use (P = .029) to be associated with 30-day ipsilateral stroke risk, but contralateral ICA occlusion remained an independent predictor in that model (odds ratio, 2.29; P = .026). However, after adjustment for other factors (Cox proportional hazards), risk of ipsilateral stroke (including perioperative) during follow-up was not significantly greater with contralateral ICA occlusion (hazard ratio, 1.21; P = .32). Results comparing propensity score-matched cohorts mirrored those from the larger data set. CONCLUSIONS: This study demonstrates likely clinically insignificant differences in early stroke or death in comparing CEA patients with and those without contralateral ICA occlusion. After adjustment for other factors, contralateral ICA occlusion was not associated with a greater risk of ipsilateral stroke (including perioperative) in longer follow-up. Mortality was greater with contralateral ICA occlusion, and this difference was more pronounced at 1 year despite younger age of the contralateral ICA occlusion group. CEA risk remains low even in the presence of contralateral ICA occlusion and appears to be explained at least in part by other factors. CEA should still be considered appropriate in the face of contralateral ICA occlusion.

Impact of an Integrated Antibiotic Allergy Testing Program on Antimicrobial Stewardship: A Multicenter Evaluation.

Background: Despite the high prevalence of patient-reported antibiotic allergy (so-called antibiotic allergy labels [AALs]) and their impact on antibiotic prescribing, incorporation of antibiotic allergy testing (AAT) into antimicrobial stewardship (AMS) programs (AAT-AMS) is not widespread. We aimed to evaluate the impact of an AAT-AMS program on AAL prevalence, antibiotic usage, and appropriateness of prescribing. Methods: AAT-AMS was implemented at two large Australian hospitals during a 14-month period beginning May 2015. Baseline demographics, AAL history, age-adjusted Charlson comorbidity index, infection history, and antibiotic usage for 12 months prior to testing (pre-AAT-AMS) and 3 months following testing (post-AAT-AMS) were recorded for each participant. Study outcomes included the proportion of patients who were "de-labeled" of their AAL, spectrum of antibiotic courses pre- and post-AAT-AMS, and antibiotic appropriateness (using standard definitions). Results: From the 118 antibiotic allergy-tested patients, 226 AALs were reported (mean, 1.91/patient), with 53.6% involving 1 or more penicillin class drug. AAT-AMS allowed AAL de-labeling in 98 (83%) patients-56% (55/98) with all AALs removed. Post-AAT, prescribing of narrow-spectrum penicillins was more likely (adjusted odds ratio [aOR], 2.81, 95% confidence interval [CI], 1.45-5.42), as was narrow-spectrum ß-lactams (aOR, 3.54; 95% CI, 1.98-6.33), and appropriate antibiotics (aOR, 12.27; 95% CI, 5.00-30.09); and less likely for restricted antibiotics (aOR, 0.16; 95% CI, .09-.29), after adjusting for indication, Charlson comorbidity index, and care setting. Conclusions: An integrated AAT-AMS program was effective in both de-labeling of AALs and promotion of improved antibiotic usage and appropriateness, supporting the routine incorporation of AAT into AMS programs.

A comparison of results of carotid endarterectomy in octogenarians and nonagenarians to younger patients from the Mid-America Vascular Study Group and the Society for Vascular Surgery Vascular Quality Initiative.

OBJECTIVE: Carotid endarterectomy (CEA) reduces stroke risk in selected patients. However, CEA risk profile may be different in older patients. We compared characteristics and outcomes of octogenarians and nonagenarians with those of younger patients. METHODS: Deidentified data from CEA patients were obtained from the Society for Vascular Surgery Vascular Quality Initiative (VQI) database. Prior CEA, carotid artery stent, or combined CEA and coronary artery bypass were excluded, yielding 7390 CEAs in octogenarians and nonagenarians (≥80 years of age) and 35,303 CEAs in younger patients (<80 years of age). We compared post-CEA outcomes, including periprocedural cerebral ischemic events and death, and details such as operative time, bleeding, and return to surgery. RESULTS: Octogenarians and nonagenarians were more likely to have pre-CEA neurologic symptoms (51.4% vs 45.6%; P < .001) and to have never smoked (37.8% vs 22.0%; P < .001), and they were slightly more likely to have required urgent CEA (16.1% vs 13.4%; P < .001). Stenosis ≥70% was similar (octogenarians and nonagenarians, 94.2%; younger patients, 94.4%; P = .45). Perioperative ipsilateral neurologic events and ipsilateral stroke were slightly more common among octogenarians and nonagenarians (1.6% vs 1.1% [P < .001] and 1.2% vs 0.8% [P = .002]). Multivariate modeling (logistic regression) showed that pre-CEA neurologic symptoms (odds ratios, 1.35 [P = .005] and 1.42 [P = .007]), pre-CEA ipsilateral cortical ischemic event (odds ratios, 1.18 [P < .001] and 1.20 [P < .001]), and urgency (odds ratios, 1.75 [P < .001] and 1.67 [P < .001]) remained strong predictors of any ipsilateral neurologic event and any ipsilateral stroke, respectively. However, age ≥80 years remained a significant predictor of these outcomes (odds ratios, 1.37 [P = .003] and 1.44 [P = .004]). Kaplan-Meier estimated survival was lower for octogenarians and nonagenarians at 30 days and 1 year (98.6% vs 99.4% and 93.7% vs 97.0%; log-rank, P < .001). Age ≥80 years was also associated with a greater rate of discharge to other than home after CEA, a difference that was only partially explained by comorbidities in multivariate modeling. CONCLUSIONS: CEA was performed with low rates of perioperative neurologic events and mortality. Multivariate testing showed that the higher rate of neurologic complications in octogenarians and nonagenarians appeared partially related to symptomatic status and urgent surgery; but after adjusting for these factors, age ≥80 years still predicted a slightly higher rate. Periprocedural CEA outcomes appear similar in comparing older and younger patients, although longer term survival is lower for older patients, and older patients are at greater risk of discharge to other than home. CEA was associated with slightly higher risk of neurologic complications in older patients but may be considered appropriate for selected octogenarians and nonagenarians.

A comparison of results with eversion versus conventional carotid endarterectomy from the Vascular Quality Initiative and the Mid-America Vascular Study Group.

OBJECTIVE: Carotid endarterectomy (CEA) is usually performed with eversion (ECEA) or conventional (CCEA) technique. Previous studies report conflicting results with respect to outcomes for ECEA and CCEA. We compared patient characteristics and outcomes for ECEA and CCEA. METHODS: Deidentified data for CEA patients were obtained from the Society for Vascular Surgery Vascular Quality Initiative (SVS VQI) database for years 2003 to 2013. Second (contralateral) CEA, reoperative CEA, CEA after previous carotid stenting, or CEA concurrent with cardiac surgery were excluded, leaving 2365 ECEA and 17,155 CCEA for comparison. Univariate analysis compared patients, procedures, and outcomes. Survival analysis was also performed for mortality. Multivariate analysis was used selectively to examine the possible independent predictive value of variables on outcomes. RESULTS: Groups were similar with respect to sex, demographics, comorbidities, and preoperative neurologic symptoms, except that ECEA patients tended to be older (71.3 vs 69.8 years; P < .001). CCEA was more often performed with general anesthesia (92% vs 80%; P < .001) and with a shunt (59% vs 24%; P < .001). Immediate perioperative ipsilateral neurologic events (ECEA, 1.3% vs CCEA, 1.2%; P = .86) and any ipsilateral stroke (ECEA, 0.8% vs CCEA, 0.9%; P = .84) were uncommon in both groups. ECEA tended to take less time (median 99 vs 114 minutes; P < .001). However, ECEA more often required a return to the operating room for bleeding (1.4% vs 0.8%; P = .002), a difference that logistic regression analysis showed was only partly explained by differential use of protamine. Life-table estimated 1-year freedom from any cortical neurologic event was similar (96.7% vs 96.7%). Estimated survival was similar comparing ECEA with CCEA at 1 year (96.7% vs 95.9%); however, estimated survival tended to decline more rapidly in ECEA patients after ∼2 years. Cox proportional hazards modeling confirmed that independent predictors of mortality included age, coronary artery disease, chronic obstructive pulmonary disease, and smoking, but also demonstrated that CEA type was not an independent predictor of mortality. The 1-year freedom from recurrent stenosis >50% was lower for ECEA (88.8% vs 94.3%, P < .001). However, ECEA and CCEA both had a very high rate of freedom from reoperation at 1 year (99.5% vs 99.6%; P = .67). CONCLUSIONS: ECEA and CCEA appear to provide similar freedom from neurologic morbidity, death, and reintervention. ECEA was associated with significantly shorter procedure times. Furthermore, ECEA obviates the expenses, including increased operative time, associated with use of a patch in CCEA, and a shunt, more often used in CCEA in this database. These potential benefits may be reduced by a slightly greater requirement for early return to the operating room for bleeding.

Do kids with forearm fractures need opioids at discharge from the emergency department? Analgesic prescribing and pain control following closed reduction of pediatric forearm fractures.

Objective: The purpose of this 2-part study is to determine opioid prescribing patterns and opioid use and pain control after discharge following closed reduction of pediatric forearm fractures. Methods: A retrospective study was conducted from December 2016 to January 2018 at a level 1 trauma center to determine opioid prescribing habits for patients 1-17 years old with forearm fractures treated with closed reduction. A prospective study was then conducted from August 2019 to October 2020 to determine pain control and opioid use after discharge. Data were collected through chart review and with telephone surveys on post-discharge days 1, 3, and 5 to collect pain scores and opioid use. Results: Fifty patients with a median age of 8 (interquartile range [IQR], 5-11) years old and 51 patients with a mean age of 9 (IQR, 6-11) years old were included in the retrospective and prospective cohorts, respectively. From the retrospective study, 21 patients (42%) were prescribed a median of 10 opioid doses (IQR, 8-12) at discharge. From the prospective study, 12 patients (24%) were discharged with a median of 8 opioid doses (IQR, 5.5-10), for a total of 98 total doses. Of those, only 7 doses (7%) were used by 3 patients. Higher weight and initial pain score were associated with increased rates of opioid prescription. Conclusions: Pediatric patients who undergo closed reduction of a forearm fracture under procedural sedation in the emergency department are prescribed approximately 14 times the amount of opioid that is used. We propose that prescribing only non-opioid analgesics to these patients would afford equivalent pain control without the side-effects and abuse potential of opioid use at an early age.

Improving communication of critical test results in a pediatric academic setting: key lessons in achieving and sustaining positive outcomes.

By applying the Institute for Healthcare Improvement's framework for strategic change (will, ideas and execution), The Hospital for Sick Children, in Toronto, Ontario, developed processes to improve patient safety through the effective communication of critical test results. In response to an adverse patient event, near misses and accreditation requirements, a task force with representatives from the laboratories and clinical services was established to ensure the timely and reliable communication of critical test results for biochemistry, hematology, coagulation, therapeutic drug monitoring and microbiology. The task force critically assessed processes and best practices, identified practical alternatives, tested changes, codified new processes in a hospital-wide policy and procedure and carried out post-implementation outcome audits. Lessons learned in sustaining improvements included the following: there is value in identifying strategies from a larger system perspective; there exist merits to working collaboratively as an inter-professional team (i.e., laboratory and clinical leaders); there is value in learning from failure; higher-cost but "higher-leverage" approaches can be pivotal; and regular monitoring and vigilance of policy compliance are required.

An Ambulatory Antimicrobial Stewardship Initiative to Improve Diagnosis and Treatment of Urinary Tract Infections in Children.

BACKGROUND: Antibiotic stewardship efforts should standardize treatment of common infections when possible. Urinary tract infections (UTIs) are common in children and require appropriate diagnostic methods and treatment. A pediatric emergency department (ED) identified an opportunity to improve care by standardizing uncomplicated UTI diagnostic testing and treatment according to local bacterial resistance patterns from January 2017 to December 2018. METHODS: Using the Model for Improvement, researchers undertook a quality improvement (QI) initiative to standardize the diagnosis and treatment of uncomplicated UTI in children ages 3 months to 12 years in a pediatric ED. Multiple Plan-Do-Study-Act (PDSA) cycles were used, engaging both nurses and physicians, to implement an evidence-based clinical algorithm. Primary aims were to achieve 100% of targeted patients with suspected UTI having appropriately ordered and collected specimens and to increase the frequency of targeted patients receiving algorithm-recommended antibiotics at discharge to 80%. Balancing measures included ED length of stay and revisits to the ED related to UTI. RESULTS: During this initiative, 458 children were assessed for UTI, of whom 75 received a UTI diagnosis. Guideline-concordant urine collection procedure improved from 54.7% to 96.2%. After project initiation, 100% of all antibiotic prescriptions for UTI were guideline-concordant. These changes have been sustained for 19 months since the initiative began. There was no change in UTI-related ED revisits or ED length of stay. CONCLUSIONS: This QI initiative achieved standardization of specimen collection and treatment for pediatric UTI in the ED setting, and no adverse outcomes were observed at the institution.

Effect of sympathectomy and demedullation on increased myenteric and dorsal vagal complex Fos-like immunoreactivity by cholecystokinin-8.

Chemical sympathectomy with daily, intraperitoneal (IP) injections of guanethidine sulfate to adult rats, attenuated myenteric, but not dorsal vagal complex (DVC) Fos-like immunoreactivity (Fos-LI) by cholecystokinin-8 (CCK). This technique destroys only 60-70% of the sympathetic neurons, and spares the hormonal source of catecholamines, the adrenal medulla. The goal of the current study is to evaluate the effect of complete sympathectomy or destroying 100% of the sympathetic neurons by injecting guanethidine to 1-day-old pups (40 mg/kg daily for 5 weeks), and surgically removing the adrenal medulla. In the DVC, demedullation and sympathectomy-demedullation increased Fos-LI by CCK in the area postrema and nucleus of the solitary tract, but sympathectomy-demedullation increased it only in the area postrema. In the myenteric plexus, sympathectomy increased this response in the duodenum, and demedullation increased it in the duodenum and jejunum. On the other hand, sympathectomy-demedullation attenuated myenteric Fos-LI in the jejunum. These results indicate that catecholamines may play an inhibitory role on the activation of the DVC neurons by CCK. In the myenteric neurons, however, catecholamines may have both inhibitory and excitatory roles depending on the level of the intestine e.g., duodenum vs. jejunum. This may also indicate that CCK activates the enteric neurons by different mechanisms or through different pathways.

Effect of adrenalectomy on cholecystokinin-8-induced Fos-like immunoreactivity in myenteric neurons and the dorsal vagal complex in rats.

OBJECTIVE: To investigate the effect of adrenalectomy on cholecystokinin-8 (CCK-8)-induced Fos-like immunoreactivity (Fos-LI) in the myenteric neurons of the dorsal vagal complex (DVC) in rats. ANIMALS: 16 male Sprague Dawley rats. PROCEDURES: Rats were allocated to 1 of 2 groups and underwent adrenalectomy or a sham adrenalectomy procedure. Rats were challenged with a supraphysiologic dose of CCK-8 (40 microg/kg) or physiologic saline (0.9% NaCl) solution (0.5 mL) administered IP; after 90 minutes, rats were euthanized, and Fos-LI was quantified in the DVC (at the levels of the area postrema, nucleus tractus solitarii, and dorsal motor nucleus of the vagus) and the myenteric neurons of the duodenum and jejunum by use of a diaminobenzidine reaction enhanced with nickel. The Fos-LI-positive cells were counted by use of an automated system and manually in the DVC and intestinal samples, respectively. Counts of Fos-LI in the different hindbrain levels and myenteric neurons were compared between the adrenalectomy--and shamtreated groups and between the CCK-8- and saline solution-treated groups. RESULTS: After adrenalectomy, CCK-8-induced Fos-LI was attenuated only in the myenteric neurons of the duodenum. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that the adrenal gland has a role in the activation of myenteric neurons by CCK-8 in rats.

Resting energy expenditure in the parenterally fed pediatric population with Crohn's disease.

BACKGROUND: Malnutrition is a common sequela of Crohn's disease (CD) and may result in reduced skeletal muscle function and growth retardation. Energy requirements of parenterally fed hospitalized pediatric patients with active CD were measured using indirect calorimetry, to assess whether Food Agriculture Organization (FAO)/World Health Organization (WHO)/United Nations University (UNU) equations provide appropriate estimations of energy requirements in this patient population. METHODS: Twenty hospitalized patients with active CD fed exclusively via parenteral nutrition (PN) were investigated. A chart review and patient interviews were conducted to assess disease duration, location, laboratory parameters, and symptomology associated with CD. Disease severity was quantified using the Pediatric Crohn's Disease Activity Index. Each subject underwent indirect calorimetry, bioelectrical impedance analysis, and anthropometric assessment once the ordered PN met estimated macronutrient requirements of each patient (predicted resting energy expenditure x1.3). Predicted resting energy expenditure (REE) was determined using the FAO/WHO/UNU equations. RESULTS: REE showed a strong correlation with predicted REE (r(2) = .73, p < .01). CONCLUSIONS: Measured REE did not significantly differ from predicted resting energy requirements. This indicates that REE for the parenterally fed pediatric patients with CD can be accurately predicted using the FAO/WHO/UNU equations.

Decreasing time to antibiotics in febrile patients with central lines in the emergency department.

BACKGROUND AND OBJECTIVE: Rapid antibiotic administration is essential for the successful management of patients who have central lines and present with fever. We conducted an emergency department (ED) improvement initiative to deliver antibiotics to 90% of patients within 60 minutes and to minimize process variation. METHODS: Our setting was an academic ED. We assembled a multidisciplinary team, identified contributing factors to the care delivery problem, determined key drivers and intervention steps, implemented changes, and used strategies to engage ED staff and promote sustainability. Outcomes were analyzed by using a time series design with baseline data and continuous postintervention monitoring. Outcomes included percentage of patients receiving antibiotics within 60 minutes, time to antibiotic administration, and accuracy for triage acuity and chief complaint. RESULTS: An 8-month baseline period revealed that 63% of patients received antibiotics within 60 minutes of arrival, with a mean time to antibiotics of 65 minutes. Multiple Plan-Do-Study-Act (PDSA) cycles were used to improve patient identification and initial management processes. The percentage of patients receiving antibiotics within 60 minutes of arrival was increased to 99% (297 of 301), and mean time to administration decreased to 30 minutes (95% confidence interval: 28-32). These gains were sustained for 24 months. Subanalysis identified a racial discrepancy, with African American patients experiencing significantly longer delays than patients of other races (95 vs 61 minutes; P < .05); this discrepancy was eliminated with our initiative. CONCLUSIONS: Our initiative exceeded our goal of 90% antibiotic delivery within 60 minutes for a sustained period of at least 24 months, decreased process variation and mean time to antibiotic administration, and eliminated race-based discrepancies in care.

Intramuscular immunization with poliovirus replicons primes for a humoral and cellular immune response to soluble antigen.

Vaccines that stimulate both cellular and humoral immunity will probably be needed to control many infectious diseases. Previously, our laboratory generated a vaccine vector that uses poliovirus genomes (replicons) in which the capsid genes have been replaced by foreign proteins. In the current study, we have evaluated the immune responses induced by immunization using poliovirus replicons encoding green fluorescent protein (GFP). Although intramuscular administration of replicons resulted in GFP expression in the muscle, the levels of anti-GFP antibodies in serum were low compared to those of mice immunized with soluble, recombinant GFP (rGFP). Intramuscular booster immunization with rGFP in animals primed with replicons encoding GFP resulted in production of both serum IgG1 and IgG2a GFP-specific antibodies. The cells isolated from spleens of animals primed with replicons and boosted with rGFP secreted IFN-gamma after in vitro stimulation with rGFP. Intramuscular immunization of animals with a single dose of replicons encoding GFP followed by two intranasal applications of rGFP resulted in serum GFP-specific IgG1 and IgG2a isotypes, consistent with induction of both humoral and cellular responses. The results of this study establish that immunization with replicons followed by boost with soluble antigen, even at a different site, can generate a more diverse immune response compared with immunization regimen using soluble antigen alone. This strategy could be exploited for the development of new vaccine approaches against infectious diseases.

Patterns of pain descriptor usage in African Americans and European Americans with chronic pain.

This study examined ethnic differences in the use of pain descriptors, comparing standardized pain assessment data from African American and European American patients with heterogeneous chronic pain syndromes. The measure was the Short-Form McGill Pain Questionnaire (SF-MPQ) including the embedded Visual Analog Scale (VAS). Exploratory factor analyses of SF-MPQ data identified differences in factor structure with the VAS loading on a different factor for each group. A 5-factor solution was obtained from the African American group and a 4-factor solution was obtained from the European American group. There was little overlap in the pattern matrices for African American and European American groups. Results suggest that the VAS is as sensitive to ethnic differences as other traditional pain measures.

Using screen-based simulation to improve performance during pediatric resuscitation.

OBJECTIVES: To assess the ability of a screen-based simulation-training program to improve emergency medicine and pediatric resident performance in critical pediatric resuscitation knowledge, confidence, and skills. METHODS: A pre-post, interventional design was used. Three measures of performance were created and assessed before and after intervention: a written pre-course knowledge examination, a self-efficacy confidence score, and a skills-based high-fidelity simulation code scenario. For the high-fidelity skills assessment, independent physician raters recorded and reviewed subject performance. The intervention consisted of eight screen-based pediatric resuscitation scenarios that subjects had 4 weeks to complete. Upon completion of the scenarios, all three measures were repeated. For the confidence assessment, summary pre- and post-test summary confidence scores were compared using a t-test, and for the skills assessment, pre-scores were compared with post-test measures for each individual using McNemar's chi-square test for paired samples. RESULTS: Twenty-six of 35 (71.3%) enrolled subjects completed the institutional review board-approved study. Increases were observed in written test scores, confidence, and some critical interventions in high-fidelity simulation. The mean improvement in cumulative confidence scores for all residents was 10.1 (SD +/-4.9; range 0-19; p < 0.001), with no resident feeling less confident after the intervention. Although overall performance in simulated codes did not change significantly, with average scores of 6.65 (+/-1.76) to 7.04 (+/-1.37) out of 9 possible points (p = 0.58), improvement was seen in the administering of appropriate amounts of IV fluids (59-89%, p = 0.03). CONCLUSIONS: In this study, improvements in resident knowledge, confidence, and performance of certain skills in simulated pediatric cardiac arrest scenarios suggest that screen-based simulations may be an effective way to enhance resuscitation skills of pediatric providers. These results should be confirmed using a randomized design with an appropriate control group.

Enhanced functional recovery from spinal cord injury following intrathecal or intramuscular administration of poliovirus replicons encoding IL-10.

Poliovirus-based vectors (replicons) have been shown to maintain the in vitro tropism of poliovirus for motor neurons of the CNS. To determine if replicons could be effective for delivery of potentially beneficial proteins to the CNS, we have constructed and characterized a replicon encoding IL-10. IL-10 was rapidly produced in tissue culture cells following in vitro infection with replicons encoding IL-10. Intrathecal inoculation of replicons encoding IL-10 into the non-injured CNS of mice transgenic for the poliovirus receptor resulted in expression of IL-10 within motor neurons at 24-48 h post-inoculation, which subsided by 72-96 h post-inoculation. Single intrathecal or intramuscular injections of replicons were given following spinal cord trauma. Animals receiving replicons encoding IL-10 demonstrated a greater functional recovery in the first 24 h after injury that was maintained throughout the testing period. Compared to animals given replicons encoding gfp, CNS tissue from animals given replicons encoding IL-10 revealed extensive expression of IL-10 from astrocytes around the CNS lesion during the first week following injury. The expression of IL-10 from astrocytes also correlated with more resting microglia as opposed to the rounded activated microglia seen in animals given replicons encoding gfp. Results of these studies establish that replicons can be used to express biologically active molecules in motor neurons of the CNS and these biologically active molecules can have a direct effect on the CNS or induce a cascade of molecules that can influence the cellular composition and activation state of cells within the CNS.

Gene expression in the muscle and central nervous system following intramuscular inoculation of encapsidated or naked poliovirus replicons.

The spread of intramuscularly inoculated poliovirus to the central nervous system (CNS) has been documented in humans, monkeys, and mice transgenic for the human poliovirus receptor. Poliovirus spread is thought to be due to infection of the peripheral nerve and retrograde transport of poliovirus through the axon to the neuron cell body, where final virus uncoating occurs and translation/replication ensues. In previous studies, we have shown that polio-based vectors (replicons) can be used for gene delivery to motor neurons of the CNS. Using a replicon that encodes green fluorescent protein (GFP), we found that following intrathecal inoculation, GFP expression was confined to motorneurons of the spinal cord. To further characterize the gene expression of poliovirus in the periphery and CNS, we have intramuscularly inoculated transgenic mice with poliovirus replicons encoding GFP. Expression of GFP was demonstrated in the muscle, sciatic nerve, dorsal root ganglion, and the ventral horn motorneurons following intramuscular inoculation. There was no evidence of paralysis or behavioral abnormalities in the mice following intramuscular inoculation of the replicon encoding GFP. Injection of replicon RNA alone (naked RNA) into the muscle of transgenic mice or rats, which do not express the poliovirus receptor, also resulted in expression of GFP in the muscle, sciatic nerve, dorsal root ganglion, and ventral horn motorneurons, indicating that transport of the replicon RNA from the periphery to CNS had occurred. GFP expression was found in the muscles and sciatic nerve as early as 6 h after injection of replicons or replicon RNA, even after sciatic nerve section. Analysis at longer times postinjection revealed GFP expression similar to 6 h levels in the cut sciatic nerves and robust expression in the nerves of uncut animals. The infection and expression of GFP in the CNS following intramuscular inoculation of encapsidated replicons encoding GFP occurred in juvenile or adult animals. The expression of GFP in the CNS of juvenile animals was more intense and lasted for up to 5 weeks, in contrast to the duration of expression of approximately 96 h for adult animals. The results of these studies establish that poliovirus replicon RNA is expressed locally within the sciatic nerve and transported from the periphery to the CNS via axonal transport and support the potential of replicons for gene delivery to the CNS.

Evaluation of a new transcutaneous bilirubinometer.

OBJECTIVE: The objective of this study was to evaluate the Minolta/Hill-Rom Air-Shields Transcutaneous Jaundice Meter model JM-103. METHODS: We studied a convenience sample of 849 newborns > or =35 weeks of gestation in 3 hospitals. These infants had total serum bilirubin (TSB) levels measured on clinical indication, and transcutaneous bilirubin (TcB) levels were obtained within 1 hour of the TSB levels. The population was 59.2% white, 29.8% black, 4.5% East Asian, 3.8% Middle Eastern, 1.6% Indian/Pakistani, and 1.1% Hispanic. RESULTS: There was a close correlation between TSB and TcB values in all of the population groups: white (n = 503, r =.949); black (n = 253, r =.822); and East Asian, Indian/Pakistani, and Hispanic (n = 93, r =.926). In the black population, the correlation was less close than in the other groups, and differences between the TcB and TSB measurements tended to increase with rising TSB values. JM-103 values differed from TSB values by 3 mg/dL or more in 2% of white, 3.2% of other, and 17.4% of black infants. In these black infants, the JM-103 value was always greater than the TSB value. CONCLUSIONS: We conclude that TcB measurements using the JM-103 jaundice meter correlate very closely with TSB levels over the range of TSB encountered in this study. Because only 3.3% of our infants had TSB values >15 mg/dL (257 micro mol/L), more data are needed in this range of TSB concentration. The correlation in black infants is not as close as in other groups, but because the tendency in blacks is for the JM-103 to overestimate serum bilirubin levels, dangerous clinical errors are unlikely to occur. The measurement technique is rapid and simple, and it is easy to perform repeated measurements over time, thus reducing the likelihood of error. TcB measurements with the JM-103 jaundice meter should obviate the need for most serum bilirubin levels in newborn infants > or =35 weeks of gestation, although serum bilirubin measurements are still required when treatment with phototherapy or exchange transfusion is being considered.

Long-term potency after iodine-125 radiotherapy for prostate cancer and role of sildenafil citrate.

OBJECTIVES: To assess the long-term sexual potency and attrition in sexual function after iodine-125 ((125)I) seed radiotherapy and the effect of sildenafil on radiation-induced erectile dysfunction (ED). METHODS: This prospective study consisted of 86 sexually active patients (mean age 63.5 +/- 7.7 years) who underwent (125)I seed implantation from 1997 to 1999 to treat low-volume prostate cancer (prostate-specific antigen less than 10 ng/mL, Gleason score 6 or less, stage T1-T2). All patients were followed up every 6 to 8 months for 4 years. Patients prescribed sildenafil citrate for ED completed the abridged five-item version of the International Index of Erectile Function (IIEF) and the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaires. RESULTS: The median follow-up was 49.7 months (range 36 to 66). Of 86 patients, 43 (50%) did not initiate drug therapy; and only 36 (83.7%) of the 43 were interviewed at 4 years. Twenty-three (63.8%) of the 36 patients had erections sufficient for vaginal penetration, with a total mean +/- SD IIEF-5 score of 15.76 +/- 1.13. The other 50% (43 of 86) initiated sildenafil citrate for treatment of ED after seed implantation, with a minimal follow-up of 6 months. At 4 years, 32 (74%) of the 43 were responding positively to sildenafil citrate, with a total IIEF-5 score of 18.3 +/- 1.2. The mean EDITS +/- SD score was 76.5 +/- 3.2, and the spousal satisfaction rate was 72% (31 of 43). The dropout rate was 37% (16 of 43); 10 (63%) of the 16 discontinued because of a lack of efficacy, 3 (19%) because of a return of natural erections sufficient for vaginal penetration, and 3 (19%) discontinued because of side effects (headaches). CONCLUSIONS: ED is a major long-term issue after (125)I seed radiotherapy, with a long-term potency rate of 29%. Sildenafil citrate improves erections in most patients after (125)I seed implantation.