The Predictors of Complete Pathologic Response in Rectal Cancer during the Total Neoadjuvant Therapy Era: A Systematic Review.

The modern rectal cancer treatment paradigm offers additional opportunities for organ preservation, most notably via total neoadjuvant therapy (TNT) and consideration for a watch-and-wait (WW) surveillance-only approach. A major barrier to widespread implementation of a WW approach to rectal cancer is the potential discordance between a clinical complete response (cCR) and a pathologic complete response (pCR). In the pre-TNT era, the identification of predictors of pCR after neoadjuvant therapy had been previously studied. However, the last meta-analysis to assess the summative evidence on this important treatment decision point predates the acceptance and dissemination of TNT strategies. The purpose of this systematic review was to assess preoperative predictors of pCR after TNT to guide the ideal selection criteria for WW in the current era. An exhaustive literature review was performed and the electronic databases Embase, Ovid, MEDLINE, PubMed, and Cochrane were comprehensively searched up to 27 June 2023. Search terms and their combinations included "rectal neoplasms", "total neoadjuvant therapy", and "pathologic complete response". Only studies in English were included. Randomized clinical trials or prospective/retrospective cohort studies of patients with clinical stage 2 or 3 rectal adenocarcinoma who underwent at least 8 weeks of neoadjuvant chemotherapy in addition to chemoradiotherapy with pCR as a measured study outcome were included. In this systematic review, nine studies were reviewed for characteristics positively or negatively associated with pCR or tumor response after TNT. The results were qualitatively grouped into four categories: (1) biochemical factors; (2) clinical factors; (3) patient demographics; and (4) treatment sequence for TNT. The heterogeneity of studies precluded meta-analysis. The level of evidence was low to very low. There is minimal data to support any clinicopathologic factors that either have a negative or positive relationship to pCR and tumor response after TNT. Additional data from long-term trials using TNT is critical to better inform those considering WW approaches following a cCR.

More problems, more money: Identifying and predicting high-cost rescue after colorectal surgery.

Background: Successful rescue after elective surgery is associated with increased healthcare costs, but costs vary widely. Treating all rescue events the same may overlook targeted opportunities for improvement. The purpose of this study was to predict high-cost rescue after elective colorectal surgery. Methods: We identified adult patients in the National Inpatient Sample (2016-2021) who underwent elective colectomy or proctectomy. Rescued patients were defined as those who underwent additional major procedures. Three groups were stratified: 1) uneventful recovery; 2) Low-cost rescue; 3) High-cost rescue. Multivariable Poisson regression was used to identify preoperative clinical predictors of high-cost versus low-cost rescue. Results: We identified 448,590 elective surgeries, and rescued patients composed 4.8 %(21,635) of the total sample. The median increase in costs in rescued patients was $25,544(p < 0.001). Median total inpatient costs were $95,926 in the most expensive rescued versus $34,811 in the less expensive rescued versus $16,751 in the uneventfully discharged(p < 0.001). When comparing the secondary procedures between the less expensive and most expensive rescued groups, the most expensive had an increased proportion of reoperation (73.4 % versus 53.0 %,p < 0.001). When controlling for other factors and stratification by congestive heart failure due to an interaction effect, a reoperation was independently associated with high-cost rescue (RR with CHF = 3.29,95%CI:2.69-4.04; RR without CHF = 2.29,95%CI:1.97-2.67). Conclusions: High-cost rescue after colorectal surgery is associated with disproportionately greater healthcare utilization and reoperation. For cost-conscious care, preemptive strategies that reduce reoperation-related complications can be prioritized.

How Far Is Too Far? Cost-Effectiveness Analysis of Regionalized Rectal Cancer Surgery.

BACKGROUND: Regionalized rectal cancer surgery may decrease postoperative and long-term cancer-related mortality. However, the regionalization of care may be an undue burden on patients. OBJECTIVE: This study aimed to assess the cost-effectiveness of regionalized rectal cancer surgery. DESIGN: Tree-based decision analysis. PATIENTS: Patients with stage II/III rectal cancer anatomically suitable for low anterior resection were included. SETTING: Rectal cancer surgery performed at a high-volume regional center rather than the closest hospital available. MAIN OUTCOME MEASURES: Incremental costs ($) and effectiveness (quality-adjusted life year) reflected a societal perspective and were time-discounted at 3%. Costs and benefits were combined to produce the incremental cost-effectiveness ratio ($ per quality-adjusted life year). Multivariable probabilistic sensitivity analysis modeled uncertainty in probabilities, costs, and effectiveness. RESULTS: Regionalized surgery economically dominated local surgery. Regionalized rectal cancer surgery was both less expensive on average ($50,406 versus $65,430 in present-day costs) and produced better long-term outcomes (10.36 versus 9.51 quality-adjusted life years). The total costs and inconvenience of traveling to a regional high-volume center would need to exceed $15,024 per patient to achieve economic breakeven alone or $112,476 per patient to satisfy conventional cost-effectiveness standards. These results were robust on sensitivity analysis and maintained in 94.6% of scenario testing. LIMITATIONS: Decision analysis models are limited to policy level rather than individualized decision-making. CONCLUSIONS: Regionalized rectal cancer surgery improves clinical outcomes and reduces total societal costs compared to local surgical care. Prescriptive measures and patient inducements may be needed to expand the role of regionalized surgery for rectal cancer. See Video Abstract at http://links.lww.com/DCR/C83 . QU TAN LEJOS ES DEMASIADO LEJOS ANLISIS DE COSTOEFECTIVIDAD DE LA CIRUGA DE CNCER DE RECTO REGIONALIZADO: ANTECEDENTES:La cirugía de cáncer de recto regionalizado puede disminuir la mortalidad posoperatoria y a largo plazo relacionada con el cáncer. Sin embargo, la regionalización de la atención puede ser una carga indebida para los pacientes.OBJETIVO:Evaluar la rentabilidad de la cirugía oncológica de recto regionalizada.DISEÑO:Análisis de decisiones basado en árboles.PACIENTES:Pacientes con cáncer de recto en estadio II/III anatómicamente aptos para resección anterior baja.AJUSTE:Cirugía de cáncer rectal realizada en un centro regional de alto volumen en lugar del hospital más cercano disponible.PRINCIPALES MEDIDAS DE RESULTADO:Los costos incrementales ($) y la efectividad (años de vida ajustados por calidad) reflejaron una perspectiva social y se descontaron en el tiempo al 3%. Los costos y los beneficios se combinaron para producir la relación costo-efectividad incremental ($ por año de vida ajustado por calidad). El análisis de sensibilidad probabilístico multivariable modeló la incertidumbre en las probabilidades, los costos y la efectividad.RESULTADOS:La cirugía regionalizada predominó económicamente la cirugía local. La cirugía de cáncer de recto regionalizado fue menos costosa en promedio ($50 406 versus $65 430 en costos actuales) y produjo mejores resultados a largo plazo (10,36 versus 9,51 años de vida ajustados por calidad). Los costos totales y la inconveniencia de viajar a un centro regional de alto volumen necesitarían superar los $15,024 por paciente para alcanzar el punto de equilibrio económico o $112,476 por paciente para satisfacer los estándares convencionales de rentabilidad. Estos resultados fueron sólidos en el análisis de sensibilidad y se mantuvieron en el 94,6% de las pruebas de escenarios.LIMITACIONES:Los modelos de análisis de decisiones se limitan al nivel de políticas en lugar de la toma de decisiones individualizada.CONCLUSIONES:La cirugía de cáncer de recto regionalizada mejora los resultados clínicos y reduce los costos sociales totales en comparación con la atención quirúrgica local. Es posible que se necesiten medidas prescriptivas e incentivos para los pacientes a fin de ampliar el papel de la cirugía regionalizada para el cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/C83 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Does Preoperative Calcium and Calcitriol Decrease Rates of Post-Thyroidectomy Hypocalcemia? A Randomized Clinical Trial.

BACKGROUND: Postoperative hypocalcemia is the most common complication after thyroidectomy. Postoperative supplementation with calcium and calcitriol reduces its occurrence; however, prophylactic preoperative supplementation has not been studied systematically. The primary objective of this study was to determine whether pre- and postoperative calcium and calcitriol supplementation reduces postoperative hypocalcemia after total thyroidectomy compared with postoperative supplementation alone. STUDY DESIGN: We conducted a single-institution prospective randomized trial enrolling 82 patients undergoing total thyroidectomy from July 2017 through May 2019. Those undergoing partial thyroidectomy or concurrent planned parathyroidectomy were excluded. The intervention group started calcitriol 0.25 µg po bid and calcium carbonate 1,500 mg po tid 5 days preoperatively and continued postoperatively. The control group started these medications postoperatively. The primary end point was clinical or biochemical hypocalcemia. Secondary outcomes were postoperative calcium levels, need for intervention, length of stay, and readmission. RESULTS: Thirty-eight patients were randomized to the intervention group and 44 to the control group. There were 12 episodes of hypocalcemia; 5 (13.2%) in the intervention and 7 (15.9%) in the control group (p = 0.76). No differences were found in secondary outcomes; including postoperative calcium levels at each measured time point, need for intervention (n = 10 [26.3%], n = 15 [34.1%]; p = 0.48), length of stay (mean [SD] 32.3 [15.6] hours, 30.7 [10.5] hours; p = 0.6), or readmissions (n = 0 [0.0%], n = 3 [6.8%]; p = 0.24). CONCLUSIONS: Starting supplementation with calcium and calcitriol preoperatively does not reduce postoperative hypocalcemia compared with postoperative supplementation alone after total thyroidectomy. These findings do not support the practice of routine calcium and calcitriol supplementation before total thyroidectomy.

Has National Colorectal Cancer Awareness Month increased endoscopy screening rates and public interest in colorectal cancer?

BACKGROUND: National Colorectal Cancer Awareness Month occurs each March to promote awareness and screening for colorectal cancer. The effectiveness of this public health campaign is unknown. The aim of this study was to determine the impact of National Colorectal Cancer Awareness Month on rates of screening endoscopies and on public interest in colorectal cancer. METHODS: To examine the impact of National Colon Cancer Awareness Month on screening endoscopy rates, the National Endoscopy Database was retrospectively reviewed from 2002 through 2014. A time series of monthly number of colorectal cancer screening endoscopies per endoscopist in the data set was evaluated. To examine public interest in colorectal cancer, Google Trends data were collected on the monthly rates of terms related to colorectal cancer from January 2004 to July 2019. Impact of the month on screening endoscopies and public interest was assessed through an analysis of variance. Seasonality was tested for by how well a sinusoidal model fit the time series as opposed to a linear model utilizing a sum-of-squares F test. RESULTS: Review of National Endoscopy Database yielded 1,398,996 endoscopies, 94% were colonoscopies and 6% sigmoidoscopies, with 47% for colorectal cancer screening. Colorectal cancer screening endoscopy rates were not impacted by the month of the year, and these rates had no seasonality. However, Google searches related to colorectal cancer were significantly impacted by month of the year, specifically March, with significant seasonality observed in the data. CONCLUSIONS: National Colorectal Cancer Awareness Month is associated with an increased public interest in colorectal cancer based on user Google search trends. Yet, this has not translated into a demonstrable increase in the rates of screening. This presents an opportunity to capitalize on this increased public interest and harness this enthusiasm into increased screening.

Endoscopic Step Up: A Colon-Sparing Alternative to Colectomy to Improve Outcomes and Reduce Costs for Patients With Advanced Neoplastic Polyps.

BACKGROUND: The optimal strategy for colonic polyps not amenable to traditional endoscopic polypectomy is unknown. Endoscopic step up is a promising strategy for definitive treatment. OBJECTIVE: The purpose of this study was to determine whether endoscopic step up leads to improved outcomes and decreased costs compared with planned colectomy for endoscopically unresectable colon polyps. DESIGN: This was a retrospective review of a prospective database. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Consecutive patients referred for endoscopically unresectable colon polyps 15 to 50 mm in size were included. INTERVENTIONS: Patients underwent planned colectomy or endoscopic step up at the surgeon's discretion. Endoscopic step up began with diagnostic colonoscopy in the operating room. If the polyp was amenable to endoscopic removal, endoscopic mucosal resection or endoscopic submucosal dissection was performed with progression to combined endoscopic-laparoscopic surgery or laparoscopic colectomy, as indicated. MAIN OUTCOME MEASURES: The primary outcome was 30-day adverse events. We also examined length of stay, hospital charges, insurer payments, and polyp recurrence. RESULTS: A total of 52 patients underwent planned colectomy (48 laparoscopic), and 38 underwent endoscopic step up (28 endoscopic mucosal resection, 2 endoscopic submucosal dissection, 6 combined endoscopic-laparoscopic surgery, and 2 colectomy). Compared with planned colectomy, endoscopic step-up patients had fewer complications (13% vs 33%; p = 0.03) and shorter length of stay (median, 0 vs 4 d; p < 0.001). There was 1 readmission in the endoscopic step-up group and 5 in the planned colectomy group. Endoscopic step-up patients had lower hospital costs ($4790 vs $13,004; p < 0.001) and insurer payments ($2431 vs $19,951; p < 0.001). One-year polyp recurrence-free survival was 84% (95% CI, 67%-93%) in endoscopic step-up patients. All of the recurrences were benign, <1 cm, and managed endoscopically. LIMITATIONS: The study was limited by its nonrandomized design and short follow-up. CONCLUSIONS: An endoscopic step-up approach to colon polyps is associated with less morbidity, decreased healthcare costs, and colon preservation in 95% of patients. Additional studies are needed to evaluate long-term quality of life and polyp recurrence in this group. See Video Abstract at http://links.lww.com/DCR/B188. ENDOSCOPIC STEP UP: UNA ALTERNATIVA A COLECTOMíA PARA PRESERVACIóN DE COLON CON LOS PROPóSITOS DE MEJORAR RESULTADOS Y REDUCIR COSTOS EN PACIENTES CON PóLIPOS NEOPLáSICOS AVANZADOS: Se desconoce la estrategia óptima para los pólipos de colon no susceptibles a la polipectomia endoscópica tradicional. Endoscopic Step Up es una estrategia prometedora para el tratamiento definitivo.Determinar si Endoscopic Step Up produce mejores resultados y menores costos en comparación con la colectomía programada para pólipos de colon endoscópicamente no resecables.Revisión retrospectiva de una base de datos prospectiva.Centro de referencia de tercer nivel.Pacientes consecutivos remitidos para pólipos de colon endoscópicamente irresecables de tamaño 15-50 mm.Los pacientes se sometieron a colectomía programada o Endoscópico Step Up a discreción del cirujano. Endoscopic Step Up comenzó con una colonoscopia diagnóstica en el quirófano. Si el pólipo era susceptible de extirpación endoscópica, la resección endoscópica de la mucosa o la disección submucosa endoscópica se realizaba con progresión a cirugía endoscópica-laparoscópica combinada o colectomía laparoscópica, según a cosnideraciones clínicas en el transoperatorio.El resultado primario fue los eventos adversos a 30 días. Duración de la estadía hospitalaria, los cargos hospitalarios, los pagos de las aseguradoras y la recurrencia de pólipos también fueron examinados.Un total de 52 pacientes se sometieron a colectomía programada (48 laparoscópicas) y 38 se sometieron a Endoscopic Step Up (28 resección endoscópica de la mucosa, 2 disección submucosa endoscópica, 6 cirugía endoscópica-laparoscópica combinada y 2 colectomía). En comparación con la colectomía programada los pacientes endoscópicos Step Up tuvieron menos complicaciones (13% versus 33%, p = 0.03) y una estadía hospitalaria más corta (mediana 0 versus 4 días, p <0.001). Hubo 1 reingreso hospitalario en el grupo Endoscopic Step Up y 5 en el grupo de colectomía programada. Los pacientes endoscópicos Step Up tuvieron costos hospitalarios más bajos ($ 4,790 versus $ 13,004, p <0,001) y pagos de la aseguradora ($ 2,431 versus $ 19,951, p <0,001). La supervivencia libre de recurrencia de pólipos a un año fue del 84% (IC 95% 67-93) en pacientes endoscópicos Step Up. Todas las recurrencias fueron benignas, <1 cm, y manejadas endoscópicamente.Diseño no aleatorizado y seguimiento corto.El abordaje endoscópico Step Up para pólipos de colon se asocia con menos morbilidad, disminución de los costos de atención médica y preservación del colon en el 95% de los pacientes. Se ocupan más estudios para evaluar la calidad de vida a largo plazo y la recurrencia de pólipos en este grupo. Consulte Video Resumen en http://links.lww.com/DCR/B188. (Traducción-Dr Adrián Ortega Robles).

Should They Stay or Should They Go? The Utility of C-Reactive Protein in Predicting Readmission and Anastomotic Leak After Colorectal Resection.

BACKGROUND: Hospital readmission and anastomotic leak following colorectal resection have a negative impact on patients, surgeons, and the health care system. Novel markers of patients unlikely to experience these complications are of value in avoiding readmission. OBJECTIVE: This study aimed to determine the predictive value of C-reactive protein for readmission and anastomotic leak within 30 days following colorectal resection. DESIGN: This is a retrospective review of a prospectively compiled single-institution database. PATIENTS: From January 1, 2013, to July 20, 2017, consecutive patients undergoing elective colorectal resection with anastomosis without the presence of proximal intestinal stoma, who had C-reactive protein measured on postoperative day 3, were included. MAIN OUTCOME MEASURES: The primary outcome measured was the predictive value of C-reactive protein measured on postoperative day 3 for readmission or anastomotic leak within 30 days after colorectal resection. RESULTS: Of the 752 patients examined, 73 (10%) were readmitted within 30 days of surgery and 17 (2%) had an anastomotic leak. Mean C-reactive protein in patients who neither had an anastomotic leak nor were readmitted (127 ± 77 mg/L) was lower than for patients who were readmitted (157 ± 96 mg/L, p = 0.002) and lower than for patients who had an anastomotic leak (228 ± 123 mg/L, p = 0.0000002). The area under the receiver operating characteristic curve for the diagnostic accuracy of C-reactive protein for readmission was 0.59, with a cutoff value of 145 mg/L, generating a 93% negative predictive value. The area under the curve for the diagnostic accuracy of C-reactive protein for anastomotic leak was 0.76, with a cutoff value of 147 mg/L generating a 99% negative predictive value. LIMITATIONS: This study was limited by its retrospective design and because all patients were treated at a single center. CONCLUSIONS: Patients with a C-reactive protein below 145 mg/L on postoperative day 3 after colorectal resection have a low likelihood of readmission within 30 days, and a very low likelihood of anastomotic leak. See Video Abstract at http://links.lww.com/DCR/A761.

Inactivation of the infralimbic prefrontal cortex in rats reduces the influence of inappropriate habitual responding in a response-conflict task.

Previous research suggests the infralimbic cortex is important in situations when there is competition between goal-directed and habitual responding. Here we used a response conflict procedure to further explore the involvement of the infralimbic cortex in this relationship. Rats received training on two instrumental biconditional discriminations, one auditory and one visual, in two distinct contexts. One discrimination was "over-trained" relative to the other, "under-trained," discrimination in the ratio 3:1. At test, animals were presented with incongruent audiovisual stimulus compounds of the training stimuli in the under-trained context. The stimulus elements of these test compounds have previously dictated different lever press responses during training. Rats receiving control infusions into the infralimbic cortex showed a significant interference effect, producing more responses to the over-trained (habitual), but context-inappropriate, stimulus element of the incongruent compound. This interference effect was abolished by inactivation of the infralimbic cortex; animals showed a reduced tendency to produce the habitual but inappropriate response compared with animals receiving control infusions. This finding provides evidence that the infralimbic cortex is involved in attenuating the influence of goal-directed behavior, for example context-appropriate responding.

Contextual control of biconditional task performance: evidence for cue and response competition in rats.

A novel paradigm is presented that was designed to mimic aspects of cue and response competition seen in humans in conflict procedures such as the Stroop task. Rats were trained simultaneously on two biconditional discrimination tasks, one auditory and one visual, in two different contexts: C1, in which A1:LP1-->R, A2:LP2-->R; and C2, in which V1:LP1-->R, V2:LP2-->R, where C1/C2 represent different training contexts (produced by different operant chambers), A1/A2 are different auditory cues, V1/V2 are different visual cues, LP1/LP2 are discrete operant responses, and R is reward. At test, rats received presentations of audiovisual compounds of these training stimuli in extinction. These compounds had dictated either the same (A1V1 or A2V2) or different (A1V2 or A2V1) responses during training: termed congruent and incongruent trials, respectively. Experiment 1 showed that following equal training on the two biconditional tasks, the contextual cues came to control responding to conflicting information provided by incongruent stimulus compounds such that animals responded according to the stimulus element previously trained in that test context. Experiment 2 demonstrated that differential training on the biconditional discriminations (with rats receiving training on the two discriminations in the ratio 3:1) resulted in greater interference from the overtrained task when animals were tested in the undertrained context. This finding is similar to the classic Stroop asymmetry seen in human performance whereby dominant word reading interferes with colour naming for incongruent colour-word compounds. Further analysis also revealed some evidence for a reverse Stroop effect in which the undertrained stimulus element interfered with performance on the overtrained task.

Practice patterns in the management of chronic obstructive pulmonary disease in primary practice: the CAGE study.

BACKGROUND: The information on usual care for patients with chronic obstructive pulmonary disease (COPD) in primary care is limited in Canada. OBJECTIVE: To evaluate primary care practice in patients with COPD in Quebec and Ontario compared with recommended care. METHODS: The COPD Care Gap Evaluation (CAGE) was a prospective, cross-sectional study. Physicians' self-reported data of enrolled COPD patients were compared with the recommended care for the level of disease severity (using the Canadian Thoracic Society classification by symptoms) and stability, derived from Canadian Thoracic Society COPD guidelines. Pharmacological treatment, spirometric confirmation of diagnosis and nonpharmacological management, including smoking cessation counselling, influenza immunization and referral for pulmonary rehabilitation, were assessed. RESULTS: Participating physicians (n=161; 44 in Quebec, 117 in Ontario) recruited 1090 patients (320 in Quebec, 770 in Ontario). The mean (+/- SD) age of the patients was 69.9+/-10.4 years; 60% were male and 40% were currently smoking. Pharmacological treatment that matched guideline recommendations was identified in 34% of patients. Discrepancies between reported and recommended treatment stemmed from nonprescription of long-acting bronchodilators (LABDs) for patients with moderate (27%) and severe (21%) COPD, nonprescription of two long-acting beta agonists (a beta(2)-agonist and an anticholinergic) for patients with severe COPD (51%), and prescription of inhaled corticosteroids (63%) and LABDs (47%) for patients with mild COPD for which the treatment is not recommended. Spirometric confirmation of diagnosis, as recommended by the guidelines, was reported in 56% of patients. For nonpharmacological management, smoking cessation counselling (95%) and influenza immunization (80%) were near optimal. Referral for pulmonary rehabilitation (9%) was not common. Differences between provinces were seen mainly in the prescription of short-acting bronchodilators (89% in Quebec, 76% in Ontario) and LABDs (60% in Quebec, 80% in Ontario). CONCLUSIONS: Substantial gaps between recommended and current care exist in the management of COPD patients in primary care practice. Undertreatment of patients with severe COPD has potential clinical implications, including loss of autonomy and hospitalization.

The cost of moderate and severe COPD exacerbations to the Canadian healthcare system.

BACKGROUND: The cost of exacerbations in chronic obstructive pulmonary disease (COPD) has not been well studied. The aim of this study was to identify and quantify the (average) cost of moderate and severe exacerbations (ME and SE, respectively) from a Canadian perspective. METHODS: Resources used during ME and SE were identified in a year long prospective, observational study (Resource Utilization Study In COPD (RUSIC)). The units of analysis were ME and SE. Unit costs (2006$CAN), based on provincial, hospital and published sources, were applied to resources. The overall cost per ME and SE were calculated. The population burden of exacerbations was also calculated. RESULTS: Among study participants (N=609, aged 68.6+/-9.4 years, 58.3% male) there were 790 exacerbations: 639 (80.9%) MEs and 151 (19.1%) SEs. Of the 790 exacerbations, 618 (78.2%), 245 (31.0%) and 151 (19.1%) included a visit to an outpatient clinic, emergency department (ED) or hospital, respectively. For ME, 85.9% and 13.1% involved visits to GPs and respirologists, respectively. Pharmacologic treatment changes in the outpatient setting involved antibiotics (63.1%) and corticosteroids (34.7%). The overall mean costs for outpatient and ED services for MEs were $126 (N=574) and $515 (N=105), respectively. The average overall cost of a ME was $641. For SEs, the average hospital stay was 10.0 days. The overall mean costs of outpatient, ED and hospitalization services for SE were $114 (N=44), $774 (N=140) and $8669 (N=151), respectively. The average overall cost of a SE was $9557. CONCLUSION: The economic burden associated with MEs and especially SEs, in Canada, is considerable and likely has a substantial impact on healthcare costs. The overall burden of exacerbations has been estimated in the range of $646 million to $736 million per annum.

Medial prefrontal cortex lesions abolish contextual control of competing responses.

There is much debate as to the extent and nature of functional specialization within the different subregions of the prefrontal cortex. The current study was undertaken to investigate the effect of damage to medial prefrontal cortex subregions in the rat. Rats were trained on two biconditional discrimination tasks, one auditory and one visual, in two different contexts. At test, they received presentations of audiovisual compounds of these training stimuli in extinction. These compounds had dictated either the same (congruent trials) or different (incongruent trials) responses during training. In sham-operated controls, contextual cues came to control responding to conflicting information provided by incongruent stimulus compounds. Experiment 1 demonstrated that this contextual control of responding was not evident in individual rats with large amounts of damage that included the prelimbic and cingulate subregions of the prefrontal cortex. Experiment 2 further dissociated the result of Experiment 1, demonstrating that lesions specific to the anterior cingulate cortex were sufficient to produce a deficit early on during presentation of an incongruent stimulus compound but that performance was unimpaired as presentation progressed. This early deficit suggests a role for the anterior cingulate cortex in the detection of response conflict, and for the medial prefrontal cortex in the contextual control of competing responses, providing evidence for functional specialization within the rat prefrontal cortex.

Comparative efficacy of terbutaline sulphate delivered by Turbuhaler dry powder inhaler or pressurised metered dose inhaler with Nebuhaler spacer in children during an acute asthmatic episode.

AIMS: To compare the efficacy of terbutaline sulphate delivered via Turbuhaler with a pressurised metered dose inhaler (pMDI) connected to Nebuhaler spacer in a population of asthmatic children presenting to emergency departments because of an acute episode of asthma. METHODS: Randomised double blind, double dummy, parallel study of acute asthma in the emergency department. A total of 112 children (6-16 years), who had a diagnosis of asthma, a baseline FEV1 of 25-60% of predicted normal value (PNV), and the ability to perform spirometry were studied. Patients received two doses of 0.5 mg/10 kg (maximum 2.0 mg) of terbutaline sulphate at time 0 minutes and time 30 minutes. The two groups were also stratified into subgroups based on FEV1: 25-45% and 45.1-60% PNV. FEV1 before treatment and at two 15-minute intervals after each treatment was the main outcome measure. PIF, PEF, heart rate, SpO2, and tremor were also measured at these times. RESULTS: Both the Turbuhaler and pMDI+Nebuhaler groups showed significant increases from baseline to final value in their FEV1 results, 49% and 50% change from baseline to t = 60 min, respectively (p < 0.001) using last value carried forward. No significant difference was found between the two groups for these results. Subanalysis of the stratified groups revealed similar results. In addition, no significant difference was found in the group and subgroup comparisons for heart rate, SpO2, and tremor. CONCLUSION: Results show that Turbuhaler and pMDI+Nebuhaler are similar in terms of benefit and side effects in the treatment of acute moderate to severe asthma attacks in this study population.

A randomized, controlled trial of high dose, inhaled budesonide versus oral prednisone in patients discharged from the emergency department following an acute asthma exacerbation.

OBJECTIVE: Prednisone (PRED) is recommended at discharge to reduce the relapse rate following emergency treatment for an asthmatic attack. However, PRED has systemic side effects. Inhaled anti-inflammatory medications, such as budesonide (BUD), are well tolerated. This study was designed to compare the effectiveness of PRED and BUD on relapse rate. DESIGN: A prospective, randomized, double-blind, double dummy, parallel group design. SETTING: Tertiary referral emergency departments. POPULATION STUDIED: One hundred and eighty-five patients with acute asthma who received standard treatment with bronchodilators and systemic glucocorticosteroids in the emergency department, had a forced expiration volume in 1 s (FEV1) greater than 50% predicted and who were deemed well enough to be discharged from the emergency department. INTERVENTION: Patients were randomized to receive either BUD Turbuhaler 600 microg qid or PRED 40 mg in the morning for seven to 10 days. At discharge and final visit, symptoms, medication use, FEV1, peak expiratory flow (PEF) and quality of life (QoL) were assessed. Relapse rate to the emergency department during the follow-up was determined by a yes and/or no questionnaire. MAIN RESULTS: The PRED (n=85) and BUD (n=90) treatment groups were comparable at baseline (emergency department discharge) for age (mean +/- SD; 27.6+/-8.5 years and 29. 2+/-8.7 years) and prebronchodilator FEV1 (1.77+/-0.79 L and 1. 75+/-0.78 L), respectively. BUD was at least as effective as PRED in preventing a relapse to the hospital; relapse rate was 10 (11.8%) during PRED treatment and nine (10.0%) for BUD treatment (95% CI PRED-BUD, -7.5% to 11.0%). Improvements in FEV1, asthma symptoms, PEF and QoL were not significantly different between treatments. CONCLUSIONS: In patients whose acute asthma has been stabilized in the emergency department, high dose BUD may be an alternate to PRED as a follow-up treatment.

A cost-benefit analysis using a willingness-to-pay questionnaire of intranasal budesonide for seasonal allergic rhinitis. Rhinocort Study Group.

BACKGROUND: The cost-benefit of intranasal steroids for the treatment of seasonal allergic rhinitis is unknown. OBJECTIVE: To determine the cost-benefit of intranasal budesonide for seasonal allergic rhinitis. METHODS: Subjects who were symptomatic for a baseline period of 7 to 10 days were randomized to receive intranasal budesonide by Turbuhaler (400 microg) (n = 121) or aqueous spray (256 microg) (n = 121) once daily for 4 weeks. A willingness-to-pay questionnaire that measured benefits of treatment was administered before and at study completion. Costs were collected and compared with benefits. RESULTS: Subjects were willing to spend on average $15.89/wk (range $1 to $75) to alleviate the problems of seasonal ragweed rhinitis. Eighty percent of subjects felt that, with treatment, rhinitis had less of an impact on their lives, compared with previous years. The mean willingness-to-pay for the drug used during another ragweed season was $12.95/wk. This was 92% (95% CI, 85% to 100%) of the pre-treatment estimate. There was no relationship between an indirect assessment of income and willingness-to-pay estimates. The benefit was greater than the cost by a mean of $5.80/wk (95% CI, $3.52 to 8.08), P < .0001. There was no difference in costs, willingness-to-pay, or cost-benefit comparing delivery modes. A sensitivity analysis revealed the conclusions were robust. CONCLUSIONS: Intranasal budesonide is cost-beneficial in the treatment of seasonal allergic rhinitis and a willingness-to-pay questionnaire may provide a useful method to assess a therapy's benefit.

Comparison of budesonide Turbuhaler with budesonide aqua in the treatment of seasonal allergic rhinitis. Rhinocort Study Group.

OBJECTIVE: To compare the effect of budesonide Turbuhaler 400 microg/day with budesonide aqua 256 microg/day in the treatment of seasonal allergic rhinitis (SAR). Secondarily to ascertain patients' preferences for the two nasal devices and to assess quality of life. DESIGN: Randomized, multicentre, double-blind, double- dummy, parallel groups study. SETTING: Private practices and hospital clinics in Ontario, Quebec and Manitoba. POPULATION: Two hundred and eighty-four out-patients with SAR, who were symptomatic during the ragweed season, volunteered for enrolment (243 randomized). RESULTS: Mean daily nasal symptom scores were significantly reduced with treatment. There were no statistically significant changes from baseline for eye symptoms. Most patients (more than 80%) achieved substantial control of their symptoms with budesonide. The most common nasal and non-nasal adverse events for both groups were epistaxis and headache. Turbuhaler was easier to use and more convenient to carry, had less of an unpleasant taste, and caused less nasal irritation than the aqua spray. More than twice as many patients preferred Turbuhaler to the aqua spray (69% versus 31%). Improvement in quality of life from baseline to clinic visits was statistically significant in both groups. CONCLUSION: Once daily use of 256 mg of budesonide aqua and 400 mg of budesonide Turbuhaler are equally safe and efficacious in the treatment of SAR. Patients preferred the budesonide powder formulation delivered via Turbuhaler two to one over the aqua formulation.