Endocarditis.

Infectious endocarditis (IE) is a universally fatal condition if left unmanaged, requiring urgent evaluation and treatment. Fever, new heart murmur, vegetations found by echocardiogram, and bacteremia are the most common symptoms and findings. Blood cultures and echocardiography are obligatory diagnostic modalities and should be used with the modified Duke criteria, the accepted diagnostic aid, when establishing a diagnosis of IE. When IE is suspected, consultations with cardiology, infectious disease, and cardiothoracic surgery teams should be made early. Staphylococci, Streptococci, and Enterococci are common pathogens, necessitating bactericidal antimicrobial therapy. Importantly, up to 50% of patients with IE will require cardiothoracic surgical intervention.

An evaluation of naloxone transit for opioid overdose using drones: A case study using real-world coroner data.

BACKGROUND AND AIMS: Opioids are now the most cited class in fatal overdoses. However, the antidote for opioid overdose-naloxone-is not always readily available. Our aim was to evaluate the feasibility of naloxone transit via drone to provide rapid access at the point of care. METHODS AND FINDINGS: Real-world data pertaining to opioid overdoses, which occurred in the Teesside area of the UK 2015-2019, were extracted from the National Programme on Substance Abuse Deaths (NPSAD). The original locations of these opioid overdoses were used to compare the projected response times of ambulances with that of drones when considering the impacts of actual traffic and weather conditions, respectively; 58 cases were identified where a bystander-who could have called for and administered emergency naloxone-was likely present. RESULTS: In 78% of cases (n = 45/58) a class C1 commercial-off-the-shelf drone carrying naloxone could have reached the overdose location in 7 min-the benchmark time for the arrival of emergency services for Category 1 calls in England. With the implementation of recent advances in drone engineering, such as increased speeds and temperature-controlled cargo cradles, it is estimated that 98% of overdoses could have been reached in this timeframe (n = 57/58). Ambulances were able to reach a significantly lower number of cases in 7 min, even when considering best-case scenario traffic conditions (14%, n = 8/58, χ2 P < 0.001). CONCLUSIONS: This study provides proof-of-concept that, in the Teesside area of the UK, drones are more likely than ambulance to get naloxone to the site of an opioid overdose in 7 min.

Outcomes for Muscle-invasive Bladder Cancer with Radical Cystectomy or Trimodal Therapy in US Veterans.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) remains undertreated despite multiple potentially curative options. Both radical cystectomy (RC) with or without neoadjuvant chemotherapy and trimodal therapy (TMT), including transurethral resection of bladder tumor followed by chemoradiotherapy, are standard treatments. OBJECTIVE: To evaluate real-world clinical outcomes of RC with neoadjuvant chemotherapy (RC-NAC), RC without NAC, TMT with National Comprehensive Cancer Network guideline-preferred radiosensitizing chemotherapy including cisplatin or mitomycin-C and 5-fluorouracil (pTMT), and TMT with nonpreferred chemotherapy (npTMT). DESIGN SETTING AND PARTICIPANTS: US veterans with nonmetastatic MIBC (T2-4aN0-3M0) were studied. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall mortality (OM) was evaluated with multivariable Cox proportional hazard model. Bladder cancer-specific mortality (BCSM) was evaluated with multivariable Fine-Gray regression. Salvage cystectomy rates were obtained by chart review. RESULTS AND LIMITATIONS: Overall 2306 patients were included: 1472 (64%) with RC without NAC, 506 (22%) with RC-NAC, 163 (7%) with pTMT, and 165 (7%) with npTMT. On multivariable analysis, pTMT was associated with similar OM (hazard ratio [HR] 1.19; 95% confidence interval [CI] 0.94-1.50; p = 0.15) and BCSM (HR 1.34; 95% CI 0.99-1.83; p = 0.06) to RC-NAC; npTMT was associated with worse OM (HR 1.30; 95% CI 1.04-1.61; p = 0.02) and BCSM (HR 1.45; 95% CI 1.09-1.94; p = 0.01). RC without NAC was associated with similar OM (HR 1.08; 95% CI 0.95-1.24; p = 0.24) and BCSM (HR 1.02; 95% CI 0.86-1.21; p = 0.79). When stratified by age, among patients ≥65 yr of age, treatment with pTMT was associated with similar OM (HR 1.14; 95% CI 0.87-1.50; p = 0.35) and BCSM (HR 1.11; 95% CI 0.76-1.62; p = 0.60). Among patients <65 yr of age, pTMT was associated with worse OM (HR 1.82; 95% CI 1.14-2.91; p = 0.01) and BCSM (HR 2.51; 95% CI 1.52-4.13; p < 0.01). The 5-yr cumulative incidence of salvage cystectomy in the TMT group was 3.6%. CONCLUSIONS: In MIBC, patients receiving pTMT have comparable survival in RC-NAC patients ≥65 yr and inferior survival in RC-NAC patients <65 yr. Salvage cystectomy rates were low. PATIENT SUMMARY: Management of muscle-invasive bladder cancer is a multidisciplinary effort requiring thoughtful discussions with patients about treatment options, including trimodal therapy, which is an effective treatment option.

Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.

BACKGROUND: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high-dose interferon (HDI) in patients with resected, high-risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost-effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. METHODS: We designed a Markov model simulating resected, high-risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost-effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality-adjusted life-years (QALYs), assessed cost-effectiveness. ICERs <$100,000/QALY were deemed cost-effective. We measured model uncertainty with one-way and probabilistic sensitivity analyses. RESULTS: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost-effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost-effective treatment option 96.2% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high-risk melanoma patients, though this would not be considered cost-effective due to the high price of ipilimumab.

Cost-Effectiveness Analysis of Stereotactic Ablative Radiation Therapy in Patients With Oligometastatic Cancer.

PURPOSE: The Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors phase 2 randomized clinical trial found that stereotactic ablative radiation therapy (SABR) improved outcomes among cancer patients with oligometastatic disease. Yet, the cost of SABR along with the large number of patients with oligometastatic disease raises the important question of value. This study sought to evaluate the cost-effectiveness of the addition of SABR compared with standard therapy alone among cancer patients with oligometastatic disease. METHODS AND MATERIALS: We constructed a Markov model to simulate treatment with stereotactic ablative radiation therapy or standard therapy among patients with oligometastatic cancers. The model derived transition probabilities from Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors clinical trial data to estimate risks of toxicity, disease progression and survival. Health care costs and health utilities were estimated from the literature. Probabilistic and one-way sensitivity analyses evaluate model uncertainty. Cost-effectiveness was estimated from both the health care sector and societal perspectives with an incremental cost-effectiveness ratio (ICER) defined as dollars per quality-adjusted life year (QALY). An ICER less than $100,000/QALY was considered cost-effective. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. RESULTS: The addition of SABR increased total costs by $54,260 (health care sector perspective) or $72,799 (societal perspective) and improved effectiveness by 1.88 QALYs compared with standard therapy, leading to an ICER of $28,906/QALY (health care sector perspective) or $38,783/QALY (societal perspective). The model was modestly sensitive to assumptions about tumor progression, although the model was not sensitive to assumptions about survival or cost of treatment. Probabilistic sensitivity analyses demonstrated that SABR was the cost-effective treatment option 99.8% (health care sector perspective) or 98.7% (societal perspective) of the time. CONCLUSIONS: The addition of SABR increased costs and improved quality adjusted survival, overall leading to a cost-effective treatment strategy for patients with oligometastatic cancer.

Evaluation of the Use of Cancer Registry Data for Comparative Effectiveness Research.

Importance: Researchers often analyze cancer registry data to assess for differences in survival among cancer treatments. However, the retrospective, nonrandomized design of these analyses raises questions about study validity. Objective: To examine the extent to which comparative effectiveness analyses using observational cancer registry data produce results concordant with those of randomized clinical trials. Design, Setting, and Participants: In this comparative effectiveness study, a total of 141 randomized clinical trials referenced in the National Comprehensive Cancer Network Clinical Practice Guidelines for 8 common solid tumor types were identified. Data on participants within the National Cancer Database (NCDB) diagnosed between 2004 and 2014, matching the eligibility criteria of the randomized clinical trial, were obtained. The present study was conducted from August 1, 2017, to September 10, 2019. The trials included 85 118 patients, and the corresponding NCDB analyses included 1 344 536 patients. Three Cox proportional hazards regression models were used to determine hazard ratios (HRs) for overall survival, including univariable, multivariable, and propensity score-adjusted models. Multivariable and propensity score analyses controlled for potential confounders, including demographic, comorbidity, clinical, treatment, and tumor-related variables. Main Outcomes and Measures: The main outcome was concordance between the results of randomized clinical trials and observational cancer registry data. Hazard ratios with an NCDB analysis were considered concordant if the NDCB HR fell within the 95% CI of the randomized clinical trial HR. An NCDB analysis was considered concordant if both the NCDB and clinical trial P values for survival were nonsignificant (P ≥ .05) or if they were both significant (P < .05) with survival favoring the same treatment arm in the NCDB and in the randomized clinical trial. Results: Analyses using the NCDB-produced HRs for survival were concordant with those of 141 randomized clinical trials in 79 univariable analyses (56%), 98 multivariable analyses (70%), and 90 propensity score models (64%). The NCDB analyses produced P values concordant with randomized clinical trials in 58 univariable analyses (41%), 65 multivariable analyses (46%), and 63 propensity score models (45%). No clinical trial characteristics were associated with concordance between NCDB analyses and randomized clinical trials, including disease site, type of clinical intervention, or severity of cancer. Conclusions and Relevance: The findings of this study suggest that comparative effectiveness research using cancer registry data often produces survival outcomes discordant with those of randomized clinical trial data. These findings may help provide context for clinicians and policy makers interpreting observational comparative effectiveness research in oncology.

Analysis of the dynamic Bacillus subtilis Ser/Thr/Tyr phosphoproteome implicated in a wide variety of cellular processes.

The physiological role of proteins phosphorylated on serine/threonine/tyrosine (Ser/Thr/Tyr) residues or the identity of the corresponding kinases and phosphatases is generally poorly understood in bacteria. As a first step in analysing the importance of such phosphorylation, we sought to establish the nature of the Ser/Thr/Tyr phosphoproteome in Bacillus subtilis, using in vivo labelling with [(32)P]-orthophosphate, one-unit pH 2-DE, combined with MS. Highly reproducible 2-D profiles of phosphoproteins were obtained with early stationary-phase cells. The 2-D profiles contained at least 80 clearly labelled spots in the pH range 4-7. Forty-six spots were analysed by MS (confirmed in most cases by LC-MS/MS), identifying a total of 29 different proteins, with 19 identified for the first time as bacterial phosphoproteins. These phosphoproteins are implicated in a wide variety of cellular processes, including carbon and energy metabolism, transport, stress and development. Significant changes to the profiles were obtained as a result of cold, heat or osmotic shock, demonstrating that, in stationary-phase cells, the phosphoproteome is dynamic. An initial comparative study indicated that at least 25 [(32)P]-labelled spots were also stained by Pro-Q Diamond, with apparently six additional phosphoproteins uniquely detected by Pro-Q.

Performance validation of an improved Xenon-arc lamp-based CCD camera system for multispectral imaging in proteomics.

Advances in gel-based nonradioactive protein expression and PTM detection using fluorophores has served as the impetus for developing analytical instrumentation with improved imaging capabilities. We describe a CCD camera-based imaging instrument, equipped with both a high-pressure Xenon arc lamp and a UV transilluminator, which provides broad-band wavelength coverage (380-700 nm and UV). With six-position filter wheels, both excitation and emission wavelengths may be selected, providing optimal measurement and quantitation of virtually any dye and allowing excellent spectral resolution among different fluorophores. While spatial resolution of conventional fixed CCD camera imaging systems is typically inferior to laser scanners, this problem is circumvented with the new instrument by mechanically scanning the CCD camera over the sample and collecting multiple images that are subsequently automatically reconstructed into a complete high-resolution image. By acquiring images in succession, as many as four different fluorophores may be evaluated from a gel. The imaging platform is suitable for analysis of the wide range of dyes and tags commonly encountered in proteomics investigations. The instrument is unique in its capabilities of scanning large areas at high resolution and providing accurate selectable illumination over the UV/visible spectral range, thus maximizing the efficiency of dye multiplexing protocols.

Dispensing error rate in a highly automated mail-service pharmacy practice.

STUDY OBJECTIVE: To measure the rate of dispensing errors and to identify the types and sources of dispensing errors in a highly automated mail-service pharmacy practice. DESIGN: Descriptive analysis of a random sample of completed prescriptions. SETTING: A high-volume mail-service pharmacy practice comprising a network of prescription processing and dispensing pharmacies in the United States. MEASUREMENTS AND MAIN RESULTS: During September and October 2003, new and refill prescriptions were retrieved before shipping and evaluated for dispensing accuracy. Container contents were compared against the container label, and the label record was compared against the original prescription order. The overall dispensing error rate was 0.075% (16 dispensing errors among 21,252 prescriptions, 95% confidence interval 0.043-0.122). Fourteen errors involved incomplete or incorrect directions on the final label. All dispensing errors were associated with the initial stages of prescription processing (including order entry); no errors were associated with the mechanical stages of product dispensing. CONCLUSION: A highly automated mail-service pharmacy can achieve a dispensing error rate of less than 1 error/1000 prescriptions, which is substantially lower than the rates reported for retail pharmacies. A high degree of automation in the mechanical aspects of dispensing appears to be a key factor in achieving this high dispensing accuracy.

Supervised Learning Extensions to the CLAM Network.

The contextual layered associative memory (CLAM) has been developed as a self-generating structure which implements a probabilistic encoding scheme. The training algorithms are geared towards the unsupervised generation of a layerable associative mapping ([Thacker and Mayhew, 1989]). We show here that the resulting structure will support layers which can be trained to produce outputs that approximate conditional probabilities of classification. Unsupervised and supervised learning algorithms operate independently permitting the unsupervised representational layer to be developed before supervision is available. The system thus supports learning which is inherently more flexible than conventional node labelling schemes. Copyright 1997 Elsevier Science Ltd. All Rights Reserved.